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Published: Tuesday, 2/12/2002

Working on a cure: With progress comes problems

BY JENNI LAIDMAN
BLADE SCIENCE WRITER

(Last year, five women with recurring cancer allowed Blade science writer Jenni Laidman and photographer Jetta Fraser to follow them through an experimental drug trial at the Medical College of Ohio. This is the third of a five-part series about that trial -- called "Working on a cure: Cancer on trial". It begins a yearlong examination of cancer by The Blade. )

They watch as her face flushes pink, then red, then redder. The skin under her nails purples.

Nurses run. Pat forces down her panic and tries to breathe deeply. She wheezes.

There's a strange pressure in her head.

“Oh, my head is blowing up,'' she says. It feels like a balloon, filling with air. The pressure moves to her chest. It burns. Is it the drug? The sensation moves into her kidneys.

Nurses unhook the intravenous line dripping into her arm.

Pat's relief is quick.

A moment later, it's as though it never happened. Pat's breathing is normal. The nausea is gone.

Thus begins the third week of an experimental cancer treatment for Pat Krzeminski, Cissi Jackson, and Mary Griffith. They are three of a dozen patients who will try a new antibody called H11 before 2001 ends. The trial began in December, 2000, at the Medical College of Ohio. Until this second week of March, it was trouble free.

That easy era slams to an end with Pat's allergic reaction.

Pat's problem compounds uncertainty stemming from a U.S. Food and Drug Administration decision four days earlier. The FDA closed the drug trial to new patients. The agency is looking at deaths that occurred in animal studies of H11.

Pat's reaction does not appear linked to blood coagulation troubles discovered in mice. But later that same day, the blood test results of a new patient hint at something far more dire than Pat's problem.

Usha Mohan serves tea at her Ottawa Hills home. Although her first 20 doses of H11 seemed to help, a new ovarian tumor grew while she completed her second round of treatment. Usha Mohan serves tea at her Ottawa Hills home. Although her first 20 doses of H11 seemed to help, a new ovarian tumor grew while she completed her second round of treatment.
FRASER / BLADE Enlarge

Pat Krzeminki's H11 reaction is called Red Man Syndrome. The Petersburg, Mich., woman experienced it once before, six years ago, during her first chemotherapy for ovarian cancer.

It's easily prevented. Pat's drip is slowed. Now, instead of receiving H11 over the course of an hour, the drip takes two hours.

Pat, 49, treats the frightening allergic response as though it makes her special.

“I knew if something went wrong, it would go wrong for me.”

The real mystery is, when did things really start going wrong for Pat Krzeminski? It might have been 20 years ago, when life revolved around infant daughters she could swoop to either hip.

Maybe it was a few years later. No one can roll the tape backward to the moment when the first tiny change began on Pat's long road to ovarian cancer.

But hidden somewhere in an egg-shaped organ that itself keeps a horde of nascent eggs in cozy waiting, an error arose, an error as simplXe as a misplaced X.

It's a tiny misprint. A typo.

But for Pat, the typo has life-threatening consequences.

Mary and Don Griffith listen intently as nurse Cindy Peters talks about Mary's participation in this experimental drug trial. Mary and Don Griffith listen intently as nurse Cindy Peters talks about Mary's participation in this experimental drug trial.
FRASER / BLADE Enlarge

At first occurrence, an error that can lead to cancer is innocent. More than innocent, it's harmless.

Swaddled within a tidy package of DNA, sequestered inside the protected nucleus of each cell, lies Pat's family heritage: 23 pairs of chromosomes carrying the genes from mother and father. Stretched straight, the DNA in a single cell would extend 6 feet. But as chromosomes, it is twisted and coiled onto protein spools, and neatly packed away.

Pat, who celebrates a good day by energetic house cleaning, would appreciate this dedication to order on the part of her cells.

Little harm can come to the genes in their tightly coiled state. The risk comes in division, as a cell prepares to multiply. Before that split, the cell fattens and grows. Inside the plumped cell, chromosomes unravel.

Once unraveled, the DNA splits in half like a nanoscopic zipper. Each zipper tooth - there are some three billion per side - is one of four chemicals called nucleotides. On the unzipped DNA, these four chemicals - cytosine, guanine, adenine, and thymine - become a template for the construction of new DNA.

