Screening, Early Detection,
and Early Intervention Strategies for Lung Cancer
Henry Wagner, Jr, MD, and John C. Ruckdeschel, MD
Thoracic Oncology Program
at H. Lee Moffitt Cancer Center & Research Institute
Screening for lung cancer
has been utilized for several decades without demonstrating overall survival
benefit. However, recent advances in treatment of lung cancer, improvements
in our biologic understanding of lung cancer development, and an increasing
population of healthy ex-smokers provide cause for optimism. Several chemoprevention
trials suggest that it may be possible to intervene in the oncologic process
prior to the development of invasive malignancy, resulting in a delay or reversal
of these changes.
If discoursing on a difficult
problem were like carrying weights, when many horses can carry more sacks of
grainthan a single horse, I would agree that many discourses would do more than
a single one; but discoursing is like coursing, not like carrying, and one Barbary
courser can go faster than a hundred Frieslands.
Galileo Galilei, The Tester,
cited by Italo Calvino in Six Memos for the Next Millenium. NewYork,
NY: Vintage Books; 1993:43.
Introduction
Lung cancer is the most
frequent cause of cancer death in both men and women. While the incidence of
lung cancer appears to have decreased in white men, it continues to rise in
nonwhite men and in women. Most lung cancer is caused by cigarette smoking,
but strategies to prevent or reduce this addiction have met with only modest
success to date.[1] Smokers who quit remain at an increased though gradually
declining risk of lung cancer over at least the next decade.[2] For these individuals,
early detection and treatment of the cancers that they may still develop remains
the best hope of further reducing their risk of death from lung cancer.
Strategies for dealing with
early lung cancer fall into three themes: true screening programs for
the evaluation of asymptomatic individuals believed to be at high risk for lung
cancer; early detection programs for the evaluation of patients presenting
with ambiguous symptoms; and early intervention programs aimed at stopping
or reversing the processes involved in lung carcinogenesis before the development
of invasive malignancy.
Since approximately 90%
of lung cancer develops in individuals with a history of cigarette smoking,
many of whom have chronic respiratory symptoms, the distinction between screening
and early detection is blurred. Individuals who participate in "screening"
programs may be motivated by subtle changes in their baseline cough or sputum
production (or by a family member's prodding that such a change has occurred)
and thus may not truly represent the larger population of smokers and ex-smokers
from whom they are drawn.
Lung Cancer Presentation,
Staging, and Treatment Outcome
Table 1 shows the stage
distribution of 170,000 cases of lung cancer diagnosed in the United States
in 1993. While a few patients with stage III disease (those with minimal weight
loss and good performance status) may be cured by aggressive multimodality therapy,
only those patients with stage I or II disease are classically considered to
be resectable with high probability of cure. If only those patients with T1N0
disease are considered as truly early presentations, more than 85% of patients
with lung cancer currently present with more advanced disease.
Table 1. -- Stage Distribution
of Lung Cancer at Presentation ______________________________________________________________________
Stage and Clinical
Operability Group |
Cases per Year
(U.S.) |
| T1NO |
19,600 |
| T1N1, T2N0, T2N1 |
25,900 |
| IIIA resectable |
10,500 |
| IIIA partially resectable |
7,000 |
| IIIB nonresectable |
7,000 |
| IV |
100,000 |
| Total |
170,000 |
|
From Holmes EC. Adv Oncol.
1993;9:15-21.
________________________________________________________________________
Radiographically detectable
lung cancer is hardly early disease. To be seen on routine chest radiograph,
in the favorable circumstance of a peripheral nodule that does not overlie shadows
of rib or mediastinal structures, a lesion has to be approximately 1 cm in diameter.
Such a mass will typically contain 10 to the 9th tumor cells, representing about
30 doublings under an ideal condition of no cell loss. Such conditions never
occur in human tumors; a comparison of actual and potential doubling times suggests
that cell loss factors in the range of 80% to 90% are common.[3] At this point,
the "early" tumor has undergone most of its life span. This long preclinical
history for even the smallest radiographically detectable tumors gives ample
opportunity for the mutational appearance and clonal selection of phenotypes
capable of invasion, metastasis, and drug resistance.
