Cancer: Hype vs. Hope

They're not cures, but new cancer treatments offer genuine progress

There is a basic disconnect in the complex arena of cancer research between the scientists fighting the battles and the public watching from the sidelines. Many scientists believe a turning point has been reached in the struggle against the disease. They point to a stream of promising data just issued from the world's largest cancer meeting, including strong responses achieved by Genentech (DNA ) Inc.'s Avastin and ImClone Systems (IMCLE ) Inc.'s Erbitux against colon cancer. The news came only weeks after two other novel treatments, Millennium Pharmaceuticals (MLNM ) Inc.'s Velcade and AstraZeneca (AZN ) PLC's Iressa, won Food & Drug Administration approval. All four drugs are at the vanguard of a new generation of targeted cancer therapies that take direct aim at tumor cells.

For the first time in years, cancer specialists are talking about new standards of treatment that are kinder, gentler, and more effective. The investment community is also excited, bidding up to new heights the stocks of biotech companies at the forefront of cancer drug development. The Standard & Poor's biotech index has climbed about 30% since the beginning of the year, breaking out of an 18-month slump on the strength of recent cancer developments. It would be easy to assume that a cure is near.

It's not. Half of the 1.3 million people diagnosed with cancer in the U.S. this year will die from their disease within five years, a mortality rate that has barely budged for the past decade. For all their promise, the newest drugs often work on no more than 10% of patients, and at best they merely hold the cancer at bay. To the public, this does not sound like a win.

Oncologists know this all too well. Consequently, the mood of cancer specialists attending the early June gathering in Chicago of the American Society of Clinical Oncology (ASCO), the premier showcase for new drug studies, was eerily subdued. "This meeting is one for the record books. We're seeing very exciting progress," says Dr. Leonard Saltz of Memorial Sloan-Kettering Cancer Center in New York, a leading colon cancer specialist. "But is it good enough? No. It stinks."

Yet the hunger for a silver bullet remains, and can make it hard for patients, and investors, to dispassionately assess new cancer treatments. It can also lead companies and researchers to overplay marginal results. When hyped drugs don't deliver blockbuster results, public confidence in both the science and the drug industry plummets.

Cancer specialists are trying to break that cycle with more realistic assessments, but the message doesn't always get through. "Remember, none of these drugs are curative. They are added tools," cautions Dr. Robert J. Mayer, director of the Center for Gastrointestinal Oncology at Dana-Farber Cancer Institute in Boston.

It is becoming clear, however, that the more tools available, the more options patients have, and the longer some of them will survive. That's the good news. Doctors know that tumor cells are among the craftiest of nature's creations -- they can figure out how to resist just about any treatment. But evidence is mounting that patients may be kept alive for years by following one drug with another, and then another, outwitting the cancer with an ever-changing arsenal of treatments.

Any silver bullet, in other words, will likely be a combination of drugs, not just one. Cancer specialists, more than most doctors, are willing to experiment with such combinations precisely because there are so few effective stand-alone treatments. "I believe we learn a lot more about a drug once it's on the market than before," says Dr. Michael A. Friedman, president of City of Hope Cancer Center in Los Angeles. This is particularly true of the new targeted therapies, because they are not tumor-specific. Almost of all them are being tested against a range of cancers.

Novartis (NVS ) Gleevec is a case in point. The FDA speedily approved the drug in 2001 based on its remarkable efficacy in controlling rare forms of blood and stomach cancer. Since then, researchers around the world have reported promising results with the drug against lung, breast, and prostate cancer. But as effective as Gleevec is, it has not beaten the resistance problem: It stops working in some 75% of patients who stay on it for more than two years. So Dana-Farber oncologist Dr. George D. Demetri is treating Gleevec-resistant patients with another experimental drug, Pfizer (PFE ) Inc.'s SU11248, with good results in 11 of 18 patients. "Each new drug gives us more clues about what targets we need to hit," says Demetri.

The search for those targets has been fraught with setbacks. Avastin and Erbitux, though the stars of the 2003 ASCO meeting, were among the biggest disappointments just one year earlier. In 2002, the two drugs washed out when tested against breast cancer and head and neck cancers, respectively. This year, Genentech and ImClone were far more successful in deploying their drugs against deadly colon cancer.

Avastin had the extra advantage of extending the lives of deathly ill patients, the gold standard of cancer trials. Most targeted therapies have a proven ability to shrink tumors, but rarely improve survival -- a contradiction that has mystified researchers. The Avastin results at least showed that longer life is possible. In Genentech's 800-person study, patients survived a median of 20.3 months when given Avastin plus chemotherapy, compared with 15.6 months for patients on chemo alone.

Five months is a long way from a cure, but in cancer it can be a very big deal. Patients who have advanced colon cancer rarely live more than a year; for the 56,700 U.S. patients who will die from the disease, five months would probably be welcome. Dr. Mace L. Rothenberg of Vanderbilt-Ingram Cancer Center in Nashville notes that two decades ago, few patients with colon cancer survived more than six months. "Now we are talking about a median survival of 20 months. I can't think of any other solid tumor cancer with that kind of improvement."

Erbitux may offer colon cancer patients yet another option. This is the drug at the center of the insider trading scandal that ensnared Martha Stewart after the FDA rejected ImClone's approval application in December, 2001. The agency did not like the design of ImClone's clinical trial and wanted more data on the condition of the patients. ImClone's then-chief executive, Samuel Waksal, is scheduled for sentencing on June 10 after pleading guilty to tipping off family members to sell their stock before the FDA rejection was made public.

The irony is, the clinical trial results presented at ASCO exactly match the findings rejected by the FDA. Germany's Merck (MRK ) KGaA (no relation to Merck & Co.) , which holds the rights to Erbitux in Europe, reported the drug significantly shrank tumors in 22.9% of advanced colon cancer patients when combined with chemo, and in 10.8% when used on its own. "As clinicians, we've felt a strong sense of frustration about this valuable agent," says Dr. David Cunningham of the Royal Marsden Hospital in London. "We would like to see it in the clinic as soon as possible."

Whether they will is up in the air. Unlike the Avastin trial, the 329-patient Merck trial did not achieve a survival benefit. Neither did AstraZeneca's Iressa, which targets the same cellular growth factor as Erbitux. That drug won FDA approval on the basis of shrinking tumors in 10% of lung cancer patients. Still, analysts are unsure whether the FDA will consider the Merck data, or insist on waiting for results of a Phase Three trial under way by ImClone and partner Bristol-Myers Squibb (BMY ) Co.

Most oncologists are eager to get their hands on the drug one way or the other. The buzz at the ASCO meeting was not whether Erbitux works, but whether it would work even better if combined with Avastin. Sloan-Kettering's Saltz says such combination trials are already in the planning stages.

That kind of experimentation is providing hope to patients like Steven A. Small of Anchorage. The father of three was given three months to live when he was diagnosed with liver cancer in December, 2001. Surgery and intense chemo gave him another year of life, but he had eight tumors in his liver by January, 2003. In March he enrolled in a clinical trial of Erbitux at City of Hope. For three months, Small has flown to Los Angeles once a week for an infusion. After six weeks his tumors shrank by 20%, and at 12 weeks his disease stabilized. "I never thought I'd see my 40th birthday, and on June 30, I'll see my 41st," says Small. "For the first time since I was diagnosed I'm making plans for the future." In cancer research, that counts as a breakthrough.

By Catherine Arnst in Chicago

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