25 Years in Lung Cancer: An Arduous Fight

Jan. 3, 2009— -- "For those of us with cancer, the fear of death lingers coyly. ... It creeps up at the oddest moments, like when it was time to renew my passport and I realized I could expire before the document does."

Those words -- written by Newsday reporter Lauren Terrazzano shortly before she lost a three-year struggle with lung cancer -- resonate far too loudly with the majority of today's lung cancer patients.

"The large majority of patients diagnosed with lung cancer continue to die of lung cancer," said Dr. Charles Rudin, an oncologist at Johns Hopkins in Baltimore. "We've improved the duration of survival and the quality of life, but the disease remains highly, highly fatal."

Only 15 percent of lung cancer patients can expect to be alive five years after their diagnosis. It is the leading cause of cancer-related mortality, not only in the United States, but worldwide.

That's despite decades worth of research. Although the last 25 years have seen improvements in surgical techniques, chemotherapy protocols, radiation therapy, and disease staging, researchers generally characterize the progress in lung cancer treatment as slow, calling it "step-wise" or "incremental."

Yet some say progress has increased "exponentially" over the past five years, thanks to a better understanding of tumor biology that has led to the development of targeted agents that can extend survival in certain susceptible patients.

Although these treatments have yet to prove curative, they may bring at least a glimmer of hope to the 160,000 patients in the U.S. expected to die this year from the disease.

The Role of Chemotherapy

There was no defined role for chemotherapy in lung cancer patients 25 years ago. The data was starting to come together for small cell lung cancer, which today accounts for 15 percent of cases, but there was little reliable evidence for its role in non-small cell disease.

"There was disagreement if it improved survival in advanced stages of the disease, and there were some promising studies of it in combination with radiation therapy, but nothing was definitive," said Dr. Jeffrey Crawford, chief of medical oncology at Duke University in Durham, N.C. "There was no recommended use of it after surgery, and no adjuvant use."

But as clinical trials in the 1990s began producing data, researchers became somewhat more confident that chemotherapy could extend survival.

"It ended up generating drugs that changed survival from six months to 10 months," said Dr. Bruce Johnson, a thoracic oncologist at Dana Farber Cancer Institute in Boston. "So it prolonged median survival by four months, or for the real optimists it was a 67 percent increase in survival."

Crawford said being able to define the role of chemotherapy in non-small cell lung cancer has been one of the major advances over the last quarter-century.

"Now in advanced disease, it's approved for front-line use, and we have regimens approved for second- and third-line use," he said. "We have standard regimens incorporated with radiation, and we have adjuvant chemotherapy which has proven benefit in improving survival."

The availability of better chemotherapy drugs has been part of that equation, as has been better pairing of those agents.

However, many researchers now believe that traditional chemotherapy agents have reached a therapeutic plateau. And even despite the chemotherapeutic advances, most characterize the late '90s and the early part of the 21st century as a "stagnant" time for advances in treatment.

"We tried a lot of drug combinations, and combining targeted agents," Johnson said, but often to little avail.

Progress was even slower for the small cell type of lung cancer. Crawford said oncologists are still using the same treatments they did 20 years ago for treating this subtype of disease.

Its biology is less well understood, and it becomes chemoresistant very quickly, he added. Patients often don't live long enough to be enrolled in clinical trials, and they certainly don't live long enough to go on to become vocal advocates.

"We haven't made nearly the progress that we have in non-small cell lung cancer," he said.

So what do the advances in treatment mean for patients? Arriving at the clinic in 1984 with early-stage non-small cell lung cancer that could be treated with surgery carried a 40 percent chance of survival, researchers say.

Today, survival in this group stands at about 50 to 60 percent. But the problem, researchers say, is that the vast majority of patients -- about 70 percent -- present with advanced-stage disease. Survival rates for advanced disease have increased by only about 15 percent above 1984's meager 20 percent.

Targeted Therapies, Personalized Treatment

But some researchers say they've started to see a glimmer of hope for patients with advanced disease. Many predict that targeted therapies, which began to be better understood in the middle of this past decade, are the future of lung cancer treatment.

The first targeted therapy in lung cancer was bevacizumab (Avastin), an antiangiogenic agent that prevented the formation of new blood vessels in tumors. The drug showed prolonged survival in advanced non-small cell lung cancer patients.

Erlotinib (Tarceva) and gefitinib (Iressa) also appeared on the market, but it wasn't until about 2004 that researchers began to figure out why these two agents worked particularly well for certain lung cancer patients.

Meanwhile, improved imaging techniques have contributed to advances in surgery, staging, and radiation treatment for lung cancer patients.

Surgical incisions have been getting smaller, partly because surgeons have a better idea of the exact location of the cancer. And it's easier to figure out if a patient is a candidate for surgery because better images lead to better staging.

"The impact of much better imaging techniques has led to changes in how we diagnose and accurately stage lung cancer," Rudin said. "Routine CT and PET scans for the initial evaluation and staging have led to much better assessment of patients for surgical eligibility and for staging multimodality therapy."

The advent of brachytherapy and intensity-modulated radiation therapy (IMRT) in particular have had an impact on treatment.

"Twenty-five years ago, it was essentially point-and-shoot," Rudin said. "There was significant radiation toxicity because it encompassed other structures within the radiation field. We've done a lot of work on refining radiation, improving delivery specifically to the tumor by incorporating advances in imaging."

But one of the most successful advances in the lung cancer battle, they say, has been the campaign against smoking.

As the number of smokers in the U.S. has been declining as a result of public health efforts, so too has the number of new cases of lung cancer.

In men, the death rate from lung cancer has been declining since the late 1990s, and it is starting to decline for women.

"Smoking rates started to fall in men about 30 years ago, and in women 20 years ago, and that is now being manifested by falling rates in the number of lung cancers and in the number of people dying from lung cancer," Johnson said.

Screening for lung cancer has been somewhat controversial. A large trial -- the National Lung Screening Trial -- should be reporting results in about a year, to help researchers make a more definitive conclusion about whether screening has benefit in patients at risk for lung cancer.

Some are already proponents of screening.

"That would be a big help if we had an effective screen," Johnson said. "Cancers that have seen a rather dramatic decline in deaths are prostate, breast, and colon -- and there are screens for all of those."

Others, however, are not so certain the screening will have similar success in a more aggressive cancer.

"It's not the quantity of tumor, it's the quality of tumor," said Dr. Roy Herbst, a thoracic oncologist at M.D. Anderson Cancer Center in Houston. "All it takes is a couple cells that spread to the brain, liver, or bone. Even if you cut that tumor out early, that patient still might end up with recurrent disease very soon."

He feels that "ultimately, screening will be very important," but not until researchers can molecularly characterize the tumor and, therefore, "understand what markers will put that patient at risk or not."

Rudin hopes the trial will answer the most important question, of whether screening actually alters lung cancer mortality: "That's a much higher hurdle to prove."