The TNM staging system,
while reasonably applicable to patients with non-small cell lung cancer (NSCLC),
generally is not used for patients with small cell lung cancer (SCLC). The distinction
between "limited" and "extensive" SCLC then reduces to a
reflection of the sensitivity of the imaging and other technology used to search
for it. The advent of computed tomography, magnetic resonance imaging, and polymerase
chain reaction in staging means that there is less "limited" disease
now than in the era of radionuclide imaging of these sites. These changes in
stage distribution based on increasing sensitivity of staging need to be considered
when we report apparent progress in treatment of subsets of patients.[4]
Shifts of stage distribution
due to earlier diagnosis should not be confused with the shifts in staging classification.[5]
In the case of changes in diagnostic sensitivity, clinicians are intervening
in the disease process at an earlier time, which may result in either a real
therapeutic gain (if effective therapies are available) or an apparent gain
(from the lead time gained in time from diagnosis to time of death). In contrast,
shifting patients from one stage to another by the use of more sensitive imaging
techniques for staging but not changing the time of initial diagnosis simply
changes the way in which the same set of clinical events are categorized and
has no effect on the survival of the entire population with the disease, but
may improve the outcome for each of its subgroups.
Figures taken from the clinical
data on which the new International Staging System was based represent that
which can be obtained with good standards of practice in staging and treatment.[6]
They do not reflect the modest improvements in survival now being reported for
the use of adjuvant chemotherapy in combination with either surgical resection
or definitive radiation therapy for locally advanced disease.[7] In selected
series with meticulous surgical staging of the mediastinum, survival for patients
with T1N0M0 disease is up to 80% higher in the series of the Lung Cancer Study
Group.[8] Survival for patients with T1N0M0 lung cancer is comparable to survival
of patients with T1M0N0 breast cancer, but only a small percentage of patients
with lung cancer are detected at this stage. It is a reasonable hypothesis that
detection of patients with lung cancer prior to the development of nodal metastases
would significantly improve survival. Patients with treated lung cancer who
relapse generally do so within the first three years; true late failures are
uncommon. Second primary tumors of the lung, esophagus, and head and neck sites
are problematic, however, and in aggregate have an incidence of approximately
2% to 3% per year.[9] Thus, the impact of screening and early detection programs
ought to be demonstrable with relatively short follow-up.
Lung Cancer Causation and
Epidemiology
At the beginning of this
century, lung cancer was a rare disease. The present global epidemic, with over
2 million deaths estimated for the year 2000, is the direct result of governmentally
sanctioned production and aggressive marketing of addictive tobacco products,
primarily cigarettes.[10] While an effective strategy for lung cancer treatment
and control will include a broad spectrum of activities, it is unarguable that
the greatest long-term reduction in lung cancer mortality will come from a decrease
in the number smokers.
In the United States, lung
cancer is most commonly diagnosed in the seventh decade of life. A generation
ago, lung cancer was predominantly a disease of men. Much early clinical research
in lung cancer, including the three large prospective trials of radiographic
and cytologic screening conducted in the US, was limited to men who smoked.
However, the increase in cigarette smoking by women starting in the 1940s changed
this situation dramatically. Deaths from lung cancer overtook those of breast
cancer for US women in the 1980s. Current US data show a decline in smoking
prevalence among white men, but smoking has continued to increase among women,
and recent data have suggested a leveling off or even reversal in the tendency
to decreased smoking in young women.[1]
At present, approximately
25% of the adult population of the United States are smokers, and an additional
40 to 50 million are former smokers.[1] The American Cancer Society Cancer Prevention
Study II has demonstrated that, while the risk of subsequent development of
lung cancer declines for both men and women regardless of the age at which they
quit smoking, the greatest gains are seen for those quitting at an earlier age,
and that this difference is significant even when correcting for the number
of years smoked.[2,11]
Lung Cancer Biology
The lung is anatomically
and physiologically at least three separate organs. The trachea and main bronchi
are normally lined by ciliated, pseudostratified columnar epithelium and also
contain neuroendocrine cells. The predominant types of tumors arising in large
central airways are squamous cell and small cell carcinomas. The thickness of
the lining epithelium gradually declines as the airways become smaller. The
pseudostratified, ciliated columnar cells gradually give way to ciliated columnar
and finally ciliated cuboidal cells in the terminal bronchioles. Epithelial
mucous cells are interspersed throughout the conducting airway. Interspersed
among the cuboidal cells of the terminal and respiratory bronchioles are Clara
cells, thought to produce the mucus covering for these small airways. The predominant
histology seen in peripherally arising lung cancers is adenocarcinoma, which
morphologically can be divided into solid and bronchoalveolar types. At the
cellular level, these tumors arise from type II pneumocytes that normally produce
surfactant. The bronchoalveolar carcinomas are believed to arise from Clara
cells that are involved in xenobiotic metabolism. Each of these cell types has
associated characteristic differentiation markers that may form the basis for
both detection and therapeutic strategies (Table 2).[12]
Table 2. -- Markers of Lung
Cancer Differentiation
__________________________________________________________________________
| Adenomatous |
Neuroendocrine |
Squamous |
| Clara 10-kDprotein |
Chromogranin A |
Cytokeratin |
| Surfactant-associated protein |
Leu 7 |
Involucrin |
| Carcinoembryonic antigen |
Neuron-specific enolase |
Epidermal growth factor receptor |
| ras oncogene activation |
Dopa decarboxylase |
Transblutaminase |
|
From Mulshine J, Linnoila
RI, Treston AM, et al. Candidate biomarkers for application as intermediate
end points of lung carcinogenesis. J Cell Biochem Suppl. 1992;Suppl 16G:183-186.
