Trojan Family Magazine

“Since about 85 percent of lung cancer is linked to the patient’s own smoking, those with the disease are often dismissed as the guilty parties who knowingly puffed themselves sick.”

Illustration by Paul Anderson

Notoriously underfunded, notoriously underresearched, lung cancer has long been a neglected medical stepchild – despite being the global leader in cancer deaths. Researchers and clinicians at USC are breathing new life into the struggle against this invisible killer.

When Mark Blinoff was a kid, his dad would bring home sheets of asbestos to use all over the family house: to build a two-car garage, as paneling in the den, as insulation in the ceiling. The stuff was free, after all. Blinoff’s father worked for Johns Manville, a major manufacturer of the popular new material.

The 69-year-old elementary school teacher from Alhambra, Calif., wasn’t laughing last April, however, when he visited his doctor for what he thought was a common cold. He was promptly admitted to the hospital with a collapsed lung due to mesothelioma, a deadly and rare form of cancer linked to asbestos exposure.

“It was really scary, to go from thinking I was relatively healthy to having CT scans and surgery,” he recalls.

A local oncologist told him he had about a year to live. “It really put pressure on the whole family,” Blinoff recalls. “I have a wife, a 19-year-old son and a 13-year-old daughter. Everybody was crying all the time.”

At a postoperative visit, however, Blinoff’s surgeon, USC’s Ross Bremner, mentioned a clinical trial at the USC/Norris Comprehensive Cancer Center using new drugs targeting a family of proteins called vascular endothelial growth factors, or VEGF.

Cancer cells develop rapidly and need an ever-increasing blood supply. So tumors must encourage new blood vessels to develop around them – a process called angiogenesis. VEGF is critical to the formation of these new blood vessels. It also directly helps certain cancers grow. Turn off the VEGF and, in theory, the cancer starves.

Blinoff met with Barbara Gitlitz, head of the USC/ Norris Center’s lung cancer program. He qualified for a trial of the new drugs; after only two treatments, his tumor shrank by an astonishing 61 percent.

“I don’t know if it’s just my body or if I got lucky, but this is a miracle,” he says. “I feel so much better.” He has returned to gardening, swimming and, in September, to his third-grade classroom at Garfield Elementary. “Before, I was just hoping to see my daughter graduate high school,” he says. “Now I’m thinking I’ll be around to see her married and see my grandkids.”

Blinoff shudders when he thinks of what might have been. Had he been diagnosed with mesothelioma only a few years ago, “there wouldn’t have been much that anyone could have done,” he says.

The lapel ribbon for lung cancer is transparent – invisible, some people might say, because nobody seems to see the disease. Notoriously underfunded, notoriously underresearched, lung cancer has long been a neglected clinical and research stepchild, despite the fact that it is the worldwide leader in cancer deaths.

According to the American Lung Association, lung cancer causes an estimated 157,200 deaths in the United States annually and accounts for an astounding 28 percent of all cancer deaths. It’s the leading cause of cancer death in women. In fact, lung cancer causes more deaths than the next three most-common cancers – breast, prostate and colon – combined.

“If there were an airplane crash every day killing all the people aboard, you bet there would be a public outcry,” says lung cancer researcher Ite Laird-Offringa. “That many people die of lung cancer every single day in the United States. And it doesn’t seem to matter that they suffer from a craving for one of the most addictive substances known to humans.”

It matters to Laird-Offringa. She’s one of a team of cutting-edge researchers and clinicians at USC who are breathing new life into lung cancer diagnosis and treatment at the USC Norris Center.

Until recently, lung cancer earned little attention, in part because it doesn’t have a huge survivor base for advocates to tap into when fundraising, rousing public awareness or lobbying Congress. The five-year survival rate in lung cancer patients is a depressing 15 percent.

Partly, too, the sympathy factor for people with lung cancer just isn’t there. Since about 85 percent of lung cancer is linked to the patient’s own smoking, those with the disease are often dismissed as the guilty parties who knowingly puffed themselves sick.

Public perception aside, the lungs are simply hard to know. In a practical sense, they’re hard to reach, making the diseased organs hard to diagnose and hard to treat. As a result lung cancer is usually found only when it has progressed to a late stage – a bleak scenario for both patients and the clinicians who treat them.