At every guanine, a cytosine is required. At every adenine, a thymine aligns - and vice versa. Six billion times in every dividing cell, the right chemical is required.

Consider it 6 billion opportunities for error in one cell division.

The one-in-a-million mistake

It turns out, mistakes are inevitable.

Most times, they're harmless. Only 1.5 percent of our DNA contains genes - less than an inch of the 6 feet of DNA in a cell nucleus. The remainder of the DNA seems to code for nothing. A typo there has no impact.

Should a misprint strike that smidgen of DNA containing genes, harm may not follow.

Genes have excellent editors. The editors check the nucleotides, righting any wrongs. If errors prove too numerous, the editors are ruthless. The cell commits suicide rather than pass on genetic mistakes.

Thus, new cells are usually born perfect.

But editors can err. One time in one million cell divisions, a mistake mars a gene. Unfortunately, these odds are not quite as good as they sound. We make 100 billion new cells each day in our small intestine - and an equivalent number of new red blood cells daily. That means there are 100,000 errors a day in intestinal lining cells alone.

Still, genetic mistakes do not guarantee cancer. Genes provide the recipes for proteins, and proteins do all the work in the cell. When the damaged gene makes a damaged protein, sometimes the result is a flawed but workable protein. No harm done.

Other times, the mistake is too critical. The gene makes a protein that is so faulty, the whole cell dies, and the error is never repeated. Or maybe the snafu hits a gene that can't cause cancer.

Then there are those other times.

Certain mutations in certain genes are trouble. A slip in a gene that tells cells to keep duplicating- a proto-oncogene - can be a critical first step toward cancer.

The infusion center at the Medical College of Ohio is noisier than usual with the H11 research subjects on hand. Pat and Ed Krzeminski, left, chat with Mary and Don Griffith. Mary and Pat both receive the experimental antibody. The infusion center at the Medical College of Ohio is noisier than usual with the H11 research subjects on hand. Pat and Ed Krzeminski, left, chat with Mary and Don Griffith. Mary and Pat both receive the experimental antibody.
FRASER / BLADE Enlarge

Such a hiccup still isn't cancer. Any of us may have a few cells with genes of this sort stuck on. The body is full of checks and balances, and it happens that proto-oncogenes are held in check by a group of genes called tumor suppressors. These demand a halt to errant multiplication. A stuck growth gene can be harmless unless a few more critical mistakes come along.

It takes more than one mistake to make a disaster.

Strange blood test

By midweek after Pat Krzeminski's Red Man attack, disaster seems to be in the making for another H11 patient. Patricia Williams' blood tests grow daily stranger. Her blood won't coagulate - the very thing that killed mice in toxicity testing, the very reason the FDA closed further access to this trial.

She joined the trial a week after Pat Krzeminski. From the day Patricia Williams started H11, she captures the other patients' sympathy. Cissi Jackson is no longer the sickest among them. Patricia Williams is in heart-breaking shape.

She sleeps most days, only occasionally waking to talk to the other H11 patients.

Her voice is soft, almost sweet. It doesn't hint at the constant pain.

It's impossible to tell what she was like before she got sick, so much does disease dominate. It hurts to breathe. Her liver is cancer filled, and the pressure of her diaphragm is hard to bear.

She has had colon cancer for only a year. It had already spread when doctors discovered it. Chemotherapy helped for a little while. But her cancer rapidly evolved beyond control.

Now this clotting problem. It is frightening.

On Monday, Patricia's blood tests are odd, but not alarming. Just to be safe, her blood clotting is now tested daily, instead of on Monday and Friday. Each morning she waits for the lab's OK before she can begin the H11 treatment.

But each day, the lab results grow a little worse. The site of her port, which nurses use to inject drugs, oozes, suggesting her blood's growing inability to clot.

This is more drama than Patricia Williams needs.

She only reluctantly agreed to try this experimental therapy in the first place. Chemo was such hell. She feared the antibody treatment would be more of the same. Without chemo, she felt pretty good. She worries she'll lose even this small hold on her well being.

“I don't know. Everybody tells me `You have nothing to lose.' I was feeling real good. I thought a lot: Is this going to make me feel bad? It took me awhile to decide. ... I didn't want to take the drug and go downhill.