______________________________________________________________________________
Approximately one fifth
of lung carcinomas are large cell undifferentiated tumors that cannot be assigned
to one of the above lineages. All histologic types can be found admixed within
a single tumor, consistent with a model of their development from a common stem
cell of variable differentiation potential. The usual anatomic distribution
of the different tumor histologies may derive from the normal distribution of
partially committed cell lineages, from variable penetration of different carcinogenic
components of cigarette smoke to different regions of the lung, and possibly
from differences in local metabolic transformation of procarcinogens and effects
of the extracellular matrix and paracrine growth factors on carcinogenesis.[12]
These distributions of normal
cell and tumor types are typical rather than absolute. Lung cancers of all cell
types may be found in any location in the tracheobronchial tree and lung. This
classification implies that, while there may be some very early events common
to the development of all types of lung cancer, further preneoplastic and neoplastic
development can follow along several divergent lines, and screening strategies
should be able to detect each of these. The observation that there has been
a shift in the proportion of lung cancers of the various histologic types over
the past several decades, with the predominant cell type changing from squamous
cell to adenocarcinoma, should be considered in a proper theory of lung cancer
initiation and promotion.[13]
Historical Screening Studies
In the 1950s, several nonrandomized
trials of screening for lung cancer were conducted in the United States and
Europe. Trials in Philadelphia[14] and London[15,16] used chest photofluorograms
obtained at six-month intervals. These studies found that approximately one
half of the cancers detected in these populations were found by the screening
examinations, and the remainder was identified on interval chest radiographs
obtained for evaluation of symptoms. While the resectability rate of the cases
detected on the screening examinations was approximately 30%, the overall resectability
for all cases was only 20%, which did not appear different from historical results
in unscreened patients.
Table 3. Prospective
Trials of Screening for Lung Cancer
_______________________________________________________________________
| Study |
Subjects |
Eligibility |
Group |
Cases
Detected |
Mortality
Rate |
Mayo Lung
Project[17] |
10,933 |
male smokers
age >45 |
prevalence |
91 |
n/a |
|
4,618 |
" |
screened |
206 |
3.2 |
|
4593 |
" |
control |
160 |
3.0 |
Johns Hopkins
Lung Project[18] |
5226
5161 |
"
" |
screened
control |
194
202 |
3.4
3.8 |
Memorial Sloan
Kettering Lung
Project[19] |
5072
4968 |
"
" |
screened
control |
144
144 |
2.7
2.7 |
|
Czechoslovak
Trial[20] |
6364
3172
3174 |
Male smokers
age>40 |
prevalence
screened
control |
19
108
82 |
n/a
3.6
2.6 |
_______________________________________________________________________
In an attempt to clarify
questions raised by these nonrandomized studies, the US National Cancer Institute
sponsored lung cancer screening trials that were conducted in the 1970s in three
institutions -- Johns Hopkins University (The Johns Hopkins Lung Project [JHLP]),
the Mayo Clinic (Mayo Lung Project [MLP]), and Memorial Sloan-Kettering Cancer
Center (MSKLP).[17-19] In addition to these three US studies, a randomized trial
has been conducted in Czechoslovakia,[20] and several recent carefully conducted
case-control studies have taken place in Europe and Japan. The individual trials
differed somewhat in their design and study population (Table 3).
The JHLP and the MSKLP trials
were designed to evaluate the incremental benefit of adding sputum examination
to chest radiography (CXR). In both the JHLP and MSKLP trials, the control groups
were offered annual CXR. The dual screen group was offered an annual cytological
examination of induced sputum plus examination of spontaneously produced sputum
at four months and eight months. The comparison, therefore, was whether the
addition of regular sputum cytology examinations to annual radiographic screening
led to a reduction of lung cancer mortality compared with annual radiographic
screening alone. Of the US studies, only the MLP trial was designed to compare
unscreened management with a policy of intensive dual screening with both CXR
and sputum cytology examinations every four months. The unscreened group, however,
was advised to obtain annual CXR and sputum cytology as part of "routine
medical care," but these individuals were not reminded to comply with this
initial recommendation. Thus, this study can be seen as comparing two different
frequencies of recommended screening and compliance.
