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The end of chemo? One magic pill may hold answer

From Tuesday's Globe and Mail

In a coffee shop, on the second floor of a Loblaws superstore in the west end of Ottawa, Zavie Miller and three friends are laughing as the sunlight falls on their faces.

They discuss travel plans and children, the usual stuff, but there is giddiness in their voices, a sense of wonder at the ordinary events in their lives.

They all have chronic myelogenous leukemia (CML), a slow-moving but deadly form of cancer. They keep it in check, however, by popping a pill or two a day.

No chemotherapy with its debilitating side effects for them. Just a drug called Gleevec.

"I take one pill a day. It is really unbelievable," says Mr. Miller, 68.

"I have virtually no side effects."

He volunteers at a soup kitchen and the National Gallery, and recently took a trip to New York with one of his daughters.

Some of his friends have side effects, but nothing like the severe vomiting, depressed immune systems, hair loss, mouth sores and other miseries caused by conventional chemotherapy. Most cancer drugs carpet bomb the body, damaging healthy cells as well as cancerous ones. Gleevec is a smart bomb, designed to kill only cancer. It has turned their leukemia into a chronic disease.

The end of chemotherapy? If that sounds too utopian, picture Mr. Miller and his friends, enjoying their coffee and their extraordinary good luck. They are the future, at least as it is envisioned by scientists convinced there must be a better way to treat cancer.

There are some side effects: Tracey Feldman, 36, for example, is a little self-conscious about her pale skin.

"We all turn white, like ghosts," she says, and shows the group her alabaster stomach. They all start to laugh, and lift their shirts to compare bellies.

Mr. Miller wants them to inspect his scalp. Other patients have reported that Gleevec restored colour to their grey hair, and he bends his head over the table, pointing to a few strands of black mixed in with the white.

They grew after he started the treatment, he insists.

Yet it's fun to listen to their happy chatter, and easy to see why Gleevec is an inspiration for scientists around the world working on drugs that will kill cancer cells but leave healthy tissue alone. Some of those researchers predict that the next 10 years will see dramatic changes in the way cancer is treated, that the next 20 or 30 years could see the end of conventional chemotherapy for most patients.

To kill cancer, doctors often come close to killing their patients.

"Many treatments put people near death," says Philip Branton, scientific director of the Institute of Cancer Research, part of the Canadian Institutes of Health Research.

That's because conventional chemotherapy drugs are essentially poisons. Nitrogen mustard, the first modern chemo drug, is a derivative of the mustard gas used during the First World War.

It destroyed the lymphatic tissue and bone marrow of its victims, and this made medical researchers think something similar might kill fast-growing cancer cells.

By 1942, two researchers at Yale, Louis Goodman and Alfred Gilman, were ready to try nitrogen mustard in a human patient. A 48-year-old silversmith volunteered. He was in the terminal stages of lymphatic cancer, but after 10 doses, his tumours disappeared.

The scientists were on to something, and nitrogen mustard became the first of many toxic compounds found to be effective against cancer. Chemotherapy became an important tool for doctors, in addition to surgery and radiation, and is used to treat many forms of the disease.

Childhood leukemia, testicular cancer and Hodgkin's disease are now regularly cured with combinations of chemotherapy drugs. But patients endure enormous suffering to rid their bodies of cancerous cells.

"We recognize it is obviously not the way to do it, not with what we now know," Dr. Branton says.

What we now know -- thanks to the genetic revolution -- is much more about what makes cancer cells different from healthy ones. They contain damaged or mutated genes. These genes produce aberrant proteins that can cause cells to go haywire, reproduce at a rapid rate and refuse to die.

The molecular approach to treating cancer involves identifying these mutated genes, finding the proteins they produce, then coming up with drugs to stop those proteins from working.

It may sound relatively straightforward. But the gene involved in CML was one of the first cancer genes to be identified in the 1970s, Dr. Branton says. It took more than two decades for researchers to figure out what it does and find something capable of stopping it.

The CML mutation occurs when two chromosomes swap chunks of genetic material. A bit of one gene, from chromosome No. 9, gets added to another gene on chromosome 22. The result is a cancer gene that produces an abnormal protein not found in healthy cells.

