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
Issue: Winter 2004
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.
By Monika Guttman
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.
“We were the asbestos family,” Blinoff jokes.
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.
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
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.
||Physician Barbara Gitlitz examines patient Mark Blinoff, who suffers from a cancer linked to asbestos exposure.
Photo by Michele A.H. Smith
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.”
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
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
||PET Imaging Center director Peter Conti
Photo by Michele A.H. Smith
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
“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
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
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
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,”
“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
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
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
Most significantly, chemotherapy and radiation treatments before
surgery are increasing the number of patients who can benefit from an
“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
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
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
“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.