The outcomes of these studies
have been presented in several formats: results of the initial prevalence examinations
in the cohorts to be screened, the follow-up of the patients detected during
the screening period, and overall pooled results of the three trials. The general
observations and conclusions of the three trials are clear, but their interpretation
has been controversial. There was agreement that "within the trials there
was no advantage in terms of mortality reduction to the group offered intensive
screening in the Mayo study, with four monthly sputum cytology and chest radiology,
while in the Johns Hopkins and Memorial Sloan-Kettering studies, there was no
advantage to the group that received sputum cytology in addition to annual chest
radiograph examinations."[21] However, the trials as designed did not address
or resolve the question of whether any pattern of surveillance CXR was better
for high-risk populations than a policy of obtaining such studies only when
patients presented with symptoms.
These studies led to a conclusion
that while the screening approaches available at that time could lead to the
detection of presymptomatic lung cancer, particularly squamous cell carcinoma,
at an earlier stage than in the control group, the overall survival for the
screened population was no longer than that of the controls. This led to adoption
of policies discouraging routine CXR and sputum screening and provided an unwarranted
nihilism regarding all aspects of lung cancer detection and treatment.
None of the US randomized
trials compared a policy of screening vs no intervention in the absence of symptoms.
The Czechoslovak trial most closely approached this design; all enrolled men
underwent an initial prevalence examination, after which the control group had
no other planned intervention for three years. Screened individuals underwent
CXR and cytology every six months. In the initial three years of the study,
36 lung cancers were detected in the study group vs 19 in the control group,
and survival of these patients with lung cancer was superior in the intervention
group compared with that in the control group, but the overall death rate from
lung cancer was greater (although not significantly -- 28 vs 18 cases) in the
study group (P=0.18). At three years, CXR and sputum cytology were performed
for both groups, followed by annual CXR. At six-year follow-up, the mortality
rate was the same for the two groups.
The studies of issues and
populations in these trials, which were designed in the late 1960s and conducted
in the early 1970s, are not entirely pertinent for the mid-1990s. The screened
populations were all men, most still smokers, and often afflicted with other
tobacco-related illnesses that led to a high frequency of interval CXRs in addition
to the screening examinations. The present candidate for screening is more likely
to be a man or woman 40 to 59 years of age, a former smoker with a history of
15 to 25 pack years, and often without illnesses requiring close medical attention.
In addition to this shift in demographics, a change in the dominant histology
of newly diagnosed lung cancer has emerged. During the period of the US collaborative
trial, most cases in both the screened and unscreened groups were squamous cell
carcinoma.[19,22] This pattern has changed in the past decade, for unclear reasons,
to one in which adenocarcinoma is the predominant histology in trials of patients
with both unresectable and resectable disease. In the past, adenocarcinomas
of the lung have been more common in women, but they have now become the predominant
histology for both sexes in the US.[13] European series continue to report higher
incidence of squamous cell carcinoma.
Use of Molecular Markers
in Screening
An ideal marker of genetic
change should appear early in the carcinogenic process, yet be specific for
malignancy or for a commitment to subsequent malignant development. It should
be detectable in body tissues that are easily and repeatedly obtainable by relatively
noninvasive and inexpensive procedures, such as exfoliated cells or peripheral
blood rather than bronchoscopic biopsies. The genetic change should be readily
detectable by automated or semiautomated methods, and structural changes in
coding regions of a gene sequence may be better targets than changes that alter
gene regulation. Finally, situations in which a limited number of genetic changes
account for the majority of tumors are appealing in that they limit the number
of mutant sequences to be screened.
For these reasons, genetic
changes in the ras oncogene have been an appealing target. Mutational
activation of ras occurs in approximately 30% of lung adenocarcinomas,
as well as in high frequency in adenocarcinomas of the bowel and pancreas. Activation
almost always involves point mutation at codons 12,13, or 61.[23] Presence of
ras mutations in lung adenocarcinoma is closely linked with prior cigarette
smoking and appears to be an adverse prognostic factor independent of stage.
Sidranski et al[24] first
demonstrated that ras mutations could be identified in exfoliated cells
present in the stool of patients with resectable and potentially curable colon
cancer. Subsequently, Tobi et al[25] were able to detect ras mutations
at codon 12 in exfoliated colonic mucosa in 40% of clinically normal individuals
at high risk for developing colorectal cancer because of strong family history
or a personal history of adenomas. Others have reported detection of mutant
ras in gastric aspirates and stool specimens of patients with pancreatic
cancer.[26,27]
Several recent reports extend
these data to lung cancer. Kelly et al[28] have demonstrated the feasibility
of detecting ras mutations in cells obtained by sputum cytology in patients
with known lung cancer. Mills et al[29] have described using a sensitive assay
for K-ras codon 12 mutations in individuals suspected of having lung
carcinoma. They studied 87 specimens of bronchoalveolar lavage fluid that had
been obtained from 86 patients, 35 of whom underwent subsequent diagnostic bronchoscopy.
