2nd International Lung Cancer Congress
Day 1 - July 18, 2001

Lung Cancer Screening and Prevention: Quit Smoking!

Robert S. Mocharnuk, MD

Introduction

Overall 5-year survival rates in nonsmall-cell lung cancer (NSCLC) have stalled at 12%, unchanged over the past decade and a half, in spite of great efforts in both research and clinical arenas. The only constant in lung cancer treatment is that patients diagnosed with earlier-stage disease enjoy 5-year survival rates greater than 50%. While it is too soon to assess the long-term impact of new treatment strategies on survival outcome, the 10% response rates being reported in many targeted therapy trials suggest that a statistical sea change is not imminent. Improvements in screening for lung cancer, the best method of detecting early-stage cancers, as well as strategies to prevent lung cancer, were discussed at the 2nd International Lung Cancer Congress in Kauai, Hawaii.

Early Detection Program Offers Significant Hope

The Need for a Screening Program

Dr. Claudia Henschke,[1] Division Chief for the Department of Radiology at the New York Presbyterian Hospital-Weill Cornell Medical Center in New York, summarized the findings of the Early Lung Cancer Action Project (ELCAP). The data shared from this lung cancer screening effort may have more of an impact on overall survival than any chemotherapy combination, biologic modifier, surgical intervention, or radiation strategy discussed in the course of this conference.

Prefacing her remarks by observing that standard screening protocols exist for breast, colon, and prostate cancer, but not for lung cancer, Dr. Henschke discussed the theory of malignant cell origination. By the time a single malignant cell has undergone 22 doublings, a 2-mm lesion is detectable on computed tomography (CT); a 10-mm lesion, detectable on chest x-ray, occurs after a doubling time of 30. Death usually occurs at a doubling time of 40.

Studies conducted in the 1970s failed to show any survival advantage with screening chest x-rays in high-risk individuals.[2] In the only randomized lung cancer screening trial (the Mayo Lung Project), compliance issues, as well as an underpowered study sample, skewed the results, leading to widespread recommendations against screening chest x-rays.[3] Since that time, widespread use of CT has enhanced the potential for screening accuracy.

Study Design and Results

The single-institution ELCAP was launched in 1993, enrolling 1000 asymptomatic individuals deemed at high risk for the development of lung cancer.[4] Study entrants were 60 years of age or older, had at least a 10-pack-year history of smoking, had no prior cancer history, and were medically fit to undergo thoracic surgery if indicated. Participants received baseline and annual screening CT scans, and data were analyzed for frequency of nodule detection, the frequency with which detected nodules proved malignant, and the frequency with which malignant nodules were cured.

A distinction was made between detection at baseline vs detection during annual screening. These data would allow for determination of both survival and cure rates based upon the size of detected malignancies, data that could be applied as a reference point to any new screening devices. Once nodules were detected by screening low-dose CT scanning, a high-resolution CT was recommended. Specific criteria were established for determining whether nodules appeared malignant or benign; growth patterns as well as size were used to select out patients requiring biopsies, although the final decision regarding biopsy was left to the referring physician.

A total of 559 nodules were found in 23% of individuals at baseline low-dose CT scanning, of which 27 (12%) were malignant. The great majority (82%) of these nodules were stage IA lesions, with most nodules measuring 2 mm to 5 mm (58%). Thirty percent of the nodules were 6 mm to 10 mm, 10% were 11 mm to 20 mm, and 2% were > 20 mm. To date, an additional 1.5% annual incidence of nodule detection was reported: 43% of the nodules were malignant and 83% represented stage IA disease. Five-year survival projections for stage IA lesions of the size detected in this study are 80%.

These data appear to confirm the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) data for nodules < 15 mm, which demonstrated 10-year survival rates of 75%. Among 233 patients with between 1 and 6 noncalcified nodules, only 33 were also detectable on chest x-ray. A majority of subjects (159) had solitary nodules, while 43 had 2 nodules, 16 had 3 nodules, 7 had 4 nodules, 6 had 5 nodules, and 2 had 6 nodules.