“They think it's nothing to lose, but to me, it's a great loss not to be able to do what I've always done.''

Instead of spending her morning in the barn with her beloved horses, she rides 90 minute from Hillsdale County to MCO. Often, her uncle drives her. Her husband and son also take turns. And now her blood tests look bad. The other patients worry about her.

It's easier than worrying about themselves.

The worst patients

No one thinks of this week's problems as good news, but the fact remains, the reactions of Pat Krzeminski and Patricia Williams are important to researchers - more important than whether anyone is getting better.

“I'm not going to be disappointed if I don't see tumor shrinkage,'' says Paul Purcheson, the drug-maker's vice president of clinical and regulatory affairs until August.

Eight rodent studies all demonstrate H11's anti-cancer powers. The drug reduces metastases, increases survival, reduces tumor size, or slows tumor growth. The company is spending a fortune trying to bring it to market.

So, why does Dr. Purcheson sound pessimistic?

Blame it on the antibody patients themselves.

“These patients, by nature - the way drugs are developed when they first get into humans - you usually end up recruiting patients who are really far gone. It's the worst possible patient to choose to look for a benefit of a new drug. But that's sort of the name of the game,'' Dr. Purcheson says.

When a drug company moves into the stage of research where its goal is to prove its product cures disease - Phase II and Phase III trials - then these most needy patients so crucial to Phase I toxicity trials, aren't much help.

Their severe illness means it's unlikely they'll be able to prove that the new drug is capable of a cure. Patients this sick are generally excluded from the trials where improvement is sought.

Recovery at this stage of disease is the exception - never the rule.

'I think it's so amazing ...'

“Tell her! Tell her!” Pat Krzeminski urges Cissi Jackson when a visitor joins them in MCO's infusion center.

Pat and Cissi hardly think of themselves as the worst possible patients described by Dr. Purcheson. Cissi, in fact, is convinced she's being cured. With everything going wrong this week, people are starting to believe that Cissi may have something going right.

“I have these tumors on my back,'' Cissi says. “My masseuse says they're softening. And I've gained a pound and a half.'' Cissi gets massages at the Victory Center on Reynolds Road, a resource center for cancer patients.

“I think it's so amazing, so fantastic, to be involved in this. This drug will not kill any of your good cells. I feel great, except for the steroids. They make you spacey. I don't like that.''

Even coughing cheers her up.

“I'm so excited about that. I couldn't do that before. I never had phlegm,'' she says.

Softening tumors sound like a good sign.

But Cissi looks bad. Her face is swelling, and the skin at her shirt collar is red and angry. Her port - the catheter implanted in her chest for intravenous drug delivery - is infected. She's on steroids to control inflammation.

Still, in Cissi's ever-optimistic assessment, the infection is a good sign, even though it makes her uncomfortable. She attributes the port infection to the work of the antibodies dripping into her system daily. It proves they are on the job.

That's not so, says her oncologist, Dr. Iman Mohamed. But that's what Cissi believes.

Not a single disease

Cissi has breast cancer. Patricia Williams has colon cancer. Pat Krzeminski, Mary Griffith, and Usha Mohan - all H11 patients - have ovarian cancer.

Each disease is distinct. Oncologists don't treat colon cancer with breast cancer drugs. The drugs that quickly control ovarian cancer in one patient, fail to make a mark in the next.

“Cancer is not a single disease,'' says Stephen Gruber, director of the Cancer Genetics Clinic at the University of Michigan. It is hundreds of diseases.

The burgeoning field of cancer genetics, which is revealing the individual traits of each disease, makes that clearer daily.

But cancer follows general rules. There is enough similarity that other researchers say their view of genetics leads to the opposite conclusion.

“I think it's a single illness,'' says Max Wicha, director of the UM Comprehensive Cancer Center. “If you asked us 20 years ago, when I first got into this business, what is cancer, at that time, to me it seemed much more daunting because the thought was that cancer was not a disease, but it was 100 different diseases, and every kind of cancer was different. How were we ever possibly going to understand what caused cancer, let alone treat it?”

Now, those variations also reveal the similarities between cancers, he says

“So I view cancer, really, as a single disease you can get through many different ways.''

