Chemoprevention of Lung Cancer*
Steven E. Benner, MD; Scott M. Lippman, MD; and
Waun Ki Hong, MD
Treatment of lung cancer remains frustrating. Most patients with lung cancer are not candidates for curative
therapy, and new therapies have not made a substantial
impact on survival. Consequently, some clinical investigators have focused their efforts on developing prevention strategies. Chemoprevention, the administration of agents to block or reverse carcinogenesis, is being investigated in ongoing trials. Studies of
chemoprevention in lung cancer have included trials to
reverse premalignant lesions such as sputum atypia or
many as 85% of lung cancer cases may be
directly attributed to cigarette smoking. As a
public health threat, tobacco is unrivaled. Smoking
cessation efforts and prevention strategies aimed at
young people must be the mainstays of lung cancer
prevention. Even with smoking cessation, however, a
significant risk for tobacco-associated malignancy
persists. Although the risk of developing lung cancer
declines among former smokers, it takes over a
decade to approach the risk for age- and sex-matched
control subjects who never smoked. Consequently,
the numbers of individuals at risk for developing lung
cancer will remain very high, even with the institution of more aggressive public health standards for
tobacco control. As an adjunct to smoking cessation,
efforts are under way to develop additional lung
cancer
prevention strategies.
Chemoprevention, the administration of drugs to
block or prevent the development of invasive cancer,
is a promising approach currently being studied in
clinical trials.' Lung cancer chemoprevention trials
have included studies designed to reverse premalignant lesions, prevent an initial lung cancer, and to
prevent second primary tumors in patients previously
treated for lung cancer.
REVERSAL
OF
PREMALIGNANCY
With current diagnostic techniques, the diagnosis
of even early-stage disease is associated with aggressive biologic behavior and poor prognosis. Changes in
*From the
Department of Thoracic/Head and Neck Medical
Oncology, The University of Texas, M.D. Anderson Cancer
Center, Houston.
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metaplasia of the bronchial epithelium. Clinical trials of lung cancer prevention have often studied
groups of participants with tobacco or asbestos exposure. Other clinical trials are being conducted among
patients who have been treated for an early-stage lung
cancer. As the result of diffuse epithelial injury, these
patients are at very high risk for developing second primary tumors, predominantly in the lungs and upper
aerodigestive tract. It is our hope that these studies may
establish a new strategy for preventing lung cancer.
squamous
(CHEST 1995; 107:316S-321S)
cytologic or histologic study that may precede clinically evident cancer are being sought. Identification
of precursor lesions could lead to an earlier diagnosis of lung cancer and, hopefully, an improved prognosis. Sputum atypia and squamous metaplasia of the
bronchial epithelium have been proposed as markers
of lung carcinogenesis. Sputum atypia is often present
when lung cancer is apparent, and its detection may
precede the diagnosis of lung cancer. With an
increase in its severity, sputum atypia becomes more
closely associated with lung cancer. Squamous metaplasia of the bronchial epithelium occurs in response
to lung injury. Exposure to carcinogens like tobacco
smoke is associated with an increase in the extent of
squamous metaplasia. Squamous metaplasia is frequently found in the lung epithelium examined in
resected lung cancer specimens.2
Studies to reverse the presence of sputum atypia
and bronchial squamous metaplasia have been performed (Table 1).3-11 The premise of these trials is
that reversal of these histologic changes, which are
associated with both carcinogen exposure and lung
cancer, could also lead to a decrease in the incidence
of lung cancer. Completed studies have evaluated the
impact of chemoprevention agents on the presence of
histologic or cytologic changes. Before any conclusions could be made regarding the relationship
between changes in biomarkers, such as premalignant lesions, and the incidence of lung cancer, the
biomarkers would have to be validated in a study
using cancer incidence as the end point.
Saccomanno et a13 evaluated the effect of 13-cisretinoic acid (cRA) (1 to 2.5 mg/kg/d) in reversing
abnormalities detected in sputum cytologic studies.