Given these impressive results in early cancer detection, the issue of cost effectiveness must be examined. Analysis of the ELCAP data showed an average annual cost of $2500 per life-year saved. This falls well below the annual cost of $10,000 needed to make screening cost-effective, given average annual Canadian lung cancer treatment expenditures.[5]

The ELCAP study also confirms previously published data showing a greater risk for lung cancer development among female smokers compared with their male counterparts.[6] These data are discussed in more detail below.

Expanding the Program Beyond the Institution's Walls

The success of ELCAP has led to statewide expansion of this program at 11 separate institutions, starting in May of 2001. In addition to the 10,000 individuals to be enrolled who fit the previously established eligibility criteria, an additional 2000 individuals have elected to enroll; these subjects are 40 years of age or older with either personal or family smoking histories. A total of 400 lung cancer cases are forecasted by March 2003 for this population.

An international screening program has also been launched, beginning with 9 charter countries, to which more than 20 others have been added. Worldwide, there are 44,000 people currently enrolled in lung cancer screening programs. Part of these screening efforts will include the sampling of blood, sputum, and buccal cells over 5 years. Since surgical resection of suspected malignant lesions is not mandated by these screening studies, it will take between 30 and 50 such cases to determine whether lungs cancers are being overdiagnosed, and at what cost.

In reality, these screening programs represent both diagnostic and therapeutic approaches, since the results of early screening generally lead to early intervention. As our knowledge regarding biomarkers increases, perhaps this information will be later integrated into screening programs, such that even higher rates of survival will be achieved.

Biomarkers as Screening Tools for High-Risk Individuals

In the United States, there are currently 50 million smokers. Among adult males, 27.6% are smokers, while 22.1% of women smoke. A total of 36.5% of teenagers, both male and female, smoke. While 1 in 10 smokers eventually develops lung cancer, the incidence of lung cancer among nonsmokers (80% of which are women) is growing.[6] Dr. Jill Siegfried,[7] from the University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, examined the differences that characterize both smoking and lung cancer rates among men and women, identifying some potentially important genetic and environmental factors that may explain differences in the statistics cited above.

Growth Factor Receptors and Estrogen

Growth factor receptor levels, including gastrin-releasing peptide/receptor (GRP/GRPR) and insulinlike growth factor-1, appear to correlate directly with lung cancer development, whereas circulating antioxidants such as beta-carotene and retinoids correlate inversely with lung cancer development.[8,9] In addition, the incidence of adenocarcinomas continues to rise, especially among individuals with no prior smoking history (eg, women).[10] This led to speculation that perhaps estrogen levels play a role in the development of lung cancer. In fact, data published by Taioli and Wynder[11] in 1994 lend credence to the fact that women smokers on estrogen replacement therapy (ERT) have the highest incidence of lung adenocarcinomas (Table 1).

Table 1. ERT and the Risk of Lung Adenocarcinomas

Use of ERT

Adjusted Overall Risk

No ERT; nonsmoker

1.0

ERT; nonsmoker

1.0

No ERT; smoker

13.1

ERT; smoker

32.4

ERT, estrogen replacement therapy

Early menses and late menopause also appear to correlate with increased lung cancer risk. This may relate to the fact that lung cancers express both estrogen receptors alpha and beta,[12-15] and that the presence of estrogen increases both tumor cell proliferation and GRPR expression.[8,11] Moreover, estrogen inhibitors, such as tamoxifen, do not appear to inhibit the growth of lung cancer cells.

Bombesin-like proteins, which are normally involved in fetal lung growth, are overproduced in lung diseases as well as in smokers.[16,17] For example, neuromedin B (NMB) is produced in NSCLC, and GRP is produced in small-cell lung cancer (SCLC). Nicotine, via nicotine acetylcholine receptors, also appears to stimulate transcription of GRPR.[18]

Since the GRPR gene is located on the female X chromosome, and appears to escape X inactivation by methylation, women seem to have twice as many active GRPR genes compared with their male counterparts. And, since women produce far more estrogen than do men, GRPR expression in airways is already greater for women than for men, a finding that was confirmed by message amplification data generated in Dr. Siegfried's lab. Given the overexpression of GRPR in smokers, augmented by both nicotine and estrogen amplification of GRPR, coupled with GRP/NMB overproduction, it appears that female smokers are at greater risk for developing lung cancer and chronic obstructive pulmonary disease compared with men.

