Working on a Cure

The Blade


Cancer on Trial,

Day 1 of 5

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.

Pat Krzeminski marches into her doctor’s office at the Medical College of Ohio. Secretaries and nurses eddy around her, snickering as they get a good look at the back of her head.

She summons her physician. Pat’s hair is punk short. Her eyes are wide, with carefully arched eyebrows, and dark liner. Dr. James Fanning, angular, bearded, and just a little confused by the unexpected visit, answers the call.

“I did something, and you need to know what I did,” Pat tells him. Then she pivots.

He looks blankly at the baby-bird fuzz covering the back of her head. He strains to figure out the pattern carved there. Glee, then embarrassment, move across his face. Carved into the quarter-inch of hair that covers her scalp are the words: “No. 1 Dr.Fanning.”

Dr. Fanning is Pat’s gynecological oncologist. That tuft of fuzz is all the hair she sprouted since finishing her seventh round of chemotherapy for ovarian cancer about two months earlier.

This is triumph.  She manages to both flatter the man she considers her lifesaver, and embarrass him. She doesn’t notice that her tribute obviously moves him as well. This is almost as good as when she cajoled nurses into pasting University of Michigan stickers to her bottom. Dr. Fanning, a Notre Dame fan, had to peel off the rival’s logo before he could begin surgery to remove Pat’s recurring cancer.

All in all, this is a good day. Next month she won’t have time for this, she tells anyone who will listen. She’s going to be too busy.

“There’s no such thing as a five-minute trip anywhere with Pat,” said her husband Ed, who works in machine repair at the GM Powertrain plant in Toledo.  “Pat talks to everybody.”

Making her way amid patients waiting to receive chemotherapy one morning, Pat stops to chat with an acquaintance.

“Don’t worry,” she tells this newly diagnosed cancer patient with a wink, “’cause I’m working on a cure.”

The monster

In an MCO laboratory just across the road from Dr. Fanning’s office, a scientist takes a small plastic container from a temperature-controlled cabinet. Within, tiny motes of light flicker in amber liquid. They look as harmless as fireflies, as lovely as teardrops. They are neither. These are monsters. This is cancer:  Single cells, suspended in nutrients, grown by researchers scrutinizing cancer’s ways. These nurtured and coddled cells may one day win Pat Krzeminski and others another chance.

This work at MCO is part of what many believe to be the dawn of a new age of cancer treatment.Almost every week, a laboratory somewhere announces a discovery, tantalizing cancer patients with visions of a cure always just out of reach. Mysteries of cancer’s growth fall open to expanding genetic technologies. Cancer may still be a monster, but it’s one whose lair is nearly surrounded.

“It’s a very exciting time, very promising,” says Dr. James Willey, who studies lung cancer at MCO.

Such optimism is common in the research community. Cancer has few secrets any longer. Yet, Pat Krzeminski, a Petersburg, Mich., mother of two, knows more about cancer than  scientists can possibly guess.The experts can surely tell her things she’s never dreamed: How her cells go wrong. How their repair machinery fails. How even death is denied nature’s mutants. But it’s the difference between reading a biography and sleeping with its subject.

Pat, 49, is cancer’s intimate.

Despite her bubbling joie de vivre, for six years Pat’s been cancer’s companion, her body the unwilling battleground for the survival-of-the-fittest duels between mutant and more mutated. It is February, 2001. For the eighth time since she turned 44, nurses prepare Pat for a new treatment. In the last six years, she’s received literally hundreds of shots, drips, infusions, and needle pokes for blood draws. Still, she flinches and yelps as the needle goes in. It’s the first blood draw of this newest assault on cancer.

By the end of 2001, 12 people, including Pat, agree to be human guinea pigs for an experimental cancer therapy at MCO. All have recurring, persistent cancer. The trial protocol demands all participants have an anticipated lifespan of at least three months.

The patients sign on to a drug trial that promises nothing. Doctors can’t say the new drug – an antibody called H11 – will do any good. Nor are they trying to find that out. They can’t even promise H11 is safe. That’s what they’re hoping to learn. But the patients don’t worry about those details. Like Pat, each is working on a cure.