In CML, the aberrant protein signals blood cells -- white blood cells in particular -- to proliferate at a rapid rate and not die. If left unchecked, those cells will eventually clog the body, turning blood into something that looks more like pus. Gleevec stops the abnormal protein from working and stops the proliferation signal from getting through. The cancerous cells stop reproducing and die.

Mr. Miller heard about the drug while it was still being tested. He applied to be part of a clinical trial in Portland, Ore.

The conventional treatment for CML -- a drug called interferon -- had almost killed him in 1999. It was supposed to boost his immune system to fight cancer. Instead, it gave him congestive heart failure.

It was a complete disaster," Mr. Miller says. "I couldn't breath. I was in a fog. I didn't even know who I was. In the photographs from the time, I look like a dead person." In March, 2001, he flew to the United States and started the new, targeted drug. He immediately started to feel better. "It was magical," he says.

Two months later, Gleevec was approved by the U.S. Food and Drug Administration. By the fall, Health Canada had followed suit. Today, Gleevec is the first line of treatment for patients in the early stages of the disease.

A five year follow-up study, presented in June, found that of 553 patients who started on the drug, 69 per cent were still taking it. Ninety-three per cent of them have survived without their cancer progressing to a more aggressive stage, and 87 per cent have no sign of cancerous cells in their blood.

But there are downsides.

Gleevec is not a cure; patients may have to stay on it for the rest of their lives. Many who take it suffer side effects, some so serious they have to get off the drug. It may cause heart problems in a small number of patients. Those in the later stages of CML frequently develop resistance, and the drug stops working.

It is effective only against two rare cancers: CML and a type of gastrointestinal tumour. Still, Gleevec is widely regarded as a phenomenal success story in a field where breakthrough drugs add mere months or weeks to patients' lives.

The big question is whether that success can be repeated with more common forms of the disease, such as breast, colon or prostate cancer. There are signs it won't be easy.

Gleevec wasn't the first targeted cancer drug. There have been a number of them, including Herceptin, which in some women helps prevent breast cancer from returning. But most targeted drugs, including Herceptin, have worked only in combination with conventional chemotherapy drugs. None have been as effective as Gleevec.

Why? There are roughly 200 kinds of cancer, and CML may be one of the rare versions of the disease with such a clear target.

This fall, researchers at Johns Hopkins University in Baltimore set out to map all the genetic changes involved in colon and breast cancer. They expected to find a handful of genes that help tumours grow. They found nearly 200. Most tumours averaged 11 of them.

This makes it hard to imagine that a drug like Gleevec, designed to target a single protein, will work for breast, prostate or colon cancer, says Vincent Giguère, a researcher at the McGill University Health Centre in Montreal.

However, a combination of them might do the trick.

"Think of a cocktail of drugs like the ones now used to treat HIV-AIDS," Dr. Giguère says. "That is how we are going to outfox cancer cells."

Researchers are working to identify all the mutations involved in different forms of cancer. Once that's finished, they will have to figure out the abnormal proteins they make and come up with drugs to block them.

By then, doctors should be able to do a genetic profile of every tumour -- identifying the mutations -- so they can concoct the most potent drug cocktail possible for each patient, Dr. Giguère says. The combination of targeted drugs and personalized medicine could transform cancer from a killer disease into a chronic one.

"This will take 20 or 30 years," Dr. Giguère says. "I think I will see it in my lifetime, and I am 50."

It may be possible to zero in on the most dangerous cancer cells.

Cancer doesn't become deadly until it spreads, or metastasizes, and many cancers follow a particular pattern.

Breast-cancer cells, for example, often move to the bones. This is quite a feat, since they first have to morph from breast cells into bone cells, Dr. Giguère says. He and his colleagues are trying to figure out how they do it -- what makes them different from the cells in the bulk of the tumour, which stay in the breast?

If scientists can identify those mutations and proteins, and find a way to stop them from triggering the changes that lead to metastasis, they may be able to stop cancer from spreading.

"Maybe the original tumour would come back, but we could deal with that," he says.