They studied a diverse group of 26 patients, including 5 who were known to have invasive cancer. All
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Table 1-Reversal of Premalignant Lesions in the Lung
Source
Study Design
Saccomanno et a13
Phase 2
Band et al4
Heimburger et al5
Observation of
uranium workers
Phase 3
Arnold et a16
Phase 3
McLarty et a17
Phase 3
Mathe et al,8
Phase 2
Gouveia et al,9
and Misset et allo
Lee et all'
Phase 3
Agent
End Point
Reversal sputum
atypia
Reversal sputum
atypia
Reversal sputum
atypia
Reversal sputum
atypia
cRA
Reversal sputum
atypia
Bronchial squamous
metaplasia
(-carotene and
retinol vs placebo
Etretinate
Bronchial squamous
cRA vs placebo
No. of Patients
Results
26
No change in a mixed
16
Improvement without
80
Improvement associated
with folate and B12
138
No difference between
groups, overall
population
intervention
Folate and B12 vs
placebo
Etretinate vs placebo
improvement
Ongoing
40
Improvement in squamous
metaplasia
69
Improvement in both
groups, associated with
metaplasia
smoking cessation
patients were treated with the retinoid. Although
some changes in cellular morphologic features were
noted, there was no change overall in the extent of
sputum atypia.
Randomized trials have also been performed. Heimburger et a15 compared a combination of folate (10
mg/d) and vitamin B12 (500 mg/d) with placebo in
participants who had a history of .20 pack-years of
smoking and bronchial squamous metaplasia detected by sputum cytologic study. Seventy-three
evaluable patients completed the 4 months of treatment. The intervention was well tolerated. The
authors believed that the folate and vitamin B12
treatment was associated with greater improvement
in sputum cytologic findings than was placebo. To
our knowledge, however, these results have not yet
been duplicated.
Arnold et a16 recently described the results of a
randomized, placebo-controlled trial using etretinate
to reverse sputum atypia. One hundred fifty smokers
were randomized to treatment with etretinate, 25
mg/d, or placebo for 6 months. Treatment was well
tolerated and there was evidence of good participant
compliance. No difference in the presence of sputum
atypia was observed between the two groups following treatment.
An ongoing randomized, placebo-controlled trial
to reverse sputum atypia is studying cigarette smokers and individuals with a history of asbestos exposure.7 The treatment is d-carotene and retinol vs
placebo. This study is much larger than the previously reported sputum atypia intervention trials.
The findings of these intervention trials must be
interpreted with an understanding of the variability
of sputum atypia. Band et a14 followed a group of 16
uranium workers with marked sputum atypia. Three
of the four patients who had both marked sputum
atypia and cells suspicious for malignancy developed
cancer within 3 years. In the remaining 13 patients,
however, the sputum specimens reverted to mild
atypia or normal sputum cytologic findings. Tests of
sputum cytology also may fail to detect changes in
endobronchial biopsy specimens.
To avoid the variability found in sputum specimens, a group of French researchers performed a
phase 2 study to evaluate changes in the bronchial
epithelium.8'10 Volunteers with a history of heavy
smoking (>15 pack-years) underwent bronchoscopy
with endobronchial biopsy specimens taken systematically from ten sites. The extent of bronchial
squamous metaplasia present in these biopsy specimens was quantified using a metaplasia index (MI),
defined as the number of histologic sections with
squamous metaplasia divided by the numbers of
sections examined and multiplied by 100 to be
expressed as a percentage. Forty volunteers with an
MI >15% received a 6-month treatment with etretinate, 25 mg/d, and then underwent a second bronchoscopy with repeated biopsy specimens taken.
Both the etretinate and the bronchoscopies were well
tolerated. Following the 6 months of treatment, the
MI had significantly declined, from 34.57 to 26.96%,
for participants who continued smoking (p<0.001).
The MI for four patients who quit smoking during the
treatment period declined to 0%.
