Between Life and Breath

by Monika Guttman

“If there were an airplane crash every day, killing all the people aboard, you bet there would be a public outcry,” argues Ite Laird-Offringa, Ph.D., assistant professor of surgery and biochemistry at the Keck School of Medicine of USC and a lung cancer researcher. “That many people die every day of lung cancer, and it doesn’t seem to matter that they suffer from a craving for one of the most addictive substances known to humans.”

What is even more distressing is that lung cancer has earned little attention in part because it does not have the huge survivor base other cancers use to rouse public awareness by conducting interviews or lobbying Congress. The five-year survival rate for lung cancer is a mere 15 percent. Partly, too, the sympathy factor for people with lung cancer just is not there. Since some 85 percent of lung cancer is linked to smoking, lung cancer patients are often dismissed as the guilty party who knowingly puffed themselves into their disease.

In a practical sense, too, the lungs are simply hard to know—they are hard to get to, reducing the ability to diagnose the disease and access it when it appears. So lung cancer is usually found only when it has progressed to late-stage disease—a bleak scenario for the patients and the clinicians who treat them. Until now.

Maybe it is the increasing numbers: Deaths due to lung cancer increased 58 percent between 1979 and 2000. Maybe it is the fact that lung cancer remains a scientific frontier, so it appeals to researchers who are drawn to under-investigated territory. Maybe it is 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 in lung cancer,” concedes Barbara Gitlitz, M.D., associate professor of oncology and head of the lung cancer program at USC/Norris Comprehensive Cancer Center. “We’re starting to see some interesting 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.”

As a clinician, Gitlitz oversees clinical trials of several new drugs for treating lung cancer. One interest is a dendritic cell vaccine—a vaccine that increases the number of dendritic cells (special cells that signal the immune system when a foreign body is present) circulating in the system. Mouse trials show some success in treating lung cancer when dendritic cells are “educated” about the lung cancer and boosted with immunotherapy agents.

Other types of treatments under investigation, Gitlitz says, include drugs that interfere with signal transduction—the movement of signals from the outside to the inside of the cell, which can alter cellular function. Those include Iressa, the newest drug approved for lung cancer. Other new drugs include angiogenesis inhibitors—drugs that interfere with the formation of new blood vessels in a tumor.

“We’re developing mechanisms for killing tumors beyond the cytotoxic agents that are classical chemotherapy agents,” she says. “These drugs have been in development over the last five years and have come to mature clinical trials only in the last few years.”

Because the drugs are so new, however, their potential is still relatively unknown, Gitlitz says. “The only application we have for Iressa is in the second- or third-line treatment of lung cancer. 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, and that’s what continued research will help define.”

Gitlitz works with other 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 PET (positron emission tomography) scanning in just the past four years “have changed the way we practice,” notes Peter Conti, M.D., Ph.D., 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 (non-cancerous) 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, says Conti, 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.”

As Conti explains, “The radioactive drug acts like glucose, a sugar normally found in human tissue. 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—to determine how far it has progressed. “It turns out if you add PET to conventional CT-scan staging, you can alter the staging in 30 to 40 percent of all patients with most being upstaged with more disease than originally thought,” he says.

In the past, almost one in 10 patients brought to the operating table and opened were simply closed up again because the cancer was 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.”

However, 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,” notes Jeffrey Hagen, M.D., associate professor of surgery. “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 have surgery. “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,” he says. “Whereas in the past, patients with Stage IIIA 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 stages and that can distinguish between different types of lung cancer to aid clinicians as they choose treatment options.

Laird-Offringa is convinced that the answer is going to come from DNA methylation, which plays a role in the regulation of genes. She explains that 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 to work. Methylation is one way cells lock genes that they do not need, so that the ones they do need can work. “Sometimes the system goes wrong,” Laird-Offringa says. “Methylation locks the genes that control cell growth, so the cells may grow unabated and become cancerous.”

Finding methylation sites in genes linked to cancer is a daunting task, but Laird-Offringa says there are important clues. “What makes methylation a really neat target as a marker is that the methylation that locks the genes responsible for cell growth is found at the front of the genes. 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. 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, a rare but aggressive cancer of the sac lining the chest, which is most often associated with asbestos exposure. “The study showed that it is possible to use methylation profiles to distinguish between different types of cancer,” she 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.

Laird-Offringa notes it may be another five to 10 years before such diagnostic tests are available. Again, she says, it comes back to money and attention—both of which have been in short supply for one of the biggest cancer killers worldwide.

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

minimal consideration

Nothing sounds more attractive to a patient facing surgery than the promise of a “minimally invasive” procedure: Less postoperative discomfort, quicker recovery time, shorter hospital stay, earlier return to full activities, and smaller scars, both inside and out.

Minimally invasive surgical procedures are conducted with the help of a video camera and several thin instruments placed through ports—small incisions in the patient’s abdomen that allow visual and physical access to the inside of the patient. Unlike traditional open surgeries that require long incisions—but allow the surgeon to see and touch the inside of the patient—minimally invasive procedures mean that the surgeon uses the images from a video camera positioned inside the patient’s body to operate. The video camera becomes the surgeon’s eyes and the instruments become extensions of the hands.

