By Cathy Dunn & Amy D’Orazio, PhD

Deborah Shaffer is playing a lot these days, enjoying her family, and riding horses on her farm in Cleveland, Texas, outside Houston. She’s just following doctor’s orders, she says. “The doctor told me in January to go home and play,” says Shaffer, who is 52.

For Shaffer it was good news. A smoker for 30 years, Shaffer was diagnosed with stage IV (metastatic) lung cancer in April 2002. She had brain surgery to remove a metastatic tumor, and in January 2003 tests showed that the tumors in her lungs were continuing to shrink after her six-month chemotherapy regimen of Paraplatin® (carboplatin) and Taxotere® (docetaxel) that ended in October 2002. Physicians would like to see success stories like Shaffer more often. Lung cancer is one of the most common cancers in the United States—and, by far, the most deadly. In fact, more people die from lung cancer than from colon, prostate, and breast cancer combined.

A Difficult Cancer
Nobody knows for sure why lung cancer is so difficult to treat effectively. But the answer may be inherent in the structure of lung cells, says Alex Adjei, MD, faculty member at the Mayo Clinic, Rochester, Minnesota.

“Because the lungs are important for breathing and are frequently exposed to unhealthy environmental elements, nature has made the cells lining the lungs extremely resistant to damage and death,” Dr. Adjei says. “When these cells become cancerous, their survival properties are magnified, making them very difficult to kill with chemotherapy.”

Complicating matters is the fact that the disease is often difficult to diagnose in its early stages. Although many people undergo high-resolution spiral CT to screen for lung cancer, so far, the U.S. Food and Drug Administration (FDA) has not approved a screening method for lung cancer.

Adding to the complexity are the numerous types of the disease. Even the most common type, non—small-cell lung cancer (NSCLC), is further divided into three categories: 1) squamous cell (similar to cells of the skin); 2) adenocarcinoma (a cancer of the mucous glands); and 3) large cell. A less common subtype of adenocarcinoma, called bronchoalveolar carcinoma, is seen more commonly in women and people who have never smoked. If that isn’t confusing enough, NSCLC is defined by stages using the International Staging System for Lung Cancer. The system classifies a tumor according to size (T), involvement of lymph nodes (N), and amount and location of cancer spread (metastasis) to other parts of the body (M). Different treatment options are prescribed for each stage.

Many people who have undiagnosed lung cancer don’t know anything is wrong; others experience symptoms—such as a nagging cough or hoarseness—that may be explained by other causes such as upper respiratory problems. By the time a diagnosis is made, the disease may have spread to other organs. In fact, about 85% of lung cancer cases are not identified until the later stages.

Finding the Good News
That’s the bad news. The good news is that lung cancer patients are beating the odds by working closely with their doctors, educating themselves about innovative treatments, and acting quickly to combat the disease. In some cases, that means undergoing traditional treatment such as surgery, radiation, or chemotherapy. In other cases, participation in a clinical trial testing a new medication may be a patient’s best chance for survival.

Doctors have an arsenal of chemotherapy drugs to treat lung cancer, with each stage and type responding differently to various drugs. For Shaffer the carboplatin/Taxotere combination worked.

Even as recently as the 1980s, doctors were unsure whether it was worthwhile to treat patients with advanced lung cancer with chemotherapy. However, after a series of clinical trials showed that chemotherapy with Platinol® (cisplatin) could prolong life and relieve symptoms, chemotherapy became more widely accepted.

Since that time several new agents have been developed (see sidebar, page 23). These include Taxol® (paclitaxel), Taxotere, Navelbine® (vinorelbine), Gemzar® (gemcitabine), and Camptosar® (irinotecan). With the exception of Camptosar, each has FDA approval for use in lung cancer patients. It has been found that these agents are most effective when combined as a “doublet” with cisplatin or carboplatin, a modified form of cisplatin that is better tolerated by most patients.

Shaffer found her treatment with carboplatin/Taxotere tolerable. “The first treatment I didn’t have any side effects, but the second one I was nauseated and had diarrhea,” she explains. “But it was manageable. I knew when I was being treated and planned for it.”

Analysis of numerous trials involving thousands of patients has shown that each of these agents alone leads to tumor shrinkage in about 20-25% of patients. When combined as a doublet with cisplatin or carboplatin, that figure increases to around 30%. The most well-known trial comparing these regimens was conducted by Eastern Cooperative Oncology Group (ECOG), which compared Gemzar/cisplatin, Taxol/carboplatin, and Taxotere/cisplatin to Taxol/cisplatin. The study found that each regimen was approximately equal in its ability to shrink the tumor and prolong time to relapse. An informal analysis of the ECOG trial and an additional 11 clinical trials that enrolled a total of almost 4,100 patients showed the same thing: Many of the regimens that combined Taxol, Taxotere, Navelbine, or Gemzar with either cisplatin or carboplatin had similar effectiveness.