The findings of this French study were tested in a
recently published randomized, placebo-controlled,
double-blind clinical trial performed at the M.D.
Anderson Cancer Center." Volunteers were enrolled
who had 215 pack-years of smoking and who had
not quit smoking more than 6 months ago. Of the 152
participants who underwent the initial bronchoscopy, 86 were found to have an MI >15% based on
biopsy specimens taken from six sites. Sixty-nine
participants completed a 6-month treatment period
with cRA, 1 mg/kg/d, or placebo. On repeated
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Table 2-Patient Eligibility for Trial to Prevent
Second Primary Tumors in Stage I NSCLC
(Intergroup Study 91-025)
Patient Eligibility
* Have undergone complete resection of NSCLC
* Have postoperative stage I (TINOMO or T2NOMO) disease
* Must be between 6 wk and 36 mo from the initial diagnosis of
lung cancer
* Have not received cbemotherapy, radiotherapy, immunotherapy
for lung cancer
* Have fasting triglyceride level <320 mg/dL
* Have no concurrent cancer or cancer within 5 yr except
localized nonmelanoma skin cancer
bronchoscopy, the MI declined from 35.8 to 28.1%
for all participants (p=0.01). There was, however, no
further improvement associated with the retinoid
treatment. The improvement in both treatment
groups was most significant for those participants
who quit smoking during the treatment. The biopsy
specimens obtained in the trial represent a unique
resource for studying the process of field carcinogenesis. The specimens are being evaluated for
aneuploidy, proliferating cell nuclear antigen, epidermal growth-factor receptors, micronuclei, oncogene expression, and nuclear retinoic acid receptors.
A follow-up study to evaluate the effects of another
synthetic retinoid, N- (4-hydroxyphenyl) retinamide
(4-HPR), has recently been initiated at M.D. Anderson Cancer Center. This study will also compare
changes in endobronchial biopsy specimens before
and after treatment. The study will recruit previously
treated cancer patients who are at high risk of field
carcinogenesis based on the presence of squamous
metaplasia or dysplasia in the bronchial epithelium.
The study uses a randomized, placebo-controlled
design.
PRIMARY LUNG CANCER CHEMOPREVENTION
Trials designed to prevent an initial lung cancer
have often focused on individuals with a history of
tobacco smoking or occupational exposure to asbestos. Because the end point of these trials is the
development of clinically apparent cancer, the trials
must be large and continue for several years. The
statistical strength of these trials is greatly influenced
by the numbers of lung cancers detected.
A large, recently published chemoprevention trial
reported the impact of at-tocopherol and /-carotene
on the development of lung cancer among 29,133
male smokers in southwest Finland.12 Men between
50 and 69 years of age with a history of smoking at
least five cigarettes per day were eligible to participate. Study participants averaged more than one
pack smoked per day and had smoked an average of
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35.9 years. The study used a 2X2 factorial design,
with patients receiving 3-carotene, 20 mg/d, a-tocopherol, 50 mg/d, both agents, or placebo. Median
follow-up was 6.1 years. The results were unexpected; there was an increase in the incidence of lung
cancers among participants who received /3-carotene
(474 cases) compared with those who did not (402
cases) (p=0.01). The increased incidence of lung
cancer among the /3-carotene users became apparent
after 18 months and continued to increase with
longer follow-up. There was no significant impact of
a-tocopherol on lung cancer incidence, and there was
no evidence of an interaction between a-tocopherol
and /-carotene. Overall mortality was also increased
by 8% among the /-carotene-treated participants
(p =0.02).
The increased lung cancer incidence and overall
increased mortality associated with /-carotene treatment appears to be at odds with earlier epiedemiologic studies. This study emphasizes the need to
confirm the hypotheses generated by the epidemiologic studies before implementing them as public
health recommendations. /-Carotene is only one
constituent of a diet high in fruits and vegetables. The
difference observed in the study could, of course, also
be the result of chance. Data from other trials using
/-carotene should help place the findings of this trial
in perspective.