Despite the debate, both statements are true at some level. Although Pat Krzeminski and Mary Griffith both have Stage 3 ovarian cancer - cancer spread locally but not metastasized - their treatment, health, and disease severity is different.

“I listen to Mary, and it doesn't even sound like we have the same disease,'' says Pat.

But all cancers still have a lot in common. For a start, cancers require dividing cells if they're going to occur at all. As a result, the most common cancers are in cells that divide most frequently, says Mel Greaves, a researcher at the Institute of Cancer Research in London.

Cells at risk

Every three days or so, the cells that line the gut are replaced. Colo-rectal cancer is the third-most commonly diagnosed form of cancer. This is what Patricia Williams has.

When a young woman enters her child-bearing years, the cells lining milk ducts multiply each month and die off if pregnancy does not occur. Breast cancer is the No. 1 cancer in women. This is Cissi Jackson's disease.

Prostate cells that secrete seminal fluid for sperm transport are regularly replaced. Prostate is the No. 1 cancer in men.

The No. 2 cancer in both men and women, lung cancer, occurs in the lining of our airways. These cells, exposed to the soup of toxins we breathe or smoke, are regularly replaced for our own good.

Although adults like Cissi Jackson will see their primary cancer migrate to bone, adults rarely have primary bone cancer. This is a disease of young people, those still growing bone.

Before a tissue is vulnerable to cancer, it must regularly produce new cells. Errors rarely creep into mature cells just doing their assigned jobs.

Second, a cell's vulnerability increases with its contact with toxic elements. Lungs bathed in cigarette smoke develop cancer at a higher frequency than lungs not so marinated.

Mouth and throat cancers thrive most often in a saut of smoke and alcohol. Alcohol kills the lining cells, forcing new growth, and smoke bathes the cell nursery with mutation-causing chemicals.

Over and over, the cells are assaulted, and, in some people, the genes are damaged and then damaged again, until enough mutations accumulate to give rise to cancer. Estimates are it may take four mutations or more before a cell becomes cancerous. About 1-in-4 of us will lose that mutation lottery and develop cancer.

Internal bleeding

It's Friday, March 16. Patricia Williams is in serious trouble. While Pat Krzeminski sits beside her, H11 flowing into her arm, Patricia is barred from drug and could be heading for the hospital.

Her blood tests are worse then ever. Her blood's ability to clot is so poor, she's at risk of internal bleeding.

This makes no sense.

When rodents bled to death in animal H11 studies, the bleeding was due to the body's overreaction to excessive clotting. But Patricia never had increased clotting, only decreased coagulation.

Nurses keep asking: “Are you sure you're not taking any drugs?”

They are hoping to find some reason for the clotting problem.

But Patricia tells them she takes a multivitamin. That's all she can recall.

Her husband remembers.

She's on Coumadin. It's a blood thinner. H11 is not the cause of her erratic blood tests.

When they take her off Coumadin her blood coagulation returns to normal, she tells Pat Krzeminski.

One disaster averted.

It's Tuesday, March 20. Mary Griffith sits down for her first dose of H11 in her final week of treatment. She and her husband Don were on vacation Monday.

The drug flows down from the IV bag, and in an instant Mary's throat tightens.

She looks down at her hands. They're red. She's hot and then clammy. Now she's choking. This has happened to her before, during chemo. They told her then this was a life-threatening drug response.

“I need some help over here,'' she says.

Pat Krzeminski and the others are already shouting for nurses. Patricia Williams watches as even Mary's eyeballs turn scarlet. Mary pants, taking air in quick gulps.

In an instant, nurses are at hand with syringes of Benadryl and Solu-Medrol. Someone pulls the IV. Another nurse puts an oxygen mask over Mary's face.

In 10 minutes, the symptoms of Red Man Syndrome vanish. But Mary is terrified. Could she ever trust H11 antibodies again?

She doesn't have to decide. She's out of the trial.

Her strong reaction, which required medication to control, is an automatic trial stopper for her.

In the days following, she'll return to her gynecological oncologist. In a week, she'll be back on chemotherapy.

She is the first patient unable to complete the trial, the only one to be removed because of an adverse drug reaction.

The drug company may be getting the results it needs. Only the patients aren't.

Tomorrow: Cissi Jackson shocks her doctors.



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