Researchers See More Effective Lung Cancer Screening, Therapy

WASHINGTON—Three cancer specialists offered a more optimistic view for the future of lung cancer patients during a congressional briefing. Despite the disease’s “dismal” 5-year survival statistics, advances in genetics, a new screening technique, and treatment improvements promise earlier diagnosis and prolonged life for some patients, they said.

Laurie Gaspar, MD, professor of radiation oncology, University of Colorado Health Sciences Center, cited “dramatic changes” during the 1990s in the treatment of lung cancer. “I really think that in the 10 years to come, my treatments will drastically change from what I am doing today,” she said.

The briefing, sponsored by the National Coalition for Cancer Research (NCCR), focused on the toll of lung cancer in women, but much of the material related to men as well as women.

Lung cancer replaced breast cancer as the leading cause of cancer death in women in the early 1980s, and in 1999, some 68,000 women will die of the disease in the United States, said Margaret R. Spitz, MD, MPH, professor and chair of epidemiology, M.D. Anderson Cancer Center. However, women diagnosed with lung cancer tend to fare better than men, Dr. Gaspar noted. “Women do slightly better, stage for stage and at each time point, compared to men, for reasons that are not entirely clear,” she said.

Smokers and former smokers account for 85% of the lung cancer cases diagnosed annually. Although more men than women smoke, men are quitting at a far greater rate, Dr. Spitz said. “We certainly believe that there is a genetic link to nicotine addiction.”

She noted that some people have variant genes that are associated with a deficiency in the dopamine-reward pathway. For these people, smoking creates a much greater reward effect from nicotine and causes them to become addicted more readily. Dr. Spitz and her colleagues have studied some of the variant genes.

In one example, “we found that 25% of the never-smokers had the variant gene, 57% of former smokers, and 78% of current smokers,” she said. Smokers with the variant gene began smoking at an average age of 17 vs age 19 for smokers who did not have it, and those who carried the variant found it harder to quit.

“In the past, smoking cessation programs have treated all smokers the same way,” Dr. Spitz said. “If we can begin to study the genetic make-up of smokers, we will be able to develop targeted interventions and find out which people do better with pharmacologic interventions.”

Advances in Screening

 Georgeann McGuinness, MD, associate professor of radiology, New York University School of Medicine, stressed the value of developing an effective screening technique to detect lung cancer in its earliest stage. “Five-year survival for lung cancer is 15%, but when you break it down by stage, 5-year survival for stage I is somewhere between 70% and 80%, with a steep drop off after stage II,” she said. But, she noted, relatively few lung cancers are stage I when diagnosed.

Several clinical trials in the 1970s found no benefit to screening for lung cancer with a combination of chest x-rays and sputum samples, and thus screening of even high-risk, asymptomatic patients has not been recommended. However, these findings have recently been called into question by a reanalysis that suggested flaws in the design and interpretation of the studies, Dr. McGuinness said.

“A strong argument has been developed that, in fact, periodic screening chest x-rays may downstage the distribution of cancers at detection, with improved resectability and survival,” she said. “Therefore, early detection efforts in asymptomatic, high-risk individuals are justified.”

Dr. McGuinness is a co-investigator in the multicenter Early Lung Cancer Action Project (ELCAP), which is led by Claudia Henschke, MD, PhD, of Weill Medical College, Cornell University. Dr. McGuinness recapped the preliminary findings of this low-dose spiral CT scanning trial aimed at screening for lung cancer in asymptomatic smokers and former smokers over age 60. The ELCAP team reported its preliminary results in The Lancet in July. [See ONI, August 1999, page 1.]

Of the 1,000 persons screened (54% male, 46% female), CT scanning detected from one to six noncalcified nodules in 233 patients, and conventional chest x-rays found nodules in 68 patients. Twenty-seven cancers were detected by CT, only 7 of which were detected by chest x-ray. Of these 27 cancers, 23 were diagnosed as stage I.

“In our study, 85% of the cancers we detected were stage I at presentation as compared to a general nonscreened population presenting to their doctors, where stage I lung cancer is a rarity, on the order of 12% to 14%,” Dr. McGuinness said.

Spiral CT scans allow volumetric measurement of irregularly shaped nodules. “We can also view the lesion with infinite viewing angles and, by so doing, detect even subtle changes in its shape and contour,” she said.

Dr. McGuinness suggested that if screening could reduce lung cancer mortality by even 20%, applied to the current 160,000 US lung cancer deaths annually, “this would translate into 32,000 lives saved, which is the equivalent of curing all lymphomas, or two thirds of breast or colon cancers.”

Dr. Gaspar focused on the progress in recent years in treating lung cancer and the potential for the future. “We are better at identifying patients who will benefit from our treatments,” she said. “We now have a standard way of combining radiation and chemotherapy for patients who aren’t eligible for surgery. We have many new chemotherapy agents available and a number of new technological developments in radiation therapy.”

She said that chemotherapy has “really come a long way. There are drugs that have direct cytotoxicity, drugs that prevent metastasis, and drugs that make radiation therapy more effective or protect the normal tissues from drug side effects.”

She also noted the increasing number of patients, particularly women, who now use complementary and alternative therapies. “Because our patients are taking these drugs, it would probably be wise of us in the future to study them,” she said.

Radiation oncologists are increasingly treating lung cancer patients with conformal radiation therapy, which is mapped out with the aid of CT scans to tighten the area to which radiation is delivered, Dr. Gaspar said. “By giving radiation treatments from many, many angles, the radiation field can be shaped to be just a little bit larger than the lung cancer,” she said. “Using this technique, we can give a higher dose, with a higher chance of controlling the tumor and less chance of side effects.”

The treatment advances of the 1990s are but a prelude to future improvements that will reduce lung cancer morbidity and mortality, she predicted.

Direction of Future Studies: An Interview With Dr. James Mulshine

To get a sense of the cost-effectiveness of lung cancer screening, researchers must keep in mind that “many of the major costs come from the downstream evaluations triggered by a positive test,” James Mulshine, MD, head of the Intervention Section of the National Cancer Institute, said in an interview with ONI.

Thus, algorithms must be developed to guide management after a positive test. “This will require parallel research to refine the management algorithms we ultimately develop,” Dr. Mulshine said. “This means that researchers must be committed to serial follow-up of screened individuals and to programmed multidisciplinary interactions among health care professionals—including oncologists, radiologists, pulmonologists, and health economists.”

Attendees at the First International Conference on Screening for Lung Cancer agreed that large-scale trials with sufficient power need to be launched as soon as possible. “While data from the Japanese cohort are extremely promising, they need to be validated in independent populations and in health care settings in the United States,” Dr. Mulshine said.

There is pressure to initiate trials quickly, Dr. Mulshine noted, because of the sense that many will start using the newer, promising screening techniques before their precise utility is proven, and before questions concerning optimal screening interval and subsequent appropriate interventions are answered.

Several trials are already in the late planning stage, and the initiating organizations will try to use common terminologies, data management forms, and imaging parameters. “The idea is that even if different testing formats go forward, there can be some retrospective comparison of the aggregate experience,” Dr. Mulshine said.