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.