Understanding the molecular biology of lung cancer – the “genetic events” that trigger the disease – is far behind that of cancer in other body organs, says pathologist Michael Koss of the Keck School of Medicine of USC. Why? Because “it’s clear that smoking is a major event in causing the disease,” Koss explains. “If you reduce smoking, you drastically reduce lung cancer rates. Once people get lung cancer, there’s not much that can be done. So everyone has followed the consensus that the best way to beat lung cancer is not to spend money on research, but to stop the behavior that leads to it.”

That perspective is changing, however, even in lung cancer pathology.

Maybe it’s the increasing numbers: Deaths due to lung cancer rose 58 percent between 1979 and 2000. Maybe it’s the fact that lung cancer remains a scientific frontier, attracting adventurous researchers drawn to under-investigated territory. Maybe it’s the realization that a new trend has emerged: a rise in adenocarcinomas and other types of lung cancer in people who have never smoked. Whatever the reason, lung cancer research is at last getting some attention.

“We’re finally making some interesting strides,” says Gitlitz, the USC oncologist. “We’re starting to see some large trials come to fruition. We’re beginning to develop drugs in more rational ways that are leading to improvements in quality of life and survival for people with lung cancer.”

Gitlitz oversees clinical trials of several new drugs. One promising candidate is a dendritic cell vaccine – used to beef up the number of dendritic cells circulating in the system. (Dendritic cells signal the immune system when a foreign body is present.) Mouse trials have shown some success in treating lung cancer when dendritic cells are “educated” about the tumor and boosted with immunotherapy agents.

Also under investigation are new drugs that interfere with signal transduction – that is, the movement of signals from the outside to the inside of the cell.

Belonging to this group is Iressa, the newest pharmaceutical approved for treatment of lung cancer. Another class of new drugs is angiogenesis inhibitors – agents that interfere with the formation of new blood vessels in a tumor. Those are the ones that saved Mark Blinoff’s life.

“We’re developing mechanisms for killing tumors beyond classical chemotherapy,” Gitlitz says. Developed over the last five years, these therapies have only come to mature clinical trials in the last few years.

Because the drugs are so new, their potential is still relatively unknown.

“The only application we have for Iressa is in the second- or third-line treatment of lung cancer,” Gitlitz says. “In those patients it has shown to improve quality of life, and in a minority of patients it sometimes leads to very nice responses. But I’m not sure we know fully how to use these drugs yet. That’s what continued research will help define.”

Gitlitz works with other USC researchers in imaging, pathology, surgery and bench research to bring the latest improvements directly to her patients. In those areas as well, lung cancer is benefiting from sophisticated improvements. For example, advances in positron emission tomography (PET) scanning in just the past four years “have changed the way we practice,” says Peter Conti, director of the USC PET Imaging Center.

In the past, it was extremely difficult to tell if some solitary nodules that showed up in lung X-rays were benign or malignant. The question required invasive procedures such as bronchoscopy – inserting a tube into the lungs for a biopsy while the patient is under sedation – or even surgery.

Today, using PET technology and an injected radioactive form of glucose, “you get better than 90 percent accuracy identifying nodules as malignant or not, and you avoid the need for invasive procedures,” says Conti.

“The radioactive drug acts like glucose, a sugar normally found in human tissue,” he explains.

“It turns out that most cancers like sugar. They use it as an energy source, while most normal organs do not – except for the brain and sometimes the heart. If the lesions are tumors, they pick up the injected drug and look ‘hot’ on the PET scan. They show up with positive signals, if you will, in the area of the cancer.” The procedure allows radiologists to identify tumors only a few millimeters in size.

PET scanning also is used to “stage” lung cancer – that is, to determine how far it has progressed.

“If you add PET to conventional CT-scanning, you can alter the staging in 30 to 40 percent of all patients, most being upstaged with more disease than originally thought,” Conti says.

In the past, nearly one in 10 patients brought to surgery were simply closed up again because the cancer proved too widespread to remove.

“It’s no longer acceptable to stage patients with limited workups and take them to surgery only to find inoperable disease,” Conti says. “With PET scanning we can eliminate many unnecessary invasive procedures.”