Additional Effects of GRPR

The joint effects of GRPR expression and pack-year history of smoking correlate also well with risk for lung cancer development (Table 2).

Table 2. Odds Ratios for Lung Cancer Development

Number of Pack-Years Smoking GRPR-Negative GRPR-Positive

0

1.0

2.5

1-25

6.8

18.0

26-50

15.8

30.0

51+

22.5

50.4

It remains to be seen whether GRPR overexpression is associated with other types of malignancy.

Chemoprevention Revisited

Dr. James Mulshine,[19] Head of the Intervention Section for Chemoprevention of Lung Cancer at the National Cancer Institute in Bethesda, Maryland, addressed the controversial subject of lung cancer chemoprevention. He prefaced his remarks by reminding the audience that lung cancer is, by far, the greatest cause of premature cancer death in the world, far outstripping breast cancer by a factor of 3. He also congratulated the tobacco industry for perfecting 1 of the most efficient methods for toxic drug ingestion ever invented. The secret additives guarded so jealously by each tobacco firm contain mixtures of some 4000 chemicals, 200 to 300 of which are known carcinogens. The cigarette allows for drug delivery at a high concentration, causing chemical burns to underlying tissue with chronic exposure, and continually depleting protective antioxidants.

Given the abysmal survival rates, he strongly supported the work of Dr. Henschke and suggested that there is a critical need for CT screening. Furthermore, these statistics cry out for some type of chemoprevention. Previous studies using oral retinoids have been disappointing, although German studies using aerosolized retinoids appear to reverse bronchoepithelial dysplasia. Current trials continue to study the effects of cyclo-oxygenase (COX)-2 selective drugs, leukotriene inhibitors, epidermal growth factor-directed agents, and farnesyl transferase inhibitors. While the goal of early detection is to locate the signature of field carcinogenesis, it is important to recognize that such tumors exist within a matrix of normal cells, making detection that much more difficult.[20]

Improving Chemoprevention Techniques

As suggested by the German experience with retinoid therapy, the method by which drug is delivered may need to be restricted in order to minimize side effects and enhance efficacy. Such is the case with aerosolized treatment, which requires far less drug to saturate far more target organ when compared with an oral formulation. Currently, there is an ongoing study investigating the usefulness of aerosolized steroid delivered by metered-dose inhalation (MDI). In spite of the negative beta-carotene legacy (a precursor to vitamin A), it is known that vitamin A controls airway cell division. Using a newer type of MDI known as an electrodynamic inhaler, the National Cancer Institute is currently revisiting the retinoid issue, employing more moderate doses in mouse models in an effort to avoid the toxicity previously reported.[21] Furthermore, aerosolized vitamin A appears to induce only airway receptors, unlike oral vitamin A, which preferentially induces retinoic acid receptors in the liver.

COX-2 inhibitors have been shown in preclinical models to prevent lung cancers, although there is some evidence to suggest that selective targeting ignores the contribution of COX-1 to tumorigenesis. Both Vanderbilt University and the MD Anderson Cancer Center will be involved in these investigations in the coming years.

Translating From Research to Clinical Practice

A recent Institute of Medicine (IOM) report has strongly criticized the healthcare system in its failure to translate knowledge generated from research into clinical practice. Given the imperiled state of medicine today, it is not surprising that the current system is unprepared to respond to the rapidity of extraordinary scientific advances being made. Signs of failure are everywhere, from the dismal 5-year lung cancer survival data to the high rate of solitary pulmonary nodule resections (20% to 40%) for benign disease. Worst of all is the staggering cost per patient for metastatic lung cancer care in spite of continued poor results, although increased costs in the short run may be required to ultimately improve care in the long term. The IOM challenges the medical community to create an infrastructure supportive of evidence-based care, making use of information technology innovations while removing barriers to practice.

