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Current Status of Retinoid Chemoprevention of Lung Cancer

Current Status of Retinoid Chemoprevention of Lung Cancer

ABSTRACT: Clinical trials have suggested that retinoid chemoprevention prevents the development of second primary tumors following head and neck or non-small-cell lung cancer. The findings of these initial studies are now being evaluated in large multi-institution chemoprevention trials. If successful, these ongoing trials will establish the clinical role of retinoids in lung cancer prevention. The findings of these trials may also lead to strategies for primary lung cancer prevention. Until the results of these studies become available, however, lung cancer chemoprevention remains an experimental approach. The recent unexpected findings of increased lung cancer incidence in a beta-carotene study in Finnish smokers stresses the importance of establishing the efficacy of chemoprevention agents in carefully conducted clinical trials. [ONCOLOGY 9(2):205-216, 1995]

Introduction

Chemoprevention is a strategy to prevent the development of cancer
through the administration of drugs. This approach is now being
widely studied in a variety of clinical settings [1]. The poor
prognosis of lung cancer patients has led investigators to study
chemoprevention as a means of decreasing lung cancer incidence.
Tobacco cessation and public health efforts to prevent the next
generation from becoming addicted to tobacco must be the mainstays
of lung cancer prevention. Even with successful cessation, however,
an increased risk of developing lung cancer persists in former
smokers for more than a decade. Chemoprevention may be a means
of decreasing the incidence of lung cancer among both current
and former smokers.

The central idea guiding lung cancer chemoprevention efforts is
the concept of the diffuse injury of respiratory epithelium resulting
from chronic carcinogen exposure. Slaughter and his colleagues
initially described this process as field cancerization [2]. The
widespread injury to the respiratory epithelium led investigators
to consider a systemic treatment. The concept of chemoprevention
is also supported by the understanding of epithelial carcinogenesis
as a multistep process.

Among the potential agents for lung cancer chemoprevention, the
use of retinoids, compounds with vitamin A-like activity, is supported
by the results of both epidemiologic studies and animal experiments
[3-6]. For clinical studies, the development of oral leukoplakia
as a model of tobacco-associated carcinogenesis has also been
useful in developing possible regimens for lung cancer chemoprevention
[7]. The lesions of oral leukoplakia are premalignant and, over
a period of years, may develop into invasive cancers [8]. Trials
have demonstrated that retinoids, including isotretinoin (Accutane,
13-cis-retinoic acid), could reverse these lesions [9].

The concept of field cancerization is supported not only by the
frequent occurrence of premalignant lesions, such as leukoplakia,
in carcinogen-exposed individuals, but also by the development
of multiple primary tumors. For patients who survive an initial
head and neck or lung cancer, development of a second primary
tumor within the respiratory epithelium represents a great threat
to their health [10-12]. For patients who have been treated for
a head and neck cancer, the lifetime risk of developing a second
primary tumor exceeds 30%. Building on the results of oral leukoplakia
studies, retinoid chemoprevention trials have recently focused
on the prevention of second primary tumors in patients who have
been treated for a head and neck or lung cancer.

Completed Retinoid Chemoprevention
Studies

In a landmark study, Hong et al [13] described a reduction of
second primary tumors in head and neck cancer patients treated
with isotretinoin. Following surgery and/or radiation therapy
for squamous cell cancer of the head and neck, patients were randomly
assigned to either isotretinoin, 50 to 100 mg/m²/day, or
placebo given for 1 year as an adjuvant treatment. In the initial
report, with a median follow-up of 32 months, second primary tumors
had developed in 12 (24%) of the placebo-treated patients, compared
with only two (4%) of the isotretinoin-treated patients (P
= .005). The retinoid treatment had no impact on the recurrence
of the initial cancer. Isotretinoin apparently suppressed foci
of damaged epithelium from progressing into invasive cancer, but
was ineffective as therapy once the cancer had developed. The
second primary tumors that occurred during the study were predominantly
in the carcinogen-exposed field of the head and neck, lungs, and
esophagus.

Although the results of this small trial (103 patients) are impressive,
the high-dose retinoid treatment was associated with considerable
toxicity. Side effects included dry skin, cheilitis, elevated
triglycerides, and conjunctivitis. One third of the isotretinoin-treated
patients were unable to complete the year of therapy as planned.

Recently the data have been reanalyzed, with the median follow-up
extended to 54.5 months (Table 1) [14]. With longer follow-up,
the retinoid-treated patients have continued to have fewer second
primary tumors; seven (14%) in the isotretinoin group, compared
with 16 (31%) in the placebo group (P = .042). When only
those second primary tumors that developed in the carcinogen-exposed
field were considered, the results were more impressive, with
second primary tumors developing in only three (7%) of the isotretinoin
patients, compared with 13 (33%) in the placebo-treated group
(P = .008). These results suggest that the beneficial chemopreventive
effect of isotretinoin persisted after the year of treatment.
The suppression of second primary tumors occurred despite the
fact that the patients, as a group, took less of the retinoid
than had initially been intended when the study was designed.

