Facing the Challenge: When Cancer Recurs

By Heather Lindsey

Gloria Caruso, a nonsmoker, underwent surgery in 1998 to remove a cancerous tumor about the size of a large pea from her right lung. Area lymph nodes were also removed and found to be cancerous, so she began chemotherapy. Despite these treatments, follow-up imaging tests later showed the cancer had recurred as a walnut-sized tumor in her neck and had spread to surrounding lymph nodes.

"There wasn’t much they could do at that point,” says the 63-year-old from Tampa, Florida. However, she began to research clinical trials online.

In February 2001, Caruso began Iressa® (ZD1839), a drug taken as a once-daily oral pill that specifically targets and inhibits the production of cancer cells while sparing healthy tissue.

“I found that most people who had surgery and chemo were not good candidates for clinical trials, until I found Iressa,” she says. An expanded access program allowed her to take the drug through the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida, even though she had undergone prior therapies.

For Caruso, Iressa worked. Her first scan in May 2001 showed that her tumors had shrunk by approximately 90%. She continues to take the drug, and further scans have shown that the drug is still working.

“Iressa was a like a last-ditch hope for me and was wonderfully effective,” says Caruso. “I treat the cancer like a chronic illness, like diabetes. It’s not a cure because if I stopped taking the medication, the tumors will come back.”

For Caruso, Iressa has successfully interrupted cell growth—in this case, cancer cell growth. Healthy cell growth is both promoted and inhibited by molecules or “factors” that are balanced to help cells grow in a controlled manner, maintaining normal organ and tissue function. When these factors get out of balance, they can lead to uncontrolled cell growth and cancer.

Unlike chemotherapy, which affects all fast-growing cells, Iressa is one of the new “targeted” drugs that aim specifically at the tumor cell. Like other targeted therapies, Iressa might not always shrink tumors, but it can often help keep them from growing.

Each cell has multiple growth factors that look for their corresponding receptors on the cell surface. Coming together, the matching of factor to receptor leads to a chemical reaction that produces a cascade of effects that result in cell growth. Interrupting this “connection” can mean stopping the tumor growth cold.

The two “factors” that researchers focused on when developing Iressa were epidermal growth factor (EGF), a protein that promotes cell growth, and epidermal growth factor receptor (EGFR), which sits on the surface of cells.
Too much EGF has been identified with runaway cell growth, resulting in a variety of cancers including colorectal, head and neck, ovarian, prostate, breast, and lung.

“You need to block the receptor,” explains Chandra P. Belani, MD, professor of medicine and co-director of the lung and thoracic program at the University of Pittsburgh Cancer Institute in Pittsburgh, Pennsylvania. “If it’s stimulated, you keep generating growth of cancer cells.”

The message to overproduce can come from either the EGF protein or the activation of the EGFR. Too many receptors occur in about 70% of all lung cancer, making lung cancer a natural focus for drug development.

When EGF binds to EGFR, it triggers a chemical signaling process that encourages growth and division. Iressa interrupts this internal process to stop the production of the chemical that gives the go-ahead for cell division.

Growing Excitement for a New Approach
“Giving selective and targeted therapies may be the wave of the future or even the wave of the present,” says Dr. Belani, who is conducting clinical trials with Iressa. Traditional treatments such as chemotherapy simply aren’t enough anymore, he adds.

Roy Herbst, MD, chief of the section of thoracic medical oncology at M. D. Anderson Cancer Center in Houston, Texas, calls Iressa the “most promising therapy for lung cancer in the past decade.” Dr. Herbst is administering the drug in clinical trials to patients with non–small-cell lung cancer (NSCLC), which accounts for about 75-80% of all lung cancer cases.

Dr. Belani says he sees EGFR blockers as having great potential in the management of lung cancer, adding that Iressa has been successful in patients who have received standard chemotherapy unsuccessfully, making researchers question whether Iressa should be used as a first-line therapy.