Even for those patients with widespread disease, improved surgical procedures and protocols are boosting survival rates. “The best chance to be cured of lung cancer is if it can be removed surgically,” says Keck School clinical surgeon Jeffrey Hagen. “Improvements in recent years have significantly increased the number of patients we can operate on.”

Most significantly, chemotherapy and radiation treatments before surgery are increasing the number of patients who can benefit from an operation.

“Sometimes because the tumor was too close to something near the lung, or because it had possibly invaded something near the lung, or maybe because it was just too widespread, patients were told they could not have surgery,” Hagen says. “Whereas in the past, patients with stage III-A lung cancer would not have been considered operable, routinely now they are given chemotherapy and radiation and that shrinks the tumors enough that we can operate.”

Hagen stresses that the multidisciplinary approach is extremely important in lung cancer surgery. “Some people evaluated elsewhere are still told they can’t be operated on,” he says. “But here, lo and behold, thanks to interactions with oncologists, we end up operating on them.”

Despite all the improvements in treatment, imaging and surgery, lung cancer still lacks what experts in the field consider the most important tool: some kind of diagnostic test that will help detect the disease in its earliest, most curable form. And a screen that can distinguish between different types of lung cancers to help clinicians choose the best treatment option.

Laird-Offringa is convinced that the answer is going to come from DNA methylation, a normal bodily function that plays a role in the regulation of genes. All cells have a full complement of genes, but the genes a liver cell needs to do its work vary wildly from those a brain cell needs. Methylation is one way cells lock genes they don’t need, so the ones they do need can kick in.

“Sometimes the system goes wrong. Methylation locks the genes that control cell growth, so the cells may grow unabated and become cancerous,” Laird-Offringa explains.

Finding methylation sites in genes linked to cancer is a daunting task, but researchers have some important clues. For example, the command for turning genes on and off is found at the front of the genes. This is exactly the part that can become methylated in cancer.

“So even though genes are hundreds of kilobases long, we can look at the beginning of the genes, at the methylation profiles, and see if we can distinguish between different types of cancer,” she says. “It’s like a red Post-It note at the beginning, letting us know which genes are locked.”

Laird-Offringa compared methylation profiles from lung adenocarcinoma, a common form of lung cancer, with profiles from mesothelioma, the rare asbestos-related cancer that struck Mark Blinoff.

“The study showed that it is possible to use methylation profiles to distinguish between different types of cancer,” Laird-Offringa says. “That’s a big step.”

The search now turns to how well the markers appear in easy-to-access fluids, such as sputum and even blood. It may be another five to 10 years before such diagnostic tests are available. Again, it comes down to money and attention – both of which have been in short supply.

“There’s still room for improvement in every aspect of lung cancer, from screening to surgical techniques to better treatments for metastatic cancer,” Gitlitz says. “There are still very important questions to be answered for treatments before or after surgery.”

Thankfully, she adds, researchers are attacking the disease from all sides.

“We aren’t yet at the same point as, say, breast or colon cancer, where there are genetic markers and more developed therapies,” Gitlitz says.

“But we need to be. Soon. Because this is a global killer.”

New research brings hope to patients like Cordelia S. Crane. The 70-year-old Rolling Hills Estates, Calif., woman was surprised last spring when a visit to the emergency room for pneumonia turned up evidence of pseudomesothelioma, a very rare form of cancer that appears in the pleura, the tissue surrounding the lungs. A non-smoker, Crane traveled to the Mayo Clinic in Rochester, Minn., to confirm the diagnosis.

“It was mind-boggling,” she recalls. “You get cancer just by having lungs.”

Although many doctors were discouraging about her prognosis, Crane came to USC/Norris because “a friend had been cured of her cancer there.” Gitlitz believed her cancer might respond to a new medication under investigation at the Norris.

It did. The thickening of Crane’s pleura has decreased dramatically, and she’s upbeat about the future.

“In my research I found that for every kind of cancer, there’s somebody who has been cured,” she says.

“I thought, ‘Well, that’s all I need to know.’ Certainly new research will help every one of us.”

Monika Guttman is a freelance medical writer. Her last article, “Cancer’s Crystal Ball,” appeared in the Summer 2002 issue.