Quitting Cancer Drugs/WSJ

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Quitting Cancer Drugs

Doctors Test Whether Patients Can Safely Stop

Taking Targeted Therapies After Years of Use

By AMY DOCKSER MARCUS

Staff Reporter of THE WALL STREET JOURNAL

May 3, 2005; Page D1

In a debate that has far-ranging implications for the most promising

new " smart drugs " in treating cancer, some doctors are now starting to

ask: Can patients ever stop taking them?

This is a question that rarely came up with standard chemotherapy

treatments, which often were so toxic that they either killed the

cancer or were stopped because of the potential harm to the patients.

The newer " smart drugs, " such as Avastin, Gleevec and Tarceva, which

target only cancerous cells and leave normal ones unharmed, have

milder side effects. They often keep a tumor from growing but don't

completely eradicate it, raising the possibility that they may be

taken for years, possibly for the rest of someone's life, transforming

cancer into a chronic illness.

Many patients who have been on the drugs for years are starting to ask

their doctors when, if ever, they can stop. Some complain that even

the so-called mild side effects, such as fatigue, nausea, swollen eyes

and legs, among other issues, are difficult to endure on a chronic

basis. The drugs often are expensive. Novartis's Gleevec, for leukemia

and gastro-intestinal stromal tumors (GIST), and OSI Pharmaceuticals

Inc. and Genentech Inc.'s Tarceva, approved to treat nonsmall-cell

lung cancer, cost around $2,400 and $2,100 a month, respectively, at

wholesale prices. Genentech's Avastin, which is approved for

colo-rectal cancer, runs around $4,400 a month. Even people with

insurance can end up with large monthly co-payments.

Also, there is only scant data on the potential effects on a fetus, so

both women and men taking the drugs are advised not to have children,

a challenging issue for patients in their reproductive years.

Now, academic centers such as M.D. Cancer Center in Houston;

the French Sarcoma Group, an organization of 36 cancer institutions in

France and Switzerland; and the Australasian Leukaemia & Lymphoma

Group, a consortium of centers in Australia and New Zealand, are

launching clinical trials that will do something that once was

unthinkable. They will enroll patients with chronic myelogenous

leukemia (CML) or GIST whose cancer is either undetectable by blood

tests or hasn't grown for the past two to three years and see what

happens when some of them stop taking Gleevec.

REASONS TO STOP

Why some cancer patients quit taking so-called smart drugs:

• Side effects: The drugs can cause fatigue, swollen eyes and

legs,

nausea and vomiting.

• Fertility issues: Both women and men often are advised to

refrain

from having children while taking these drugs.

• Cost: Even patients with insurance can have significant

co-payments,

which add up.

• Drug resistance: Some tumors develop mutations that become

resistant

to the drug and require new therapy.

The current trials involve Gleevec in part because it was one of the

first smart drugs to win Food and Drug Administration approval, in

2001, and has a group of patients who have taken it for more than

three years. The questions raised in the trials go far beyond Gleevec

users and have implications for all such drugs. Many patients

eventually become " resistant " to cancer drugs -- GIST patients on

Gleevec have a particularly high rate but it's an issue for other

targeted therapies, too. One notion that researchers are exploring is

whether taking patients off a drug for a time will extend the life of

the drug's efficacy and perhaps delay resistance. Doctors who treat

patients with breast cancer also are looking into whether longer or

shorter durations of drugs such as Herceptin or Femara help prevent

the cancer from coming back.

" Every targeted therapy is facing the same key issue: How long do we

treat patients? Two years, five years, indefinitely? " says

Druker, professor of medicine at Oregon Health & Science University

Cancer Institute in Portland and one of the developers of Gleevec.

Cases of Relapse

The trials raise ethical concerns because of data that have emerged

recently involving small numbers of patients from Oregon Health &

Science University in Portland, the French Sarcoma Group's

institutions and M.D. that indicated the vast majority of

those who stopped taking the drug quickly relapsed. All of these

patients restarted the drug and doctors say there is no evidence that

their overall survival odds are any worse than someone who never

stopped taking the drug. But two GIST patients in one study weren't

able to get their cancer back in control after restarting the drug and

saw their disease worsen; one has died.

Two years ago, s Hochhaus of the University of Heidelberg in

Manheim started collecting cases of patients who, for various reasons,

had stopped taking Gleevec. The Registry on Patients Who Stop Gleevec

After Remission now contains 20 patients in the U.S. and in Europe.

" Almost all " relapsed, Dr. Hochhaus said. " I do not think people can

stop taking Gleevec at any point. "

Diane Young, vice president of clinical development at Novartis

Oncology, says the company's position is that " right now we don't

really feel there is sufficient data to support that the drug can be

stopped safely in patients " who are doing well on it. Dr. Young said

the limited evidence that exists suggests that even patients whose

disease is undetectable using current tests may still have some

residual disease that can grow if the drug is stopped.

