PSA Rising, Nov. 8, 2004. The COX-2 inhibitor rofecoxib (Vioxx™) was removed from the market on September 30, 2004 after a two-fold increased risk of cardiovascular toxicities was identified in people taking the drug for 18 months. The trial sponsor, Merck & Co., Inc. (New Jersey), sent a letter to physicians announcing the removal of the drug and explaining the action.
Vioxx was developed, licensed and marketed around the world as a painkiller suitable for people with arthritis. But the cardiovascular damage that prompted the drug's removal happened within a 2,600 person trial to prevent colon cancer.
Vioxx is one of a class of drugs, called COX-2 inhibitors, which control pain without causing gastric irritation and which also may prevent and slow tumor growth. People with a family history of certain cancers or with early, "biochemical" recurrence have an interest in this class of drugs, not for pain control but for possible anti-tumor control.
What effect will the Vioxx withdrawal have on other cancer trials and on cancer patients who already rely on off-label use of other COX-2 inhibitors, primarily Celebrex, to help control their disease?
At the the National Cancer Institute (NCI) the Division of Cancer Prevention had planned to undertake a lung cancer prevention trial using rofecoxib, but has abandoned that plan following the withdrawal of rofecoxib.
Fawn Vrazo in the Philadelphia Inquirer reported October 28, "Merck & Co. Inc's withdrawal of the pain drug Vioxx a month ago left many arthritis patients without their favorite medicine. But scientists are now worried about the potential harm the drug's removal could have on cancer research." (posted at Breast Cancer Action, Nova Scotia)
The situation is complicated by what looks like cover-up of evidence of increased rate of cardiovascular harm in people taking Vioxx. The US Food and Drug Administration, which is in charge of overseeing clinical trials and regulating drugs, may have ignored evidence.
Science commentator Jonathan Gitlin (Ars Technica, Oct 17) says, "Data suggesting the possible cardiovascular side effects of Vioxx, and coxibs as a class of drug, have been in the public domain for several years, yet at no point did the FDA ask for clinical trials to elucidate the matter."
According to NZZ Online and the Seattle Times November 5, Swiss researchers say Vioxx should have been pulled off the market four years ago.
In an article published online by the U. K. medical journal the Lancet, the Swiss researchers said evidence was clear and overwhelming in 2000 that Vioxx doubled the rate of heart attacks and the drug should have been withdrawn.
They based this conclusion on data obtained primarily from the FDA.
The Lancet editorial concludes: "The Vioxx story is one of blindly aggressive marketing by Merck mixed with repeated episodes of complacency by drug regulators."
One may suspect that as much effort went into selecting the drug's high-impact name, Vioxx, as into timely safety warnings.
What about Pfizer's Celebrex?
On November 4 a Canadian newspaper, the National Post, reported that
documents from Canadian health authorities linked Celebrex, which is made by Pfizer, to the deaths of 14 people who were taking it over the past five years. According to the Post, Canadian health authorities have gathered more than 100 adverse-reaction reports on Celebrex over the past five years, including 19 cases of heart attack, cardiac arrest or heart failure and five strokes.
Pfizer replied in a press release: "The news report, based on voluntary spontaneous event reporting to Canadian Health authorities, is misleading. The story is not supported by any clinical or epidemiological studies and has the potential to cause undue confusion among patients and physicians."
Pfizer then took action (November 8) to warn doctors and patients about a rare but devastating problem with another of its Cox-2 inhibitor painkillers, called Bextra. Pfizer announced intention to put a severe, "black-box" warning on the label of Bextra, because it sometimes leads to a serious skin reaction.
COXIB Potential for Slowing Cancer Progression
A few days before the Vioxx recall,
Raj Pruthi, MD, FACS, assistant professor of surgery, University of North Carolina, presented results of a small one-year study of Celebrex at
the annual Clinical Congress of the American College of Surgeons. Pruthi said, "This is the first report of a Cox-2 inhibitor having a therapeutic effect in prostate cancer at any stage of the disease." He had shown that in 22 out of 24 men with biochemical recurrence of prostate cancer, 400 to 800 mg of Celebrex a day slowed the rise of prostate specific antigen (PSA), which, following primary treatment, is a marker of recurrent disease.
Pruthi's study of Celebrex ran for only 12 months (with Vioxx, cardiovascular problems appeared in patients who took the drug for 18 months or more).
The National Cancer Institute (NCI) is running scores of small studies and full scale clinical trials like Dr. Pruthi's. NCI is concerned about the impact of the Vioxx recall on its research into this entire class of drugs, including Celebrex. In order for these studies to go forward with confidence, more, not less, openness and accountability will be required. Not just two drugs but generations of even more promising knock-offs are at stake.