Of 52 patients with diagnosed lung cancer, 16 had bronchoalveolar lavage with
K-ras 12 codon mutations, including 14 of 25 patients with adenocarcinoma,
1 of 3 with bronchoalveolar carcinoma, 1 of 5 with large cell carcinoma, and
none of 14 with squamous cell carcinoma. Mutations were detected in an additional
four cases in whom cancer was clinically suspected but had not been clinically
confirmed. Tissue samples from the 35 patients with K-ras mutations in
exfoliated cytology were concordant for the same mutation in all cases. No mutations
were seen in 30 patients with diagnoses other than non-small cell carcinoma.
Unfortunately, the clinical stage of these patients was not described.
In an extension of this
methodology to patients without diagnosed malignancy but at risk, Mao et al[30]
examined sputa that had been obtained during the JHLP with a percentage of patients
having gone on to develop adenocarcinoma. Of 15 patients so identified, analysis
of the resected tumor specimen showed mutated ras or p53 in 10 patients.
In eight of these 10, the same mutation could be demonstrated in sputum samples
that had been obtained at least one year prior to clinical diagnosis.[30]
Healthy individuals as well
as those with cancer have small amounts of soluble DNA fragments in their circulation;
Sorenson et al[31] have taken advantage of this fact and developed a polymerase
chain reaction assay to look for ras mutations (codon 12) in patients
with lung cancer. They have reported preliminary findings indicating the feasibility
of such detection in patients with known lung cancer and are extending the methodology
to study high-risk individuals.
These are all preliminary
studies of limited numbers of patients, and most have used detection of ras
mutations which are present in only approximately 30% of lung cancers. Ras
mutations are not seen in SCLC, so other strategies will have to be developed
for their screening. Substantial technical issues remain to be resolved before
they can be more widely implemented.[32] These or similar tests will no doubt
be available on the internist's laboratory order sheet in the near future. As
noted above, these genetic changes are seen in both invasive tumors and preneoplastic
epithelium. Substantial questions as to their interpretation will arise, and
initial caution is in order.[33]
In determining the various
genetic and phenotypic differences between normal and malignant lung tissue,
several questions should be considered: Which genetic events are causative and
which are bystander? Is there an obligate sequence of genetic events (ie, early
vs late events) or is the cumulative mutational burden the relevant causative
factor? If there is a required or usual sequence, can early events be used as
early detection markers? Are some later events (eg, mdr amplification,
ras activation) prognostic markers independent of stage and histology?
Can an understanding of early events lead to chemoprevention strategies?
These considerations, as
well as the increasing understanding of carcinogenesis as a process comprising
multiple genetic changes occurring over years rather than a single instantaneous
change, raise the question of whether screening programs should be directed
toward the process of carcinogenesis or the end result of cancer. The answer
will depend in part on the frequency with which early events in carcinogenesis
(eg, loss of normal p53 function, loss of mutation repair capacity) result in
invasive malignancy and the toxicity of therapy used to treat them.
Circulating Tumor Markers
Several tumor markers have
been proposed either to follow disease status or for screening of lung cancer.
Both carcinoembryonic antigen and neuron-specific enolase blood levels are commonly
elevated in lung cancer (the former in all histologies, the latter primarily
in SCLC) but have not been reliably elevated in patients with minimal disease
to allow for early detection either de novo or of relapse in patients who have
undergone surgical resection or had complete response to chemotherapy.[34]
Newer approaches to the
development of serum techniques for early tumor detection have focused on detection
of growth factors produced by tumors. Most small cell carcinomas and approximately
15% of non-small cell carcinomas are under autocrine growth stimulation mediated
by gastrin-releasing peptide (GRP). Early studies that attempted to use this
as a marker were not successful, due in part to its very short serum half-life.
The pro-hormone (Pro-GRP) has a longer half-life. Miyake et al[35] have shown
that the ratio of Pro-GRP:GRP in tumor tissue is 1:2, but the ratio in blood
is 76:1. Using a cutoff of 40 pg/mL, these investigators reported elevations
in 0.5% of normal controls, 0.8 % of patients with nonmalignant pulmonary disease,
and 67% of patients with SCLC, with similar results for pure and mixed histologies.
Whether this test will show
sufficient specificity and sensitivity for screening remains to be determined.
Initial mass screening studies in Japan have reported a detection rate of approximately
0.04%. Aguayo et al[36] reported that in smokers, bronchial washing and urine
ProGRP levels are elevated but serum levels are not.