The worthwhile gamble

Cissi Jackson is an expert seamstress. She’s also ethereal and dreamy. She meditates daily, and sometimes, she says, she’s certain angels join her at her sewing table. The 61-year-old breast cancer patient barely acknowledges her collapsing health. Nor does she devote any thought to the safety tests performed on the clear liquid running into her body. Mice were in the trial that time. A scrawny 103 pounds, she may be the sickest person in the room.

Usha Mohan doesn’t look sick at all. Dr. Fanning says she’s “tough as nails.” She’s a quick study who likes to tell people that she diagnosed her ovarian cancer before physicians confirmed her supposition. The 55-year-old doesn’t mind she’s being used to find a safe drug dose. She’d gladly take more.

Mary Griffith, 69, says she doesn’t want her grandchildren to think of her as a sickly old lady. She needn’t worry. With her optimism, quick step, and engaged interest in the people around her, she seems younger than her age, and healthier than her diagnosis. Despite her nearly six years of ovarian cancer, “I don’t think I’ve been dealt a bad hand,” she says. Even though the research goal is not to find a cure, she still thinks the trial is a worthwhile gamble.

Each of the patients made this personal bet, notwithstanding the papers she signed acknowledging no expectation of improved health. Side bets are the rule when your life is at stake.

A scrappy molecule

In physical terms, the patients wager on something ever so tiny.

In a world of miniature molecules, this treatment is an ant amid elephants. Think of it as biological stick ’em, a scrap from a corner of a Post-It Note.

It is a sliver of antibody and less. In efforts to make this molecule a marvel of efficiency, scientists discarded most of the antibody’s basic Y shape. For H11, researchers threw out everything but the end of the Y’s arms. In essence, they are taking only the hands that an antibody uses to grab enemy cells.

“Intuitively, when you look at it logically, this naked molecule isn’t supposed to work. It isn’t supposed to do squat,” says Paul Purcheson, vice president of clinical and regulatory affairs until August for Viventia Biotech Inc. The Toronto company is the developer of H11. “It doesn’t even have the ability to call in the immunological army that just a plain antibody would have. But it’s doing something in all our animal tumor models.”

Antibodies have had some success against cancer. In 1998, the U.S. Food and DrugAdministration approved an antibody treatment for breast cancer called Herceptin. The Herceptin antibody acts against something called Her2, a protein found in about 30 percent of all breast tumors. But Viventia’s antibody seems effective against a far broader range of cancers. In laboratory tests, cancer after cancer fell to it: breast cancer, lung cancer, brain cancer, colon cancer, prostate cancer.

“I don’t know of another antibody that has shown activity against this variety of cancers,” Dr.Purcheson says. Most puzzling to scientists is why this naked, amputated, shouldn’t-be-able-to-do-squat antibody works.

Antibodies are not promiscuous. When an antibody scans a cell, it recognizes and attaches only to cells that carry a specific kind of docking site on their surface. These docking sites are called antigens. But in the case of H11, no one knows what the home port is. No one has identified the antigen to which it’s attracted.

“We’re treading on a class of antigens nobody has worked with,” says Dr. Purcheson.

Most of the patients in the cancer trial don’t know much of this. If they were told, they probably forgot. It doesn’t matter anyway; not to the 12 who submit to the antibody’s caprice. Not really. Because H11 is something else to them. It flashes and dances with another purpose. To them, this molecule is a glimmer of hope.

In this case, hope is fuel – rocket fuel for someone like Pat Krzeminski.

Pat’s medical record is encyclopedic and fatter than a stack of reference books. Still, it doesn’t tell half the story. It chronicles seven surgeries, seven rounds of chemotherapy using more than a half-dozen drugs, intraoperative radiation, a stem-cell transplant, the implantation of radioactive seeds, and painful surgical complications. It inventories prescriptions by the dozen: Percocet, Darvocet, morphine, opium, Ativan, Prozac, and more. It details a temporary colostomy. It lists the tiny knick that made an opening between her rectum and her vagina, allowing feces through both outlets for 30 months.

It notes the nausea, the exhaustion, the hair falling out as an almost annual tradition. But there’s no special asterisk marking the fact she hasn’t had hair at Christmas since before she got this disease. And it doesn’t footnote her joke that she never manages to lose hair in time for Halloween so she can play Uncle Fester for the trick-or-treaters.

The fact that her daughters were 13 and 14 when Pat was swept away by disease draws no special concern. That these children barely understood what cancer was isn’t in the files.