Choosing a Treatment
How then do a physician and patient decide on a treatment plan? Corey Langer, MD, director of thoracic oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, says other health conditions such as diabetes or heart disease (called co-morbidities) may impact the decision as does overall health and fitness.

“For instance, in individuals with pre-existing peripheral nerve damage, we are loath to consider Taxol at conventional doses. By the same token, pre-existing kidney disease or hearing loss will preclude cisplatin,” Dr. Langer says.

Other side effects such as hair loss can also influence treatment choice. In the randomized trials mentioned above, 80% of those patients treated with Taxol/carboplatin experienced total or near-total hair loss. In comparison, only 10% of patients treated with Gemzar/cisplatin or Navelbine/cisplatin experienced significant hair loss. But Gemzar and Navelbine both require weekly clinic visits compared to Taxol and Taxotere, which only require a clinic visit every three weeks.

For patients who cannot tolerate one treatment, other options remain. Physicians continue to prefer the doublet that contains Taxol, Taxotere, Navelbine, or Gemzar with either cisplatin or carboplatin because the clinical trial data show effectiveness, but if treatment with cisplatin or carboplatin is not possible, regimens such as Taxol/gemcitabine or Taxotere/gemcitabine are effective and more tolerable than the platinum-based therapy.

The Older Patient
Age must also be taken into consideration when planning treatment.

Interestingly, although 58% of patients with lung cancer are over 70, the median age of the patients enrolled in most clinical trials is only 59. However, Dr. Langer says age alone is not a deterrent to treatment because elderly patients who are fit do as well or nearly as well as younger, fit patients.

Dr. Langer distinguishes between patients in their 70s who appear to tolerate chemotherapy reasonably well and those over 80 because, he says, the data are “extraordinarily sparse” on patients over 80.

“The little data that exist suggests that they do considerably worse. We must also respect the potential for increased toxicity in older individuals, although we need to acknowledge that the fit elderly do as well as younger individuals from a therapeutic standpoint.”

The elderly may also be restricted by the availability of caregivers, financial concerns, or by reluctance to pursue more aggressive treatment. And physicians who believe treatment will not be as successful in the elderly patient might treat less aggressively.

Yet, growing evidence shows there are feasible and successful treatment options for the elderly patient. A large Italian study compared chemotherapy with Navelbine to supportive care without chemotherapy in elderly lung cancer patients and determined that survival was prolonged in those who received chemotherapy.

A second trial conducted in Tennessee showed that Taxotere was able to induce tumor shrinkage in 26% of lung cancer patients who were elderly and had medical conditions that would have otherwise precluded treatment. This rate is approximately equal to that seen in other Taxotere trials in younger lung cancer patients.

Lastly, a large clinical trial recently compared chemotherapy with the combination of Gemzar and Navelbine to either Gemzar or Navelbine alone. Administration of two agents is the prevailing preference among lung cancer patients as a whole, but in this group of patients over age 70, Gemzar or Navelbine as single agents worked as well and had fewer side effects than the doublet.

Dr. Langer says the key to making treatment choices is fitness and potential for physical vulnerability. “Frail patients are best served by single agents; the fit can tolerate combination regimens.”

Since no one treatment regimen is suitable for every lung cancer patient, the patient and physician must consider medical history, overall health, age, and lifestyle.

Hope for Breaking the Plateau

The combination of Taxol/carboplatin is one of the most widely used regimens in the United States for patients with newly diagnosed advanced lung cancer, but many other drugs appear to have equal effectiveness for these patients. Frustrated, many physicians have termed this the “therapeutic plateau,” because although significant progress has been made, they’d like to see even greater strides.

Many physicians and patients are banking on a new class of therapeutics known as targeted therapies to break the plateau and take lung cancer treatment one step further. Among the most promising of these new agents are Iressa™ (gefitinib), Tarceva™ (erlotinib), Erbitux™ (cetuximab or C225), ABX-EGF, and Avastin™ (bevacizumab). It is hoped that these agents can either improve the effectiveness of chemotherapy or help patients for whom chemotherapy has failed.

When Gary Lougher was a teenager, he decided not to start smoking because he didn’t want to risk developing lung cancer. He stayed true to that decision throughout his 24-year stint in the U.S. Navy. Ultimately, though, the career he loved brought on the disease he dreaded.

“As a Navy electronics technician during the 1970s, I was frequently exposed to nuclear radiation, asbestos, and a variety of chemicals,” says the 48-year-old from Chesapeake, Virginia, who has bronchoalveolar carcinoma, a rare form of lung cancer. “The Navy has determined that my particular kind of cancer has been linked specifically to nuclear radiation exposure.”