Identification of High-Risk
Groups
If screening tests had no
cost and absolute specificity, there would be little need to limit them to high-risk
populations. Since these conditions are not met by any present test, identification
of groups of individuals at a higher risk of developing lung cancer than the
general population is important for developing screening techniques for reasons
of efficiency, feasibility and predictive value.
Approaches taken to identify
high-risk individuals and groups have classically included demographic factors
(male gender, age), smoking history, and occupational history (exposure to asbestos,
uranium, and chloroethyl ether). The observation that lung cancer develops in
only approximately 10% to 15% of smokers has prompted the search for additional
risk factors. In addition to exposure to other carcinogens, a further potential
source of variability in risk derives from differences in the metabolic conversion
of procarcinogens to active carcinogens, or the degradation and/or excretion
of active carcinogens. During the past decade, interest focused on members of
the cytochrome P450 group of enzymes. There is considerable individual phenotypic
variability in the activity of this system, which may be assessed either functionally,
by rates of metabolism of test substances such as debrisoquine, or by immunoquantitation
of enzyme isotypes. While initial reports suggested that slow debrisoquine metabolizers
were at significantly altered risk,[37] more recent larger studies have not
confirmed these and fail to establish this specific metabolic phenotyping as
a valid indicator of risk.[38] The more general concept of individual variability
of risk based on differences in procarcinogen metabolism may be valid and simply
require better ways of measuring carcinogen exposure at the molecular level.
This may be done either at the level of assay of the appropriate enzymes involved
in the metabolism of key carcinogens or by looking more directly at such DNA
damage as adduct formation or production of double minute chromosomes. Spitz
et al[39] have recently reported that patients with curatively treated upper
aerodigestive cancers whose peripheral lymphocytes were hypersensitive to in
vitro mutation induction by bleomycin had a significantly higher incidence of
synchronous or metachronous second primary malignancies than those with lower
mutagen sensitivity. Mutagen sensitivity did not correlate with age, sex, smoking
status, or tumor stage. It will be important to verify this finding and extend
such studies to prospective monitoring of populations at high risk of developing
their first malignancy. The ability to use an easily obtained and renewable
tissue such as peripheral lymphocytes facilitates tests of this sort for both
the individual patient and the longitudinal studies should there be concern
about changes in mutagen sensitivity over time.[40]
A further approach to defining
individuals at high risk will be to identify those genetic changes that may
facilitate the occurrence, retention, or misrepair of somatic mutations independently
from exposure to exogenous mutagens. The delineation of the mutator phenotype
and its role in the development of human colorectal adenocarcinoma, as well
as evidence that the frequency of occurrence and the efficiency of repair of
various types of p53 mutations are important in their transforming ability,
suggest that this may be a useful approach. Such changes may antedate more specific
changes in the activation of oncogenes or tumor suppressor gene inactivation
and may provide a simpler unitary point of intervention for prevention strategies.
Prospects for New Screening
Approaches
The large trials of screening
by CXR and morphologic examination of exfoliated cells were not only criticized
in terms of their lack of statistical power to detect small differences in mortality,
but also hampered by technologies that could detect cancers late in the biologic
history of the disease. Biologic markers of earlier disease are required.
Table 4. Monoclonal
Antibody Staining of Atypical Sputum
_______________________________________________________________________
Assay Technical
Status |
Assay Result |
Subsequent Lung
Cancer |
No Subsequent
Lung Cancer |
Total |
| Satisfactory |
Positive |
20 |
5 |
25 |
|
Negative |
2 |
35 |
37 |
| Subtotal |
|
22 |
40 |
62 |
| Unsatisfactory |
|
4 |
3 |
7 |
| Total |
|
26 |
43 |
69 |
From Tockman et al[42]
_______________________________________________________________________
Immunostaining of Sputum
Specimens
One approach to improving
the sensitivity of analysis of examination of exfoliated cells is immunostaining
of sputum. Tockman et al[41] reported that immunostaining of cytologically atypical
sputa obtained and archived in the JHLP was able to predict which patients would
go on to develop invasive carcinoma, with a lead of approximately 20 months
prior to clinical diagnosis.[41] These investigators used a pair of monoclonal
antibodies, one raised against a squamous cell line and the other raised against
a small cell cancer line, to examine preserved sputa from 26 patients who were
known to have subsequently developed lung cancer and specimens from 43 participants
who did not develop cancer (Table 4).[42] This dual antibody panel was able
to detect both small cell and non-small cell histologies. The likelihood that
a premalignant specimen from a patient (from this population of patients with
cytologic atypia) who subsequently developed invasive cancer would stain positively
with one or both of the antibodies was highly significant (P=.0001).
This finding requires both
validation and evidence that earlier detection will be therapeutically beneficial.