Keri and Kristen knew cancer killed a grandfather and a great uncle. Their friends mentioned grandparents felled by cancer. But none of their friends knew anyone so young as a mother, a mother who was “goofy all the time,” kidded them, teased them, attended all their basketball and softball games and cheered them, cooked everything, cleaned everything, carted them around, spied on them if she thought they needed it. (“That’s all right. It wasn’t like she was good at it,” Keri says.)

No one like that got cancer in other people’s stories. Medical records don’t chronicle what families go through. Kristen, now a sophomore at the University of Toledo, and Keri, a junior there, watched their dad, Ed, change completely.

“He’s done a total 180,” Keri says. “He would always come home and was like mad. He would yell at anything. He doesn’t do that anymore. I really look up to him,” she says. “I think he was really scared.”

Ed says it’s not quite as scary now that his daughters are old enough to take care of themselves. But it’s endlessly frustrating.

“I feel helpless at this point. I’ve felt helpless through the whole thing. If something’s wrong at work, I can fix it.” There’s no repair manual for what they’ve been through.

“My life has been abnormal for so long that it’s the norm.”

He changed many of his habits. Going out with friends after work is seldom an option now.

“I need to be there for Pat.”

Pat isn’t an easy person to be there for. She wouldn’t let Ed take her to the hospital for her first chemotherapy sessions. She shooed him out of town when she went in for her third surgery. When Pat was in the hospital 18 days for stem-cell therapy, she ordered her family not to visit. It’s not an act. It’s just Pat, who has an overwhelming need to be strong, to shield her family from the worst, to jealously guard some moments alone. It’s the way she deals with cancer.

Her real worry is her family. She puts her hands over her face and gasps in a sudden eruption of tears when she talks about cancer’s impact on them.

“I don’t usually cry,” she apologizes. “It’s OK. But I don’t. You see, I didn’t feel bad for myself. I was at peace with it. But I could just see it. Ed would just cry. But I didn’t feel bad for myself. They were all scared. They were scared. That’s when I just thought, I’m going to have to be the strong one. And I knew it. I knew it. And I am.”

Swallowing poison

Facing cancer treatment takes courage.

The group of women in the antibody trial make the average Everest trekking party look cautious. Mountain climbers don’t swallow poison. Cancer patients live by the stuff. Only they call it chemotherapy.

Chemo is nasty. It makes hair fall out. It peels away the tender cells that run from lips to anus, leaving the exposed digestive system a factory for nausea. It wipes out immune response, poisoning the newborn immune cells with the same ferocity it uses on newborn cancer.

The No. 1 killer of cancer patients is infection. Chemotherapy enhances that vulnerability. But perhaps most horrifying is what happens when chemotherapy falls short of total victory. Chemotherapy can stimulate the development of super cells no longer subject to its poisonous chemical touch. Chemotherapy creates tougher cancer. This is what H11 must defeat.

Evolution of a killing machine

The trouble with cancer is evolution. Cancer develops through evolution. It expands through evolution. When cancer faces a barrier, like chemotherapy, it is the process of evolution — the survival of cells more fit for new circumstances — that eventually overwhelms these barriers. Chemotherapy becomes an important evolutionary force in the life of cancer.

In nature, a persistent change in the environment will slowly but surely benefit the members of a species best suited to the alteration. When weather favors a tree that drops tough, large seeds on the Galapagos Islands, finches with powerful beaks are soon the only ones left. The same rules of development allow crop pests to overcome insecticides, or bacteria to develop resistance to antibiotics. Given the right challenge and the presence of genetic diversity in the effected population and, eventually, evolution happens.

In cancer, chemotherapy becomes the weather, the antibiotic, the pesticide. It plays favorites among the cancer cells. Those best able to ignore its poison do so by whatever means possible. Soon, all that remain are tough, drug resistant, invasive cancer cells.

“Once you appreciate how cancer cells evolve, you realize most therapies are going to fail,” says Mel Greaves, a researcher at the Institute of Cancer Research in London, and author of Cancer: The Evolutionary Legacy.

‘The reason chemotherapy continues to be important is that, sometimes, it succeeds. It wipes out the cells before they have a chance to evolve. It moves beyond being a seasonal drought and creates a desert. Instead of adaptation, extinction follows. In short ,chemotherapy wins.