Once known as a disease plaguing only those who smoke, lung cancer is increasingly affecting nonsmokers as well. Bronchoalveolar carcinoma in particular is unique because 30% of patients affected with this subtype of lung cancer have never smoked. Other carcinogens, such as secondhand smoke, radon, and asbestos, play a role in the development of lung tumors.

When Lougher was diagnosed in 1998, his cancer had already spread to surrounding lymph nodes, causing severe chest pain. He had surgery to remove part of his lung, underwent radiation therapy, and was treated with three different chemotherapies. But nothing seemed to slow the disease.

“I had terrible side effects, including complete hair loss, severe diarrhea to the point of dehydration, and extreme weakness,” Lougher explains. “I had reached the point where I couldn’t even shower without my oxygen tank nearby. I thought I had about three months to live, so I called my family and asked them to visit me one last time.”

That’s when Lougher heard about a new drug called Iressa (see sidebar) from an online lung cancer support group. He decided to try it.

“I started taking Iressa in April 2001, and I saw miraculous effects overnight,” he says. “I literally skipped into the kitchen the next morning, amazing my family. I am very thankful for every extra day I’ve been given to spend with my family and friends. Taking Iressa has made that possible for me.”

New Hope With Targeted Therapies
Iressa is taken in pill form and is the first drug available in the United States from a new class of anticancer drugs called selective epidermal growth factor receptor (EGFR) inhibitors, which target signaling pathways necessary to the growth and survival of cancer cells. By blocking these pathways, Iressa helps stop tumor growth. In phase II trials, Iressa reduced disease-related symptoms with relatively minor side effects in patients with NSCLC who had progressed after previous treatment.

“NSCLC accounts for up to 80% of lung cancer cases, so finding an effective treatment is of utmost importance,” says Roy Herbst, MD, PhD, chief of the section of thoracic medical oncology, M. D. Anderson Cancer Center, Houston.
“In U.S. clinical trials, Iressa seems to have improved the quality of life for many patients. About 10% of the participants have experienced tumor shrinkage of 50% or more in large phase II studies with previously treated patients,” he adds.

Dr. Herbst says Iressa is still effective as a single agent, and further studies will be needed to find other combinations that will enhance that effectiveness.
Tarceva is another EGFR inhibitor that is undergoing clinical trials in lung cancer. Three large trials of Tarceva, either by itself or in combination with chemotherapy, have completed accrual. Results should be available later this year.

Chandra Belani, MD, co-director of the Lung and Thoracic Program at the University of Pittsburgh Cancer Institute, is involved in clinical testing of ABX-EGF, another drug that, like Iressa, targets EGFRs. ABX-EGF, a fully human monoclonal antibody, is given by infusion.

“ABX-EGF is well tolerated and produced relatively mild side effects such as rash and diarrhea in phase I trials,” says Dr. Belani. “We’re now moving forward with phase II trials, testing ABX-EGF in combination with standard chemotherapy. Although we don’t have all of the data yet, we’re optimistic about this drug’s impact on lung cancer treatment.”

Targretin® (bexarotene) is another novel agent being evaluated in combination with chemotherapy for lung cancer patients. In the United States, Targretin plus Taxol/carboplatin is under evaluation. Targretin, an oral agent that was first evaluated in lymphoma patients, showed some activity in lung cancer patients in phase I trials, leading to both the U.S. trial and one in Europe evaluating Targretin with Navelbine/cisplatin.

Avastin, another monoclonal antibody playing a significant role in novel lung cancer therapies, is known as an anti-VEGF because it has the potential to block vascular endothelial cell growth factors, one of the key proteins providing blood supply and nutrients to cancer cells, thereby stimulating tumor growth. In late June 2003, Avastin was given fast-track designation from the FDA for treatment of advanced colon cancer.

Side effects from the infusions tend to be mild, although earlier trials showed bleeding and blood clots as risk factors.

“Avastin isn’t a cure,” says Alan Sandler, MD, medical director of thoracic oncology, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee. “But it may one day help us control lung cancer to the point where it becomes more of a chronic disease. Then we can concentrate on controlling problem symptoms while we continue to search for a cure.”

Dr. Sandler says this is where clinical trials play a crucial role because they often provide better care with more individual attention from some of the best doctors, nurses, and technicians in the profession.

“Patients sometimes tell me they want to participate in clinical trials to help save the lives of those who will have the disease in the future,” Dr. Sandler remarks.

“That’s a very noble thing to do, but I tell them to get involved to help themselves first. I encourage them to be selfish for a very simple reason: I want them to get better.”

Editor’s note: Gary Lougher passed away Feb. 10, 2003. CURE is proud to honor his memory.