In the meantime, at least 40 targeted drugs designed to work in a similar fashion to Gleevec are in clinical trials. Some have failed late in development. Some have two targets within a cancerous cell. Others are aiming for abnormal proteins that may be common in many different kinds of cancer cells.

Dr. Branton is a believer. He knows patients and their families are tired of waiting. But years of basic research into the molecular machinery of cancer cells are about to pay off, he says.

"Over the next 10 years, there will be a dramatic change in the way we treat cancer. . . . We will be using treatments that will have considerably reduced side effects."

Back at the coffee shop, Mr. Miller and his friends are chatting about what it is like to live with cancer as a chronic disease. Their conversation offers a glimpse of what the future may hold for Canadians who get it in 10, 20 or 30 years.

Ron Lemieux, 60, loves to ride his motorcycle and ski. He recently returned from a trip to California with his 30-year-old daughter.

"I've had no side effects, other than feeling good. I get the odd cramp in my toe."

Eleanor Paul-Robillard, 68, is the only grandmother in the group. Gleevec didn't work for her, but she is on another targeted drug developed by the same company, Novartis. It is called Tasigna, and it may help patients who develop resistance to Gleevec or get severe side effects from it.

So far so good, she says. She and Mr. Miller lead the group in an impromptu square dance when they go outside to have their photograph taken for this article.

Tracey Feldman, 36, was diagnosed five years ago when her daughters were 7 and 9. She wished desperately to see them through puberty.

"I'm loving puberty," she says.

They are profoundly grateful to be alive, but there are times when it can be hard to live with chronic cancer. There is the uncertainty. If they stop taking Gleevec, their cancer will most likely come back, and doctors have no idea how long the drug will continue to keep their cancer at bay. Not knowing is also hard on their families.

Ms. Feldman frets about getting her girls through high school. She also wonders what being on the drug for the rest of her life will do to her body.

Gleevec inhibits the work of two other proteins found in healthy cells, and one of them may be involved in skin pigmentation. Many patients find their skin lightens considerably.

Water retention is another side effect, especially around the eyes. Ms. Feldman gets frequent diarrhea, but Imodium controls it.

There are occasions where she finds herself envying people with solid tumours. The treatments can be horrific, she says, but they are relatively short-lived.

"For us, we will never be cured."

But she is convinced she owes her life to Gleevec. It was new when she was diagnosed, and her doctor was skeptical. He wanted her to have a bone-marrow transport. She insisted on trying the drug.

"I would be dead, otherwise. It is a miracle."

Niels Hansen-Trip, 59, knows something about miracles. He was given three months to live when he was diagnosed in 2000, because his disease had progressed to a more acute phase.

But he responded to a treatment that involves removing excess white blood cells, and eventually qualified for a clinical trial with Gleevec, which he has been on ever since. He gets terrible muscle cramps in his legs and suffers from gastrointestinal problems.

Not that it stops him. He runs his own project-management business and travels. He tells funny stories. During one extended stay in Belize, he had to get a veterinarian's assistant to test his blood for signs of cancer. Turns out he is perfectly healthy -- for a chicken.

"Life is tough," he says, becoming serious for a moment. "But it is also wonderful."

Chemotherapy options

Depending on the type of cancer and the kind of drug used, chemotherapy drugs may be administered in a multitude of ways. Often, doctors will use two or more methods at the same time. But no matter what method is used, chemotherapy drugs are absorbed into the blood and carried around the body.

Oral chemotherapy:

Oral medications can be encased in different pill coatings. Depending on the coating, the stomach acids take differing amounts of time to release the drug, allowing for time delay. This technique allows longer periods of time between doses. Fast-release medications can be placed directly under the tongue.

Intrapleural chemotherapy:

Chemotherapy is given through a chest tube inserted into the space between the lung and the lining of the lung.

Intramuscular injections:

The chemo injection is given through the skin into the muscle layer. Most chemotherapy cannot be given this way because of the harshness of the chemical.

Subcutaneous injection:

The chemo injection goes into the space between the skin and the muscle. Especially useful if the patient's platelet count is low, because subcutaneous injections are less likely to cause bleeding.

Intraperitoneal chemotherapy:

A catheter is placed through the abdominal wall with the catheter draining into the abdominal cavity. Chemotherapy is then infused directly into this cavity.