Iressa and Clinical Trials: When Will We Know?
Iressa is the furthest along in clinical trials of all the drugs in its class and was submitted to the Food and Drug Administration for fast-track approval at the end of last year.

Trials of Iressa presented at the May 2002 meeting of the American Society of Clinical Oncology (ASCO) reported that between 25 and 50% of patients had tumors that either reduced in size or did not grow any bigger. These patients had advanced NSCLC, which had progressed following other treatments.

Dr. Herbst and his colleagues observed 10-15% of patients having at least a 50% shrinkage of the tumor in his clinical trial. These people had previously been treated for lung cancer and are now taking Iressa daily by mouth as a single agent. Overall, the drug is safe and well tolerated, he notes. However, patients may experience diarrhea and acne.

The drug is also in phase III clinical trials in patients with NSCLC used in combination with standard chemo-therapy. More than 2,000 patients at 477 trial centers around the world have been enrolled. Two global multicenter trials are currently under way that test Iressa as a single agent in patients with NSCLC whose disease has progressed following standard chemotherapy. Results from these trials should be available later this year.

Researchers are also investigating the potential of Iressa to prevent lung cancer in people at high risk of developing the disease, says Dr. Belani.

Tarceva™
Scientists are investigating several new drugs like Iressa that target lung cancer at the molecular level. Tarceva (erlotinib, OSI-774), another medicine that is given as a pill by mouth like Iressa, inhibits the chemical response within the EGFR that results in cell growth.

“The drug interrupts this pathway in tumors and can delay tumor growth and decrease tumor size,” says Philip D. Bonomi, MD, director of the section of medical oncology at Rush Medical College in Chicago, Illinois.

A phase II study of 57 patients with advanced, chemotherapy-resistant NSCLC at New York University School of Medicine’s Kaplan Comprehensive Cancer Center resulted in 2% of patients experiencing a total disappearance of all visible tumor (complete response), while 12% of patients had at least 50% tumor shrinkage (partial response) and 26% of patients experienced disease stabilization for three or more months.

At Rush Medical Center, three of 16 patients experienced tumor shrinkage with Tarceva. One person had lung cancer that had spread to the lymph nodes, another had lung tumors that had spread to the liver, and the last patient had lung cancer with kidney metastases. These patients had shown disease progression after or during multiple courses of chemotherapy and received Tarceva by mouth as a single agent.

Phase III trials, the last study stage before a drug becomes available, in the United States and Europe are looking at chemotherapy plus or minus Tarceva in stage IV NSCLC. Tarceva is also an attractive agent to study in locally advanced disease and in patients whose lung cancer has been surgically removed (adjuvant setting), notes Dr. Bonomi. In combination with chemotherapy, the drug may have the potential to improve earlier-stage lung cancer, he adds. Tarceva also has the potential to be used as a chemopreventive agent in people who are at high risk of developing lung cancer, he says.

Tarceva has also shown activity in head and neck and ovarian cancers, says Dr. Bonomi.

Monoclonal Antibodies
Unlike Iressa, which attaches to the inside of the cell, Erbitux™ (cetuximab, IMC-C225) acts directly on the cell’s surface, says Jennifer Tseng, MD, department of medical oncology and hematology at the M. D. Anderson Cancer Center in Orlando, Florida.

Erbitux is a monoclonal antibody, an antibody made in a laboratory to target a specific molecule. In the case of Erbitux, the antibody seeks out EGFR and binds to its cell surface, meaning it no longer will allow binding with EGF. The process is a bit like sticking gum in a lock, with Erbitux being the gum and the EGF receptor being the keyhole.

Unlike Iressa and Tarceva, monoclonal antibodies need to be given intravenously. Erbitux tends to cause less diarrhea in patients than Tarceva and Iressa, notes Dr. Belani. All three drugs can cause significant rash in patients. Clinical trials with Erbitux in combination with chemotherapy drugs have begun.

It is clear that cancer research is ushering in a new era in lung cancer treatment. Iressa, Tarceva, and other targeted agents should give new hope to patients with not only advanced but also early-stage lung cancer.