‘I was so tired’

Pat’s plunge into a personal relationship with evolution started when she noticed her stomach swell after even the smallest meal. A can of pop made her unsnap and unzip her pants.

“And I was tired. I was so tired. I would get up and go to work and come home and go to bed. And I drive school bus. All I could do is cook supper and go back to bed.”

She drove a bus for Bedford Public Schools. Her menses were irregular and dark brown. Pat’s gynecologist told her she was probably nearing menopause. She was 44 years old. She never doubted him.

Misdiagnoses of ovarian cancer are common, it seems. In a recent survey of 1,700 ovarian cancer patients published in the medical journal Cancer, 95 percent of the women said doctors ignored or misdiagnosed their symptoms.

A doctor may seldom see ovarian cancer in his or her practice. Although it is the sixth most common cancer in women – not counting the nonmelanoma skin cancers — it accounts for only 4 percent of all cancer in women. The American Cancer Society predicts 23,300 new cases of ovarian cancer this year. Nearly 14,000 women will die of the disease. Among cancers of the reproductive organs, this is the most lethal.

It is so lethal because it is rarely caught early. Usually, the cancer is spreading by the time a doctor discovers it. At the moment, no screening test for ovarian cancer exists, although some promising research may soon change that.

Now, there is only the hope that a physical exam and the patient’s complaints lead to the diagnosis.

When Pat woke from her first surgery, her gynecologist was talking to Ed.

“I heard him tell my husband that it was ovarian cancer. And I heard my husband say, ‘Well,what are the odds?’ And I’m listening to all of this, and they think I’m asleep. And I thought, ‘Oh my God!’ And then I heard him say a 90 percent chance of recovery. I got really peaceful. I thought, ‘Those are really good odds. I can be one of those 90 percent.’

“It’s hard to say just what Pat heard. Ed doesn’t remember it that way. The five-year survivalrate for a woman diagnosed with Stage 3 ovarian cancer, as Pat’s was, is 50 percent. Pat beat those odds in June of 2000.

Of mice and women

After what the H11 patients have been through, the risks of this trial seem negligible to Pat and her fellow study subjects. The antibody is not poison, per se, although anything in a high enough dose is.

In December, 2000, when the trial began, researchers planned to observe four groups of patients. The first three patients would receive the lowest dose, 50 milligrams of drug per square-meter of body surface five days a week for a month. The next three patients would receive 200 mg. The following three would receive 400 mg. The last group of three would take 600 mg.

It’s called a dose-escalation trial, and the purpose of this stair-step arrangement is to ascertain safety at each dose. The researchers at Viventia gave mice five times more drug than any of the MCO patients will receive. At that level, a few mice developed blood coagulation problems and bled to death.

The drug trial is under way when the company discovers this high-dose effect. Although humans will receive nowhere near as much antibody, twice weekly tests for clotting factors become part of the patients’ regimen. When Pat Krzeminski joins the trial, such clotting tests are routine.

Each patient signs a form stating she understands the risks and the aim of the research. Efficacy is not what matters here. Determining a safe dose for patients who come later is the concern. That becomes impossible to remember as the weeks roll on.

Pat’s first treatment

The antibody treatment seems easy enough, even pleasant: Sit for two hours or so in the infusion center, a large room with reclining chairs in the lower level of the Ruppert Center. Nurses draw blood, administer IVs, even supply juice and coffee if the patient likes. Two televisions play quietly.

Many of the patients are elderly. Most are cancer patients, but some receive IV antibiotics, or other medications, via infusion. A young boy sits in a corner recliner watching cartoons while clear liquid drips into his arm. Usually it’s a quiet room. Most patients nap, some read, a few talk softly to the spouse at their side.

Pat and the other H11 patients sit at the far end of the room. They grow louder and more animated every day. Cissi Jackson, who would dearly love to doze, can’t, as her fellow research subjects grow more boisterous. Pat finishes her first H11 treatment and heads for home. She’ll come back in four hours for her final blood draw of the day.

She’s on Reynolds Road when it hits, waves of nausea too powerful to fight. Ed pulls the car over just in time. Pat throws up. She’s sick for hours. This wasn’t supposed to happen.

Tomorrow: Cancer patients all over the country clamor to get into H11 study.

Feb. 2002

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