To facilitate these studies, the Lung Cancer Early Detection Working Group has
begun a prospective trial of evaluation of patients with previously resected
T1-2N0M0 NSCLC. This group is at high risk (approximately 3% per year) of developing
second lung cancers (as well as other aerodigestive tumors), which will reduce
the number of cases required for validation of this concept.[42,43] Patients
are being evaluated by annual induced sputum that is investigated both by conventional
cytologic analysis as well as immunostaining. As of December 1995, this trial
had accrued 956 of a planned 1260, with completion of accrual expected early
in 1997. A correlative study is collecting bronchoalveolar lavage fluid from
these patients for analysis of tumor growth factors, analysis of oncogene mutations
in exfoliated cells, and other possible early tumor markers.
Fluorescence Bronchoscopy
A variety of substances
will preferentially accumulate in neoplastic and preneoplastic tissues. Several
fluorescent porphyrins derivatives show such selectivity. Hung et al[44] observed
differences in the intensity and wavelength of the intrinsic fluorescence of
normal and atypical bronchial mucosa. They have developed a fluorescence bronchoscope
that allows real-time video display of false color images based on ratios of
fluorescence at two different wavelengths. This allows for the localization
and biopsy of areas of bronchial epithelium that appear normal under conventional
white-light bronchoscopy but which display abnormal fluorescence characteristics
(Figure). In preliminary studies of 53 patients and 41 volunteers, white-light
and fluorescence bronchoscopy had similar specificity of 94%, while the sensitivity
of the fluorescence bronchoscopy was 72% compared with 48% for white-light bronchoscopy.[45]
Several questions need to be addressed before fluorescence bronchoscopy can
be widely adopted. While it appears that the technique can identify areas of
epithelial abnormality not seen on conventional bronchoscopy, the true sensitivity
(compared to biopsy) is unknown. Prospective correlation of fluorescence bronchoscopy
and biopsy with examination of the entire bronchial tree removed in patients
undergoing resection would be a valuable way to ascertain such sensitivity information.
Although the technique has been useful in the experience of its developers,
its more general applicability with both pulmonologists and pathologists less
committed to development of such new methodologies is uncertain.
Whitelight and fluorescent
bronchoscopic examination in a patient with carcinoma in situ. The area of reddish
fluorescence represents the lesion. Reproduced from Xillix Technologies Corp,
Richmond, B.C., Canada.
Intervention Strategies
in High-Risk Populations
There is emerging consensus
that carcinogenesis, rather than cancer, is the appropriate target for the major
focus of our clinical strategies. In the past, scientists have concentrated
on the end result (eg, tumor, lump, shadow on CXR) rather than on the molecular
or cellular processes that underlie and antedate it. Such a developmental and
preventive approach is particularly appealing in the setting of a carcinogenic
process that involves a broad field of tissue, such as the respiratory epithelium,
and where multifocal disease (either synchronous or metachronous) is common,
since approximately 3% of patients who survive their first lung cancer develop
a second one each year.[9,46]
Retinoids have key roles
in facilitating normal differentiation of squamous epithelia and in reversing
premalignant changes. Pioneering studies in head and neck cancer[47] have demonstrated
both a reversal of leukoplakia and a reduction in the risk of second malignancies
in patients given high doses of 13-cis retinoic acid. Current confirmatory trials
in head and neck cancer are being conducted with drug doses that are somewhat
lower and better tolerated.
A similar strategy in lung
cancer is rational, and preliminary data are encouraging. Pastorino et al[48]
randomized 307 patients who had undergone curative resection for stage I NSCLC
to observation or treatment with daily oral retinoyl palmitate for one to two
years. After a median follow-up of 46 months, 48% of the control patients and
37% of the treated group developed recurrence or a second primary tumor. Looking
only at second primary tumors in the "field of prevention" (lung,
head and neck, bladder), the treated group experienced a significant reduction
in events from 25 to 13. Neither local recurrence nor distant metastasis was
significantly reduced by treatment. These encouraging results were achieved
with modest toxicity; approximately 10% of patients discontinued treatment due
to objective or subjective toxicity.
These results should not
be interpreted as mandating the routine use of chemopreventive agents. Two recent
reports[49,50] suggest caution in our approach to implementing chemoprevention
strategies based on our present understandings and agents.