Intriguing Reports

The doctors setting up the current trials are being driven by the

small yet intriguing reports being published that showed some patients

were able to go off the drug and not relapse for extended periods of

time. Jean-Yves Blay, president of the French Sarcoma Group, presented

data at the American Society of Clinical Oncology annual meeting last

year involving 259 patients with GIST who were taking Gleevec. In an

interim report, Dr. Blay said 32 patients were taken off Gleevec to

see how they responded, and 24 of them saw their tumors start to grow

again. The median time to relapse was six months. Dr. Blay said he and

the other doctors recommended that everyone go back on the drug, but

as of February 2005, four patients refused to do so and still hadn't

relapsed after having been off for 12 to 14 months. Eventually, they

all started taking Gleevec again, because of encouragement from their

families. The group's doctors are studying the patients' tumors to see

if there is some kind of mutation in the proteins targeted by the

tumor that can be tied to the likelihood of relapse after stopping the

drug.

Dr. Blay said one question that remains is whether the patients would

have fared better if they had stopped after being on the drug for a

longer period of time. The patients in the first trial had been in

remission only for a median of two years. Later this year, he said the

French Sarcoma Group will start a new trial involving GIST patients

who have been taking Gleevec for three years with no sign of cancer

progression, to see if some of these patients no longer need the drug.

At M.D. , Cortes, deputy chairman of the department of

leukemia, is enrolling patients in a trial where they receive Gleevec

and interferon, rather than Gleevec alone. If the levels of leukemia

cells in their blood remain undetectable for two to three years, they

then will stop taking the drugs. The idea is " if we add other drugs to

the Gleevec, maybe it will improve their chances of staying in

remission once they stop taking Gleevec, " Dr. Cortes said.

In a paper published in the journal Leukemia Research, a group of

doctors at Oregon Health & Science wrote about two patients who

stopped taking Gleevec. One of them asked to discontinue because of

worsening fatigue. She relapsed two months later. The second patient,

a 36-year-old woman diagnosed with leukemia in 2000, stopped taking

the drug after 17 months because she found out she was pregnant. One

year later, after delivering a normal child, the levels of leukemia

cells in her blood still were undetectable, according to the paper.

One month later, despite the fact that she still remained in

remission, she decided to go back on the drug after speaking with her

doctor.

Dr. Druker says her case and others show that " there is a potential

for differing outcomes when the drug is stopped. "

Experience with Gleevec

This potential is what convinced Jennie Tilley to enroll in a

25-person trial expected to start this fall being run by the

Australasian Leukaemia and Lymphoma Group. Ms. Tilley, 63, was

diagnosed in 1995 with leukemia. She was initially treated with

interferon but had terrible mood swings and lost weight. She had a

bone-marrow transplant but her leukemia counts kept rising. In 2001,

she went on Gleevec. Her disease has been undetectable since 2003.

Ms. Tilley, who lives in Port MacDonnell in the southern part of

Australia, said she has suffered side effects from the Gleevec. She

gets constant subcutaneous eye hemorrhages, which she says are very

painful and feel " like a hot needle is going through your eye. " Her

hair " pulls out in chunks, " she said. But she said she was most

concerned by a recent study done by Novartis showing an increased

frequency of genitourinary tumors in rats treated with Gleevec daily

for 24 months. Ms. Tilley said the report reminded her that " they

don't know the long-term effects of taking this drug because it is so

new. "

Novartis's Dr. Young says the rat study is continuing, but that in

safety data from more than 9,000 patients, there hasn't been findings

of increased incidence of any kind of tumor. She added that the

company did send out a letter to physicians in November 2004 about the

rat data and updated the Gleevec label to reflect the findings.

Ms. Tilley said the knowledge she can go back on the drug if her

counts go up, and that others who have done this have been able to get

the cancer back into control, made her feel that, " I've got a

parachute. "

Write to Amy Dockser Marcus at amy.marcus@...

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Stopping Cancer Drugs

Clinical trials starting this year where some patients will stop

taking their medication to test whether the cancer will progress:

Sponsor Trial Contact

M.D. , Houston Leukemia patients will take Gleevec and

interferon. If they remain without detectable levels of cancer in

their blood for two to three years, the drugs will be stopped.

Cortes, 713-794-5783

French Sarcoma Group, 36 institutions in France and Switzerland* GIST

patients whose cancer hasn't progressed for at least three years will

be eligible for a trial where some people will stop taking Gleevec.

Jean-Yves Blay, Blay@...

Australasian Leukaemia and Lymphoma Group, Australia** Leukemia

patients with undetectable levels of cancer in their blood for at

least two years will be eligible for a trial where some people will

stop taking Gleevec. www.petermac.unimelb.edu.au/allg

*Accredited oncology centers in the U.S. are eligible to participate

**Available only to patients in Australia