Glee Over Gleevec

Each year, 26,000 of the world's oncologists parade their accomplishments at the annual meeting of the American Society of Clinical Oncology (ASCO). In May, the media was filled with reports of the impending conquest of cancer. This happens every year, but this year's mania exceeded all others. The front cover of Barron's screamed, "Investing in Health: Curing Cancer." The article stated baldly: "We are finally winning the war." The business weekly predicted that, for our children, cancer will be just another ho-hum disease, for which they will "pop a few pills every day." The New York Times announced "the long-awaited payoff from decades of research into the molecular biology of cancer. Unlike chemotherapy and radiation"the new agents are designed to kill cancer cells alone. In principle, they should eliminate malignancies more effectively while being far gentler on the patient."

An oncologist at the University of Arizona told reporters that in 20 years "he might just be out of a job." But it was Time magazine (May 28, 2001) that went over the top. Its cover read, "There is new ammunition in the war against cancer".Is this the breakthrough we've been waiting for?" The word "CANCER" was two inches high. This message of cure was carried to the farthest corners of the globe. An elderly relative of mine, who is not sure who is president of the United States, had heard about the cancer cure.

So, is the end in sight? To answer this, we need to examine Gleevec, the drug that triggered the hysteria. In May, Gleevec was approved by the FDA as a treatment for chronic myelogenous leukemia (CML). Time's sources call it "a magic pill"a miracle"a breakthrough." CML affects 4,500 Americans per year, about 0.3 percent of the 1.2 million new US cancer patients. The treatment is logical. Since 1960, it has been known that CML patients have a small "Philadelphia chromosome" that is not found in other people, including other cancer patients. This provides a unique molecular target for a new drug. However, this clear-cut target is lacking for most other cancers.

Surprisingly, Gleevec was not tested in randomized controlled trials (RCTs) before being approved by the FDA. In the results of a small test reported in the New England Journal of Medicine, Gleevec did restore normal blood counts in 53 out of 54 interferon-resistant CML patients (2001;344:1031-7). But whether or not Gleevec positively affects long-term survival is still not known. As Richard Klausner, MD, director of the National Cancer Institute, has correctly said, "It is still unclear for how long Gleevec will control CML. Nor is it known if the drug actually cures CML patients or delays the onset of more advanced forms of the cancer."

Another use for Gleevec might be in the treatment of gastrointestinal stromal tumor (GIST), which also affects about 5,000 Americans annually. With daily Gleevec treatment, for up to three months, there were partial responses in 54 percent of GIST patients. The disease stabilized in 34 percent of patients. However, these patients have only been studied for a few months.

Now that Gleevec has been approved, people with other kinds of cancer are demanding this "miracle drug." Prescribing Gleevec for other tumors may be "irresponsible," to quote researcher Allan van Oosterom, but try and stop patients from getting it! Not surprisingly, this "miracle" comes at a high price: Novartis is charging $2,400 per month, or almost $30,000 per year. And patients may need to continue taking it for life.

Is the tentative success of Gleevec the "proof of principle" that similar drugs will work in more common forms of cancers? I don't think so. Most of the other new drugs do not have such clear-cut molecular targets. In fact, for most anticancer drugs, the preliminary clinical evidence is not very encouraging.

Fate of Endostatin

It is instructive to look at Endostatin, a much-touted anti-angiogenesis treatment. Just three years ago, the New York Times touted Endostatin as a virtual cure of cancer. But at the 2001 ASCO meeting, scientists from M.D. Anderson Cancer Center reported the results of a phase I clinical trial. Of 22 patients, only one showed any evidence of anti-tumor activity; a second patient was celebrated just for remaining in the study for one year.

Time assembled ten other alleged miracle drugs. The list includes AstraZeneca's Iressa. At the company's website, Iressa is described as "exciting," "novel" and a "breakthrough." The drug "has shrunk tumors in phase I trials in patients who have failed multiple lines of chemotherapy," they say. And this is technically true, since there was a partial response in two patients, one with non-small cell lung cancer (NSCLC), the other with prostate cancer. The overall partial response rate was 1.5 percent (Proc ASCO 2000 #686). Undeterred, company spokespersons classify this as "encouraging anti-tumor activity in a selected range of tumor types." At this year's ASCO meeting, one small Japanese trial showed 5 out of 23 partial responses in lung cancer (ASCO 2001 #1292). Nor is Iressa entirely non-toxic: there were "skin changes" in 58%, diarrhea in 33%, nausea in 25% and vomiting in 22% of patients. Four patients had to withdraw because of toxicity.