Retrospective studies of
dietary habits of smokers who did or did not develop lung cancer suggested a
protective effect from consumption of carotenoids and, to a smaller extent,
alpha-tocopherol. In 1985, a joint United States-Finnish trial was designed
to prospectively evaluate the effects of dietary supplementation with beta-carotene,
alpha-tocopherol, or both, in male smokers 50 to 69 years of age.[49] Using
a two-way randomization design, 29,133 patients were entered. In 1994, a total
of 876 new cases of lung cancer were reported. No reduction in incidence was
seen in the men receiving alpha-tocopherol (change in incidence = -2%; 95% CI,
-14% to +12%). An increased incidence of lung cancer was seen in the men who
received beta-carotene (change in incidence 18%; 95% CI, 3% to 36%). Overall
mortality also was also higher in the men receiving beta-carotene (95% CI, 1%
to 16%, P=0.02). The increased incidence and mortality were surprising and contrasted
with results from animal data, with other human trials using beta-carotene,
and with results of retrospective studies correlating dietary intake with risk
of lung cancer. Although the apparent harmful effects seen in this study may
have been due to chance, it is unlikely that a strong protective effect was
missed.
Lee et al[50] have recently
reported a prospective trial of the use of isotretinoin in a population of heavy
smokers. This was an attempt to replicate in a controlled trial observations
from earlier uncontrolled European trials that the use of the retinoid etretinate
led to reductions in squamous metaplasia. Patients were randomized to treatment
with isotretinoin (1.0 mg/kg) or placebo for six months and were evaluated by
regular bronchoscopy with biopsies taken from multiple sites. The major study
endpoint was change in bronchial metaplasia. The overall metaplasia index decreased
over time for both the treatment and control groups, although the change was
significant only for the control group, and the difference in the change in
metaplasia index for the two groups was not significant.[50] Significant reductions
in dysplasia were seen in 54.3% of the isotretinoin subjects and in 58.8% of
controls. A confounding factor was the cessation of smoking by a large number
of members of both the treatment and control groups; significant reductions
in metaplasia were seen only in those subjects who continued to smoke. It is
unclear from this trial whether the use of the metaplasia index as an intermediate
marker was an unfortunate choice or the pharmacologic intervention was ineffective.
Changes in smoking (and possibly dietary) behaviors that may accompany participation
in trials of chemopreventive agents may alter the processes of carcinogenesis
and need to be carefully analyzed in phase III trials.
The message from these two
"negative" trials is not that chemoprevention has failed, but rather
that it remains an area warranting increased laboratory and clinical investigation.
Cautions in the Application
of New Screening Methods for Preneoplasia
The rapid development of
highly specific and sensitive tools for detection of genetic changes in respiratory
epithelium must be applied with both speed and caution in the clinic. There
is little if anything in biology with absolute specificity. Cancer represents
a maladaptive (to the individual organism, although not necessarily to the species)
choreography of the usual repertoire of cellular responses and processes. Even
structurally abnormal oncogene products (eg, mutated ras gene product)
work their harm by performing a normal function (signaling for cell growth)
in improper circumstances (the absence of an activating ligand for a growth
factor receptor). The line between malignancy and premalignancy is likely to
be ill marked and may shift over time. Benefit is likely to be seen not only
in approaches that aim for early detection and intervention in what is clearly
malignant, but also in detection and interference with the process of carcinogenesis;
however, a clarity as to which of these processes we are dealing with is essential.
Acceptable costs, both social and individual, are likely to be different for
the two approaches.
The high incidence and lethality
of lung cancer have prompted a variety of therapeutic and diagnostic approaches
to reduce this appalling toll. Primary prevention through the reduction of cigarette
smoking is likely to be the most successful strategy in achieving this goal.
However, were all current smokers in the United States to quit today, we would
still face more than a million cases of lung cancer developing over the next
decade from cigarettes already smoked.
Conclusions
No screening strategy has
yet been shown in a prospective trial to reduce lung cancer mortality, although
screening of a high-risk group of male smokers 45 years of age or older could
provide a shift to earlier stage at diagnosis and greater resectability for
the screened cases. These gains, which are consistent with the shifts that would
be seen from lead-time bias and length biased sampling, did not translate to
consistent benefit either in survival of the detected cases or in a reduction
in mortality for the population as a whole.
On a general health policy
level, present data do not support the implementation of screening policies
based on regular CXR and sputum cytology in older male smokers. This should
not lead primary physicians to believe that an indolent approach to symptoms
consistent with lung cancer can be neglected or indolently evaluated in the
patient at risk. Past studies may not apply to the present situation. We have
different populations to screen, with an increasing number of former rather
than current smokers. Some progress in the treatment of lung cancer has been
realized, and our understanding of the early molecular and cellular events in
lung cancer development is providing us with tools that can detect preneoplastic
or early neoplastic changes at a time when the tumor burden is several logs
less than with present radiographic detection. A key step from early detection
to prevention will be made as methods are developed to arrest or reverse some
of these molecular events. The potential for application of these new technologies
to today's clinical trials and tomorrow's clinical practice should leave us
with realistic optimism for the role of screening and early intervention in
lung cancer.
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