Because the high-dose isotretinoin used in this adjuvant study
was poorly tolerated, there was considerable interest in determining
if the chemopreventive effect could be maintained using lower,
less toxic doses. The findings of a recent randomized oral leukoplakia
chemoprevention trial are encouraging [15]. Patients were initially
given a 3-month induction course of high-dose isotretinoin, followed
by a 9-month maintenance treatment with a low dose of isotretinoin,
0.5 mg/kg/day, or beta-carotene, 30 mg/day. The low-dose isotretinoin
was effective in maintaining the benefits achieved during the
induction phase; only two (8%) of the patients in the isotretinoin
group had progression of the leukoplakia during the maintenance
treatment, compared with 16 (55%) of the beta-carotene group (P
< .001). The low-dose isotretinoin was also well tolerated;
none of the isotretinoin patients discontinued therapy during
the maintenance treatment due to toxicity (Table 2).

A group from France has recently reported the findings of a study
that evaluated the efficacy of the synthetic retinoid etretinate
(marketed as Tegison in the United States for the treatment of
psoriasis) to prevent second primary tumors following squamous
cell cancer of the oral cavity or oropharynx [16]. Patients were
randomly assigned to treatment with etretinate, 50 mg/day for
1 month, followed by 25 mg/day for 24 months, or placebo. Among
the 316 patients studied, there was no reduction in second primary
tumors associated with the retinoid treatment. The two treatment
groups were equivalent both for the occurrence of second primary
tumors and relapse of the initial cancer.

This prospective trial did, however, confirm the high rate of
second primary tumors following head and neck cancer. With a median
follow-up of 41 months, 24% of the patients had developed a second
primary tumor. Consistent with the concept of field carcinogenesis,
79% of the second primary tumors occurred within the head and
neck, lungs, or esophagus. Interpretation of this report was hampered
by the lack of detail with regards to tobacco intake, alcohol
history, compliance, and toxicity [17].

In a trial performed among 307 patients following resection of
a stage I non-small-cell lung cancer, Pastorino et al [18] observed
a beneficial effect associated with retinyl palmitate treatment.
Following surgery, patients were randomly assigned to treatment
with retinyl palmitate, 300,000 IU per day for 1 year of observation.
Compliance was estimated to be greater than 80%, and the retinyl
palmitate was well tolerated. Only three patients dropped out
of the treatment arm due to toxicity from the retinoid.

Retinyl palmitate treatment was associated with a reduction in
second primary tumors. Eighteen patients in the retinyl palmitate
group developed second primary tumors, compared with 29 patients
in the control group. Reduction of tobacco-associated second primary
tumors was more pronounced. With a median follow-up of 46 months,
13 retinyl palmitate-treated patients developed tobacco-associated
second primary tumors, compared with 25 patients in the control
group. The time to the development of a tobacco-associated second
primary tumor also favored the retinyl palmitate-treated patients
(P = .045). This study provided the rationale for the ongoing
European study known as Euroscan (described below).

Another approach to retinoid chemoprevention of lung cancer has
been to test the ability of these agents to reverse histologic
or cytologic changes that may precede the development of invasive
disease. Arnold et al [19], for example, evaluated the ability
of etretinate, 25 mg/day, to reverse sputum atypia in specimens
collected from chronic smokers. Changes in sputum atypia were
assessed at the completion of a 6-month treatment period. No difference
between the etretinate and placebo groups in the degree of sputum
atypia was noted.

In order to evaluate the effect of the chemopreventive agent directly
in the bronchial epithelium, a group of French investigators performed
a study using serial bronchoscopy, with endobronchial biopsies
taken from chronic smokers [20-22]. In this uncontrolled phase
II study, patients found to have squamous metaplasia of the bronchial
epithelium in specimens obtained during their initial bronchoscopy
were treated with etretinate, 25 mg/day for 6 months. After the
completion of the treatment course, the investigators noted a
decline in the extent of squamous metaplasia.

As the result of this study, a randomized trial was performed
in the United States [23]. Asymptomatic chronic smokers were recruited
to participate. Volunteers underwent bronchoscopy with endobronchial
biopsies taken from six specific anatomic sites. Participants
who were found to have a squamous metaplasia index greater than
15% and/or dysplasia were then randomized to 6 months of treatment
with either isotretinoin, 1 mg/kg per day, or placebo. Of the
152 participants initially registered in the study, 93 had a metaplasia
index greater than 15%.

The results of the 6-month treatment course were recently published
for 69 study participants [23]. For the group as a whole, the
extent of metaplasia declined over time. There was no significant
difference, however, between the isotretinoin and placebo groups
in the reduction of metaplasia. The most important predictor of
a decline in the extent of metaplasia was smoking cessation during
the treatment period. While the results of this study were consistent
with the findings in the French study with etretinate, the presence
of a control group in the isotretinoin study completely altered
the interpretation of the results.

Neither sputum atypia nor squamous metaplasia of the bronchial
epithelium is likely to be useful as an intermediate marker of
lung carcinogenesis, and both are too variable and nonspecific
to guide chemoprevention trials. Sputum specimens, endobronchial
biopsies, or bronchial washings may, however, be used to study
other, potentially more powerful markers of lung carcinogenesis.
There is now considerable interest in studying markers of proliferation,
genetic injury, or oncogene expression, which may be critical
in tobacco-associated carcinogenesis [24-28]. Understanding of
the retinoic acid receptors may lead to the improved efficacy
and decreased toxicity of retinoid chemoprevention [29,30]. No
intermediate marker of lung carcinogenesis has yet been validated
that could serve as a surrogate endpoint for lung cancer incidence
in chemoprevention trials [31]. Such a marker would be extremely
useful in aiding the clinical development of lung cancer chemoprevention.

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