Another drug on the top ten list is C225. This is a monoclonal antibody that binds to EGF receptors and inhibits the growth of cancer cells that express that receptor. Last September, its manufacturer, ImClone Systems, moved close to FDA approval. But how effective is C225? In February 2000, J. Baselga published three small studies on a total of 52 patients. There was just one tumor regression and even that single regression "was not sufficiently great to meet the definition of an objective response" (J Clin Oncol 2000;18:904-14). These facts somehow eluded Time's writers.

Finally, I smiled sadly when I saw Virulizin on Time's list. Virulizin is not the product of high-tech drug development. It is an immune-system modulator derived from cow bile. At the Cancer Advisory Panel meeting in May, executive of Lorus Therapeutics pleaded for help from the National Center for Complementary and Alternative Medicine (NCCAM). Since there has been a total lack of interest on the part of "Big Pharma" towards this natural product. They deserve some help, to be sure, but the results have been far from spectacular.

Other than Gleevec, then, I find no dramatic successes on Time's list. So what's all the shouting about? Think economics. The market for cancer therapeutics is big and growing bigger. According to Decision Resources, Inc., the market for breast cancer drugs alone will grow from $1.7 billion in 1999 to $4.3 billion by the year 2009. Similarly, the lung cancer drug market will grow from $870 million in 1999 to $2 billion in 2009. The "new breed" of high-tech drugs will grow to at least $6.4 billion.

Such huge profits provide a powerful incentive for drug companies to boost their products. Simultaneously, the media has an insatiable hunger for sensational medical news, and nothing beats the impending "cure for cancer" for its headline appeal. Finally, medical bureaucrats not only want to keep their jobs in the new administration but hope to expand funding for the National Institutes of Health. And so, with rare exceptions, caution is kicked to the winds, and the cure for cancer is declared"at least on paper. Too bad the drugs in question don't work a little better.

Against the Double Standard: A Reply to the ACS (Part 2)

At their website (www.cancer.org), the American Cancer Society tries to differentiate between what it calls "proven" treatments and those it classifies as "quackery." (Yes, the 'Q-word' has reared its ugly head again). They suggest that cancer therapies, in order to be considered proven, must be subjected to a series of rigorous tests. These range from cell line studies all the way up to randomized controlled trials (RCTs). This is a beautiful picture. But when we try to apply these idealized criteria to actual treatments, we find that most treatments have never been proven to be safe and effective for cancer patients.

Let us look at radiation therapy, which is administered to about half of all cancer patients. Is radiation tested according to a strict set of guidelines? Simply put, no. There are no government-sanctioned trials that must be concluded before a radiation treatment protocol becomes part of what ACS calls the "collection of proven therapies." Radiation therapy was "grandfathered" into acceptable practice by the FDA without ever undergoing adequate testing. Clinical trials of radiation therapy are done haphazardly, if at all.

Now, we needn't dispute that radiation therapy may shrink tumors, control the recurrence of tumors in irradiated areas, or relieve pain due to bone metastases or other symptoms. But do these effects increase survival of patients with cancer? To answer this question requires carefully designed and implemented randomized controlled trials (RCTs), with long-term follow-up.

But, in truth, most of the claims for the survival benefit of radiation therapy are not derived from RCTs, but from case series which are then retrospectively analyzed. These are not rigorous enough to form the basis of treatment decisions. The NCI-PDQ system properly states about case series: "These clinical experiences are the weakest form of study design." Yet for many forms of radiation treatment, case series are the only form of information available to us. In other cases, RCTs have been performed but show no survival advantage whatsoever. Let me give three recent examples:

Such examples could be multiplied for many types of cancer. Despite this, the ACS classifies radiation as a "proven" therapy. Proven to do what? Patients are often told that radiation either cures their cancer, helps surgery and chemotherapy to cure their cancer, or significantly extends lives. But this is generally not the case.

The ACS also includes radiation among the "safe" therapies. Yet for over 100 years ionizing radiation has been known to cause sickness and death. Radiation therapy may be accompanied by a panoply of both short- and long-term side effects. While the potential dangers of radiation therapy are discussed in the scientific record, this information is rarely made available to patients. (See the outstanding new textbook, Radiation Pathology, edited by Luis Filipe Fajardo, for details.) For example, for 60 years it was claimed that the heart was peculiarly "radioresistant" and that cardiac complications were rare and insignificant. It wasn't until the 1960s that this misperception was refuted. It then took another 30 years to show that patients whose hearts had been irradiated (such as many women with breast cancer) had an increased risk of coronary artery disease.

In conclusion, radiation oncology may be a "mainstream" treatment to the ACS, but is emphatically not a "proven" therapy in scientific terms. There is no proof that radiation therapy actually increases the longevity of the majority of patients who receive it. It is grossly unfair to turn a blind eye on the failings of conventional medicine but to demand the highest possible level of proof from alternative treatments, as ACS routinely does.