Intra-arterial chemotherapy:

Drugs are given directly to the artery that is supplying blood to the tumour. This gives the affected area a high dose of radiation without the associated toxicity to the rest of the body.

Intravesicular chemotherapy:

Medication is injected through a catheter directly into the bladder.

Implantable chemotherapy:

As many as eight dime-sized wafers diffused with appropriate chemo drugs are left inside the skull after surgery on a brain tumour. The wafers slowly release cancer-killing radiation as they dissolve over a period of weeks.

Intraventricular and intrathecal chemotherapy:

Used when drugs need to reach the cerebrospinal fluid ( CSF) in the brain and spinal cord. Access to the CSF is gained through the spine or by threading a catheter though the skull into the lateral ventricle of the brain. Used most commonly in acute leukemia patients.

Topical chemotherapy:

Some chemotherapy creams can be applied directly to the skin. The cream is absorbed directly into the cancerous lesion. The use of topical creams is very limited in cancer treatments.

Intravenous chemotherapy:

Nontunnelled catheter: Inserted at the bedside directly through the skin into the jugular vein. The catheter then travels through the vessel into the superior vena cava. Usually only used short term. An X-ray is required to make sure the catheter is in place.

Tunnelled catheter:

Surgical procedure in which the catheter is tunnelled between skin and muscle of the mid-chest, then inserted into the superior vena cava. An Xray is required to make sure the catheter is in place.

Peripherally inserted central catheter:

Inserted into one of the large veins of the arm near the bend of the elbow. It is then pushed through veins until the tip sits in a large vein just above the heart. An X-ray is required to make sure the catheter is in place.

Angiocatheter:

Placed in the vein in the arm or hand and removed after the chemo medication is given.

Common chemotherapy side effects

Flu symptoms: Tiredness, muscle aches or headaches and chills can begin as soon as an hour after treatment and last up to three days.

Hair: Hair loss can occur on all parts of the body. Patients may lose the hair on their head, including some or all eyelashes and eyebrows, and on their body, including pubic, chest, and underarm hair.

Skin: Minor skin irritations may develop, including: redness, rashes, itching, peeling, dryness and acne.

Oral: Mouth, throat and tonsils can become very dry, making talking, chewing and swallowing very difficult.

Mouth: Sores can develop on the tongue and lips.

Eyes: Eyes become very watery, red, sore or dry and temporary changes in vision are possible.

Appetite: Desire to eat fades and eating habits change, along with food dislikes changing day-to-day. Chemotherapy drugs also cause temporary changes in taste and smell, making food less appetizing.

Nausea and vomiting: The most common and most feared symptom of chemotherapy.

Diarrhea and constipation: Irregularity ranging from loose, frequent stools to great trouble moving bowels.

Infections: Many drugs used during chemotherapy affect the immune system, limiting the body's ability to fight infection.

Bleeding or bruising: Red spots under the skin, unusual bleeding from gums or nose, bleeding from the bladder or rectum, and vaginal bleeding happen because chemotherapy affects the body's ability to make platelets, which help with clotting.

*****

SOURCES: HEALTH CANADA, THE MAYO CLINIC, CLEVELAND CLINIC CANCER CENTER WRITING AND RESEARCH BY UNNATI GANDHI AND RICHARD JOHNSON

Series schedule

Nov. 20 Drugs and dollars:

The pressure of high costs on care

Nov. 21 So tired of waiting:

Treatment is still taking too long

Nov. 22 Canada's research chasm: A nation falls behind

Nov. 23 PET scan scandal: High tech sits idle

Nov. 24 Screen test: Beating the

colorectal killer

Nov. 25 in Focus English lessons: The quest for a national strategy

Nov. 25 in NewsThe science of stem cells: A new way of looking

at cancer

Today The end of chemo: There must be a better way

Thursday Can a shot of the flu cure cancer?

Saturday In his shoes:

Eight-year-old Spencer fights to live

Wednesday, Dec. 6 It's everywhere: Is the environment killing people?

Saturday, Dec. 9 "C-type" mentality: The psychology of survival

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