Other ongoing primary lung cancer prevention
trials include the Carotene and Retinol Efficacy Trial.13 The trial was initiated first in pilot studies
performed among cigarette smokers and asbestosexposed workers.14"15 The pilot studies were used to
establish the safety of the intervention and to evaluate data monitoring and compliance issues. The
Carotene and Retinol Efficacy Trial is comparing the
efficacy of /-carotene (30 mg/d) and retinyl palmitate (25,000 IU/d) with that of placebo in preventing
lung cancer. Approximately 18,000 participants will
be enrolled and followed for a mean of 6 years.
The Physicians Health Study is also evaluating the
health effects of /-carotene. Cancer incidence and
mortality at all sites will be evaluated.
SECOND PRIMARY TUMOR PREVENTION
Patients treated for head and neck cancer or lung
cancer have a substantial risk of both relapse of their
initial tumor and development of a second primary
tumor.161-8 Inhalation of carcinogens results in diffuse epithelial injury throughout the upper aerodigestive tract and lungs. Consequently, an initial
cancer in these organs identifies the patient as being
at increased risk for a second cancer due to both
previous carcinogen exposure and host susceptibility.
The risk of these second primary tumors is most obvious in patients treated for early-stage disease. In
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Complete
resection of
stage
NSCLC
(Ti NO or T2NO)
6 wk to 3 yr
before registration
R
E
G
s
T
E
R
Run-in period
8wk
single-blind
R
A
N
D
0
M
cRA 30 mg po qd x 3 yr
z
A
T
placebo qd x 3 yr
0
N
double-blind
4-year follow-up
period after treatment
FIGURE 1. Intergroup trial to prevent second pri-
these patients, the competing risk of relapse is less
than for patients with advanced disease. Because of
the extremely high risk of developing second primary
tumors in these patients, chemoprevention trials have
focused on patients treated for head and neck cancers
or lung cancer.
Hong et al19 reported the results of an adjuvant
trial performed in patients with squamous cell cancer of the head and neck. Following primary treatment with surgery, radiation therapy, or both, patients who were free of disease were randomized to
receive 1 year of cRA (50 to 100 mg/m2/d) or placebo. The adjuvant treatment had no impact on recurrence of the initial tumor or development of distant metastases. Presumably, the retinoid could not
prevent the progression of invasive cancer. The
cRA-treated group, however, did have a much lower
incidence of second primary tumors. Only 4% of 49
cRA-treated patients vs 24% of 51 placebo-treated
patients developed second primary tumors (p=0.005).
With longer follow-up, the beneficial effect of the
retinoid treatment has persisted.20 This small trial
showed that cRA could prevent the development of
second primary tumors following head and neck
cancer. The concept of field carcinogenesis hypothesizes that the same process is taking place in the
lungs and could possibly be prevented with retinoid
treatment. In this trial, the very-high-dose retinoid
therapy was associated with significant toxic reactions, especially dry skin, cheilitis, conjunctivitis, and
hypertriglyceridemia. These side effects would limit
the use of this high-dose regimen in large chemoprevention trials.
Results from an oral premalignancy chemoprevention study demonstrated that, following 3 months
of high-dose cRA, a low-dose cRA maintenance regimen (0.5 mg/kg/d) was both effective and well tolerated.21 Based on this evidence of efficacy and decreased side effects, low-dose cRA therapy was chosen for our ongoing second primary tumor prevention
trials in patients treated for head and neck cancer or
non-small cell lung cancer (NSCLC).
The adjuvant trial using cRA following treatment
for head and neck cancer led to the chemoprevention
trial following resection of stage I NSCLC. This randomized, placebo-controlled, double-blind trial is
being performed throughout the United States and
Canada as an intergroup study. The trial will deter-
mary
tumors
following NSCLC.
mine whether cRA, 30 mg/d, taken for 3 years will
prevent the development of second primary tumors
(Fig 1). Study participants will be followed up for an
additional 4 years after the treatment period. Cur-
rently, 800 of the planned 1,260 patients have been
enrolled from 112 institutions.
