Quitting Cancer Drugs posted: 05/03/05 Doctors Test Whether Patients Can Safely Stop Taking Targeted Therapies After Years Of Use THE WALL STREET JOURNAL, 05/03/2005 By Amy Dockser Marcus 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. Anderson 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. 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 Brian Druker, professor of medicine at Oregon Health & Science University Cancer Institute in Portland and one of the developers of Gleevec. 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. Anderson 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, Andreas 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. 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. Anderson, Jorge 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." 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." 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. Stopping Cancer Drugs Clinical trials starting this year where some patients will stop taking their medication to test whether the cancer will progress: SPONSOR: M.D.Anderson, Houston TRIAL: 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. CONTACT: Jorge Cortes, 713-794-5783 SPONSOR: French Sarcoma Group, 36 institutions in France and Switzerland * TRIAL: 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. CONTACT: Jean-Yves Blay, [EMAIL PROTECTED] SPONSOR: Australasian Leukaemia and Lymphoma Group, Australia ** TRIAL: 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. CONTACT: www.petermac.unimelb.edu.au/allg *Accredited oncology centers in the U.S. are eligible to participate **Available only to patients in Australia Copyright (c) 2005 Dow Jones Reuters Business Interactive LLC (Factiva) Louis Nault Montreal, Quebec, Canada ------------------------ Yahoo! Groups Sponsor --------------------~--> Does he tell you he loves you when he's hitting you? Abuse. 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