Dr. Mulshine concluded that treatment of asymptomatic disease will require a shift from reactive to proactive (ie, preventive) care, and hopes that the healthcare system will adapt itself to fill this obvious need.

The Best Preventive Measure Is to Quit Smoking!

Dr. Carolyn M. Dresler,[22] Medical Director for Smoking Control at GlaxoSmithKline, presented data supporting smoking cessation, even among patients already diagnosed with lung cancer. It is not uncommon for both patients and physicians to take the attitude that the proverbial cat is already out of the bag once the diagnosis of cancer has been made such that smoking cessation efforts at that point are unnecessary. However, this may not be the correct approach for a number of reasons.

To begin with, lung cancer patients can quit smoking, as shown by Dresler and Johnston in independent studies.[23,24] Furthermore, duration of smoking cessation impacts significantly on the effectiveness of chemotherapy among SCLCs, with nonsmokers having the highest survival rates, current smokers having the lowest survival rates, and past smokers falling somewhere in between.

A meta-analysis of retrospective Eastern Cooperative Oncology Group data, presented in 1995 at the American Society of Clinical Oncology annual meeting, suggested that there is a weak link between smoking cessation and prolonged survival in stage III and IV NSCLC patients. This may be due in some part to the effects of smoking on drug metabolism, resulting in subtherapeutic delivery of cytotoxic drugs. In early stage I resected lung cancers, the number of pack-years smoked directly affects long-term survival, ranging from 35.7% at 10 years among patients who smoked more than 30 pack-years to 84.9% among nonsmokers. The incidence of second primary tumors among persistent smokers successfully treated for SCLC is 33%, compared with a risk of 10% among reformed smokers.[25] Additionally, the incidence of radiation pneumonitis is higher in those with low performance status, comorbid lung disease, poor pulmonary function tests, and continued smoking.[26] Smoking may even promote chemoresistance via antioxidant depletion, promote an increase in insulin resistance and the upregulation of GRPR, and affect a number of other mechanisms as well.[27]

Why Do People Smoke?

The reasons for tobacco addiction range from physiologic dependence on nicotine to the ingrained repetitive hand-to-mouth motion of puffing on a cigarette. The average smoker uses 30 cigarettes per day, drawing on each cigarette 10 times, 365 days per year. At 20 years, this represents 2.2 million puffs on cigarettes, an ingrained pattern that is relaxing while promoting a feeling of well being via stimulation of nicotinic receptors in the locus ceruleus.

Smoking Cessation Strategies

The 2 current strategies for smoking cessation are going "cold turkey" and employing 1 or more pharmacologic agents, such as nicotine replacement, nonnicotinic drugs (eg, bupropion), and potential smoking vaccines. Cold-turkey approaches are the least effective, with only 1% to 3% of individuals remaining off cigarettes for any appreciable time. Nicotine replacement therapy can be administered via nasal spray, transdermal patch, inhaler, or chewing gum, but patients who smoke more than 24 cigarettes daily should probably use higher dose regimens of replacement. Oddly enough, all current nicotine replacement therapy products provide subtherapeutic doses when compared with average daily nicotine intake from smoking. Nevertheless, the use of nicotine replacement products is inherently safe, even in vulnerable patients with other medical conditions such as cardiac disease, simply because the toxins ingested by cigarette smoking are always worse than the effects of nicotine alone.

Successful smoking cessation also depends upon physician support. This includes asking patients about their smoking history and/or efforts to quit, advising patients about the benefits of smoking cessation, as well as assessing potential candidates for cessation by gauging their motivations to quit. Arranging a quit date, discussing and writing recommendations/prescriptions for pharmacotherapeutic agents, and recommending specific behavior modification or support programs are all necessary components for success. Patients who quit smoking should be congratulated, while continued support should be provided to those who still struggle or slip. Above all, patients should be told that it is never too late to quit.

References

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