Some aspects of eligibility are summarized in Table 2. The long period of eligibility, from 6 weeks to
36 months after the initial diagnosis of lung cancer,
reflects the stable, persistent risk of second primary
tumors in this patient population. Triglyceride levels
are included in the eligibility criteria because cRA
treatment may be associated with hypertriglyceridemia, and patients with elevated triglyceride levels
without treatment appear to be most susceptible to
further increases.
The stratification variables for the study are histologic feature (squamous vs nonsquamous), T stage
(TI vs T2), and smoking status. Most of the information available on retinoid chemoprevention has
focused on its effects following squamous cell cancer.
Pastorino et a122 reported evidence of retinoid efficacy in chemoprevention following other types of
NSCLC. Because histologic features could potentially influence outcome if the treatment arms were
unbalanced, histologic features were used as a stratification variable. T stage is a stratification variable
due to the much higher relapse rates observed
following resection of T2 compared with TI lesions.
The impact of continued smoking on the development of second primary tumors is not clear. Smoking
history is a powerful predictor of initial lung cancer
and may also be a risk factor for the development of
second primary tumors.
An adjuvant trial using retinyl palmitate as treatment following resection of stage I NSCLC has
recently been reported.22 Pastorino and colleagues22
randomized 307 patients to treatment with retinyl
palmitate (300,000 IU/d) for 12 months or observation. With a median follow-up of 46 months, the investigators had observed 18 patients with a second
primary tumor in the retinyl-palmitate-treated group
compared with 29 patients in the observation group.
In the field of prevention (ie, the lungs, head and
neck, or bladder), the time to development of a second primary tumor favored the retinoid-treated patients (p=0.045). Prolongation of the disease-free
interval also favored the retinyl palmitate group,
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with borderline statistical significance (p=0.054).
Treatment was well tolerated. The side effects observed, predominantly dryness of the skin and mucous membranes, were typical for retinoid therapy.
Based on the encouraging results from this study,
a large chemoprevention trial has been initiated
throughout Europe. The study, called Euroscan,
consists of two parallel clinical trials to prevent second primary tumors following early-stage NSCLC or
head and neck cancer.23 The study uses a 2X2
factorial design. Patients receive treatment with retinyl palmitate, N-acetylcysteine, both drugs, or placebo. This study continues to accrue new patients.
There is also a tremendous risk of developing second primary tumors following small cell lung cancer
(SCLC).2425 Unfortunately, most patients will die of
their initial SCLC. In a series from the M.D. Anderson Cancer Center and the National Cancer InstituteNaval Medical Center, about 10% of patients were
alive 2 years following their diagnosis.26,27 For these
survivors, the risk of developing a second primary
tumor was extremely high: 14 of 51 patients and 18
of 55 patients, respectively, developed second primary tumors in the two series. Unlike second primary
tumors following head and neck cancer or NSCLC,
the risk of second primary tumors following SCLC
appears to increase over time. Although the population at risk is relatively small due to the lethality of
SCLC, the tremendously high risk of second primary
tumors raises the need for chemoprevention. A US
intergroup study to prevent second primary tumors
among survivors of SCLC has been proposed.
CONCLUSIONS
Chemoprevention is being studied actively as a
strategy for lung cancer prevention. At present, the
approach remains experimental. It is our hope that
ongoing studies will establish a clinical role for
chemoprevention by demonstrating a reduction in
cancer incidence. The laboratory investigations being performed in conjunction with these studies will
help explain the process of lung carcinogenesis and
may be used to guide the development of future
chemoprevention approaches.
ACKNOWLEDGMENTS: The authors express their apprecia-
tion to Helen Gard for her assistance in the preparation of the
manuscript. Drs. Benner and Lippman are recipients of American Cancer Society Clinical Oncology Career Development
Awards.
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