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The Face of Lung Cancer Changes, but New Drugs Show Promise

By Mignon Fogarty

Heather Wakelee, MD
Heather Wakelee, MD


When Christopher Reeve's wife, Dana Reeve, recently died from lung cancer, many people were shocked.  Wasn't it unheard of for a woman under 50, who had never smoked, to die from lung cancer? 

For Stanford's Dr. Heather Wakelee, however, such stories aren't so remarkable. Her recent publications -- the results of years of work -- show that more women are being treated for lung cancer than ever before. In addition, she says, “A significant proportion of lung cancer occurs in people who have never smoked.”

Although Wakelee, an assistant professor of medical oncology, considers her primary research focus to be developing new drugs for lung cancer, she found that her trials could benefit from epidemiological research, such as investigating differing outcomes between men and women. “It's very important to understand the characteristics of the people we are treating and how that has an impact on the outcome of trials,” she says.

Lung Cancer Rates are Increasing in Nonsmoking Women

In a  recent study for example, Wakelee's group found that between 1990 and 2000, more women were being treated for lung cancer than during the previous decade — possibly because genetic differences may increase women’s susceptibility to cancer-causing carcinogens found in tobacco smoke, although the nature of these differences remains controversial within the scientific community.  Yet, the study also found that, on average, lung cancer patients with advanced stage disease were surviving longer than before, particularly women, who tended to enjoy a two-month survival advantage over male patients.

Female Lung Cancer Patients Survive Longer

Although this two-month benefit might not sound like a lot, for lung cancer it is considered significant, matching the effects of such popular cancer medications as Tarceva.  However, because the survival benefit for women is the same as that seen with such drugs, it may also confound trial results: a drug tested in a trial that includes large numbers of women could appear to be providing a survival benefit when it does not.  Wakelee suggests that the survival effect in women may result from the same genetic differences that may make women more vulnerable to cancer in the first place.

These genetic differences are postulated to make women's cells less efficient at repairing DNA damage, which, although increasing the likelihood of contracting cancer, may allow treatment to destroy cancerous cells more easily.  For instance, the common cancer drug cisplatin kills rapidly dividing cells by attacking their DNA, and the body's DNA repair mechanisms attempt to repair the cells, whether they are cancerous or not. If a woman's body is less efficient at DNA repair than a man's, then her cancer cells may be more likely to die as a result of cisplatin damage.

New Drugs Target Cancer Cells

Although Wakelee finds the epidemiological results interesting, and useful for gaging the effectiveness of her early-stage clinical trials, her real passion lies with testing new treatments.  Although chemotherapy has recently gained popularity as a first-line treatment following surgery, improving patients’ chances of survival by 10 to 15 percent, Wakelee sees the possibility of supplementing it with drugs that take a more targeted approach to fighting cancer and that could improve outcomes.

For example, Wakelee has worked extensively with angiogenesis inhibitors: drugs that cut off a tumor's blood supply by blocking the messages that cancer cells often send out to attract new blood vessels.

Avastin and XL647 for Lung Cancer Patients with Brain Metastases

One such angiogenesis inhibitor is Avastin, which is already available to colon cancer patients. Wakelee explains that although a large trial recently showed that Avastin was useful for lung cancer patients, the trial parameters were so strict that they didn't test the drugs in large groups of patients, for example leaving out patients with early stage tumors that have been removed by surgery.  Dr. Wakelee will be leading a large international trial looking at the use of Avastin for these patients. 

In addition, one of her new Stanford-specific trials aims to look at an even sicker population of patients, those with brain metastases. “I have a trial open now for patients with brain metastases that have been treated with either surgery or radiation (or both) and am looking to see if the drug is safe in that population,” she says. Although she believes the drug will be safe, she notes that it is important to carry out a phase II study to see what happens when Avastin is combined with the other standard drug that these patients receive, pemetrexed, commonly known as Alimta. “It's a very carefully controlled study looking at safety endpoints,” she says.

Another anti-angiogeneic drug undergoing trials is XL647, which not only binds and interacts with the vascular endothelial growth factor (VEGF) receptor involved in angiogenesis, but also the epidermal growth factor receptor -- a receptor that is also a target for the cancer drugs Tarceva and Iressa.  Ray Williamson of Richmond, a participant in XL647 trials, has found the experimental treatments much more tolerable than the radiation therapy he previously underwent for his lung cancer. 

For example, radiation therapy affected his taste buds, but he has found XL647's side effects minor, and is optimistic about the treatments Wakelee and others are developing.  “It seems to be working pretty good so far,” he says.

Additional Early Stage Trials for Lung Cancer

Wakelee is also involved in a number of other cancer drug studies. For example, she is  testing lexitumumab, an antibody that triggers self-destruction in cells, examining its effects in conjunction with various chemotherapy drugs. (Stanford is one of only three facilities in the United States testing the drug.) Wakelee is also conducting trials in small-cell lung cancer with SNS595, a new chemotherapy drug.

She says that the explosion of new drugs available for testing is the result of hard work and basic research that has helped scientists understand the biology of cancer and choose more precise drug targets. With these new tools at hand, her outlook is hopeful. She says, “We're really entering this world of targeted therapy, and we've been seeing slow but study increases in survival time. Avastin added a  couple of months and Tarceva added a couple of months, but those are just averages, so for some patients that can mean a year or two difference in survival.”

The trials mentioned in this article are actively recruiting as of publication, and prospective participants can contact the patient coordinator at 650-736-4112.

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