The FDA approved Celebrex (celecoxib) in 1999 at the same time as Vioxx (rofecoxib). As the Lancet explains, "their debut was announced in 2000 in the medical literature with two landmark trials: VIGOR for rofecoxib, and CLASS for celecoxib. Subsequently, a number of second generation COX-2 inhibitors have been developed. These include valdecoxib, parecoxib, etoricoxib, and lumiracoxib. The indications for their use have remained largely unchanged and more 'me-too' COX-2 inhibitors are on the horizon."
Third generation versions are being tested. Last month Ohio researchers announced that a drug labeled
OSU03012, which they describe as "a bioavailable third generation celecoxib derivative
. . . that potently induces apoptosis in prostate cancer cell lines and is being developed as an anti-cancer therapy in the NCI Rapid Access to Interventional Therapy (RAID)," is cytotoxic against a type of leukemia (CLL) and type B lymphoma.
Action by Pfizer and NCI
The first obligation of companies that make these drugs under FDA licence is to protect patients who take them daily for approved uses, such as to treat arthritis pain. On October 18, Pfizer, Inc., the company that makes Celebrex, announced a trial of this drug to run for two years. The study will examine inflammation and cardiovascular events in osteoarthritis patients at high risk for heart disease. It will be conducted at major universities and hospitals around the world and is expected to start early in 2005, enrolling 4,000 patients who have had a recent heart attack and who also have a history of osteoarthritis.
Meanwhile, cancer researchers are anxious. Ernest Hawk, the NCI's chief of gastrointestinal research, said told Fawn Vazo at the Philadephia Inquirer that researchers had begun calling him to ask what the Vioxx withdrawal "'implied for our trials.'"
"In response, the NCI sent letters to its researchers confirming that 'it did not see a significant safety concern' with Celebrex, Hawk said. As an added precaution, the NCI selected an independent panel of cardiologists to keep an 'over-the-shoulder' look at the cardiovascular health of about 2,000 patients who are taking Celebrex to see if it reduces their risk for colon cancer."
How the drugs work against cancer
All NSAIDs block cyclooxygenase enzymes, which are produced by the body when there is inflammation and are also produced by precancerous tissues. Inhibition of COX-2 may help treat and prevent cancer, while inhibition of COX-1 tends over time to cause gastric irritation and stomach bleeding.
This is the great advantage and selling point of both Vioxx and Celebrex as painkillers - by blocking Cox-2 while not blocking COX-1, they provide significant pain relief without stomach upset and risk of ulcers and bleeding.
But as Gitlin says: "COX-2 isn't just bad. In addition to its role in inflammation, it also plays an important part in controlling the cardiovascular system -- stopping platelets from forming thrombi, preventing damage to vessels, that kind of thing."
For a cancer patient, "that kind of thing" may have a different value, though, than it does for the average, healthy person or a person with arthritis.
Drugs that damage cells or interfere with wound healing may extend the lives of people with cancer. Angiogenesis inhibitors (drugs that interfere with the formation of new blood vessels, which are used by tumors) can help slow progression of cancer. Some drugs that are used against advanced breast cancer weaken heart muscle; some used against advanced prostate cancer are bad for the cardiovascular system and tend to cause blood clots. Cancer patients - facing a known risk of dying from their disease - may be willing to deal with side effects by taking other drugs (for example, blood thinner to counter the effect of a clot-causing anti-cancer drug).
The key concern for cancer patients is for known risks to be openly declared, not hidden. Unfortunately in the real world this essential concern may clash with a drug company's aggressive, costly marketing agenda.
NCI says that "over a decade of scientific work has suggested the potential of COX-2 inhibitors to prevent and treat cancer." As of last month, NCI's Division of Cancer Prevention (DCP) was sponsoring more than 40 clinical trials involving Celebrex. Of these, 23 trials of varying sizes are to test the potential of celecoxib to prevent cancer in a number of organ sites. These trials range in size from under 10 participants to more than 2,000 and aim to prevent bladder, breast, cervical, colorectal, esophageal, head and neck, skin, lung, oral, and prostate cancers, as well as multiple myeloma. Most of these trials are in collaboration with Pfizer, Inc.
In addition, almost 20 trials of varying sizes are testing celecoxib as a cancer treatment. Most of these studies are small phase I or II clinical trials in cancers such as pancreatic, breast, ovarian, non-small cell lung, and solid tumors.
An example of a small study of Celebrex for prostate cancer treatment is Clinical trial, Phase II, "Celecoxib [Celebrex] in Treating Patients With Relapsed Prostate Cancer Following Radiation Therapy or Radical Prostatectomy UNC Lineberger Comprehensive Cancer Center; NCI.
This page reported by J. Strax, November 8, 2004
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