For lung cancer patients facing surgery, the option sounds particularly wonderful, because the traditional thoracotomy (the incision for a lung surgery) involves a six-to-eight-inch cut through chest wall muscles that extends to under the arm. The ribs are spread to accommodate access to the lungs as well. The surgery is known for producing significant postoperative pain and requiring a long recovery time.

To cardiothoracic surgeons such as Jeffrey Hagen, M.D., however, while the minimally invasive technique works well in many surgeries, he does not recommend it for patients with lung cancer. The reason: “When operating for cancer, the principal goal has to be removal of all of the cancer,” he says. “For larger tumors, the frequency of lymph node involvement increases, so the debate is whether complete lymph node dissection is as good with minimally invasive techniques.”

Hagen admits this is an issue of fierce debate in the cardiothoracic surgery community, where minimally invasive procedures have been used to remove lung cancer since the early 1990s. “The studies do not show significant difference in long-term pain or in recovery time between traditional and minimally invasive surgeries,” he says. “I’d hate to think you miss some of the cancer to avoid short-term discomfort.”

He does note, however, that the techniques learned from minimally invasive surgery have changed the way surgeons perform traditional lung cancer surgery—for the better.

“Minimally invasive procedures have forced us to think about ways to do traditional operations that are less debilitating,” he says. “In the standard operations, incisions are smaller than they were 15 years ago, and we cut through less muscle. We use newer, gentler ways to retract the ribs. It is definitely easier on the patient.”

In addition, he notes, “We are better at handling postoperative pain than a decade ago, because we now use preemptive analgesia so that the early discomfort is nowhere near what it used to be.”

Hagen does not rule out the possibility that, at some point in the future, minimally invasive procedures may become the standard even for lung cancer surgery. He notes that there is a lot of research on minimally invasive procedures and technologies, and points out that the Keck School of Medicine pioneered the use of minimally invasive techniques to correct thoracic and esophageal disorders.

In addition, he says, minimally invasive thoracoscopic techniques allow evaluation and treatment of a variety of other pulmonary and pleural disorders.

“I really am a big believer in minimally invasive techniques,” he says. “In terms of lung cancer surgery, we’re not there yet, but we continue to make progress.” Nothing sounds more attractive to a patient facing surgery than the promise of a “minimally invasive” procedure: Less postoperative discomfort, quicker recovery time, shorter hospital stay, earlier return to full activities, and smaller scars, both inside and out.

Minimally invasive surgical procedures are conducted with the help of a video camera and several thin instruments placed through ports—small incisions in the patient’s abdomen that allow visual and physical access to the inside of the patient. Unlike traditional open surgeries that require long incisions—but allow the surgeon to see and touch the inside of the patient—minimally invasive procedures mean that the surgeon uses the images from a video camera positioned inside the patient’s body to operate. The video camera becomes the surgeon’s eyes and the instruments become extensions of the hands.

For lung cancer patients facing surgery, the option sounds particularly wonderful, because the traditional thoracotomy (the incision for a lung surgery) involves a six-to-eight-inch cut through chest wall muscles that extends to under the arm. The ribs are spread to accommodate access to the lungs as well. The surgery is known for producing significant postoperative pain and requiring a long recovery time.

To cardiothoracic surgeons such as Jeffrey Hagen, M.D., however, while the minimally invasive technique works well in many surgeries, he does not recommend it for patients with lung cancer. The reason: “When operating for cancer, the principal goal has to be removal of all of the cancer,” he says. “For larger tumors, the frequency of lymph node involvement increases, so the debate is whether complete lymph node dissection is as good with minimally invasive techniques.”

Hagen admits this is an issue of fierce debate in the cardiothoracic surgery community, where minimally invasive procedures have been used to remove lung cancer since the early 1990s. “The studies do not show significant difference in long-term pain or in recovery time between traditional and minimally invasive surgeries,” he says. “I’d hate to think you miss some of the cancer to avoid short-term discomfort.”

He does note, however, that the techniques learned from minimally invasive surgery have changed the way surgeons perform traditional lung cancer surgery—for the better.

“Minimally invasive procedures have forced us to think about ways to do traditional operations that are less debilitating,” he says. “In the standard operations, incisions are smaller than they were 15 years ago, and we cut through less muscle. We use newer, gentler ways to retract the ribs. It is definitely easier on the patient.”

In addition, he notes, “We are better at handling postoperative pain than a decade ago, because we now use preemptive analgesia so that the early discomfort is nowhere near what it used to be.”

Hagen does not rule out the possibility that, at some point in the future, minimally invasive procedures may become the standard even for lung cancer surgery. He notes that there is a lot of research on minimally invasive procedures and technologies, and points out that the Keck School of Medicine pioneered the use of minimally invasive techniques to correct thoracic and esophageal disorders.

In addition, he says, minimally invasive thoracoscopic techniques allow evaluation and treatment of a variety of other pulmonary and pleural disorders.

“I really am a big believer in minimally invasive techniques,” he says. “In terms of lung cancer surgery, we’re not there yet, but we continue to make progress.”