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Lung Cancer — Time to Move on from Chemotherapy
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In
2001 lung cancer caused more than 1 million deaths worldwide. Despite
the well-recognized link between tobacco use and the development of
lung cancer, the number of new cases continues to rise, especially
among women. In girls and women 15 to 64 years of age, lung cancer
is now the leading cause of death from cancer, and this disease
remains the most common cause of death from cancer in men.1
During the past 20 years, numerous efforts
have been made to reduce the death rate among patients with lung
cancer. Treatment involves surgery, radiation therapy, combination
chemotherapy, or a combined approach. Yet after 20 years, the
improvement in long-term survival has been slight. Indeed, today a
minority of patients survive more than one year after diagnosis, and
less than 15 percent survive for five years. In this issue of the
Journal, two groups of
investigators report on new combination-chemotherapy regimens for
treating small-cell lung cancer2 and
advanced, inoperable non–small-cell lung cancer.3
Small-cell lung cancer accounts for 20 to 25 percent of all new
cases of lung cancer. At diagnosis, 40 percent of patients have
limited disease, defined as disease confined to the thorax. With
chemotherapy plus radiotherapy and the selective use of prophylactic
cranial irradiation, the median survival of these patients is 18 to
24 months, and up to 20 percent of them may survive for more than 2
years. Without treatment, the median survival is only 6 to 12 weeks.
Patients with extensive disease (the remaining 60 percent of all
new cases of small-cell lung cancer) have, at the time of diagnosis,
metastases involving one or more sites such as the brain, liver,
bone, or bone marrow. With combination chemotherapy, the median
survival of these patients is seven to nine months, and few, if any,
live more than two years. Twenty years of clinical trials involving
such patients have yielded an improvement in survival of only two
months.4
The current standard chemotherapy regimen is etoposide plus
cisplatin (or carboplatin). In this issue of the Journal, Noda et al.2
report results with a new combination of irinotecan (a topoisomerase
I inhibitor) and cisplatin for the treatment of extensive small-cell
lung cancer. They found a 3-month prolongation of the median
survival with this combination (12.8 months, vs. 9.4 months with
etoposide plus cisplatin), as well as an impressive 2-year survival
rate of 19.5 percent with this regimen (as compared with 5.2 percent
with etoposide plus cisplatin). These results appear to indicate an
advance in the treatment of extensive small-cell lung cancer, but
confirmatory trials are required before the new combination becomes
the standard of therapy for this disease.
The role of chemotherapy in the treatment of advanced, inoperable
non–small-cell lung cancer continues to be a subject of debate.
In the late 1990s, many phase 2, single-institution trials of new
agents alone or in combination with cisplatin found high response
rates (40 to 50 percent) with these agents, and substantial numbers
of patients survived for one or two years. The study of more than
1200 patients reported by Schiller et al. in this issue of the Journal3 and
the recent study of more than 400 patients by Kelly et al.5
compared several combinations of agents. The results continue to
raise questions about the role and efficacy of combination
chemotherapy in advanced non–small-cell lung cancer. In both
studies, the response rates were lower than expected (16.6 to 27
percent), as compared with the results of single-institution trials;
the median survival ranged from 7.4 to 8.1 months, and the 1-year
rate of survival approached 31 to 39 percent. In the study by Schiller et al., most patients had
an excellent performance status (Eastern Cooperative Oncology Group
performance status, 0 or 1). In
this trial, excess toxic effects, some fatal, were noted among
patients with a poor performance status, and after the results in
the initial 66 patients with poor performance status were analyzed, further
such patients were excluded from the trial.
These two studies3,5
confirm that the benefits of combination chemotherapy among the
fittest patients with advanced non–small-cell lung cancer are
marginal (with perhaps a gain in median survival of two to three
months). In addition, in the study by Schiller et al., there was no
superior combination regimen, and these authors conclude that
chemotherapy is best offered only to patients with a good
performance status. Whether these results are an improvement over
the results of older trials6,7 is
questionable when one considers the effects of stage migration
(resulting from the increasingly detailed workup of patients), as
well as the fact that in the other large trials,3,5
patients with excellent performance status accounted for the
majority of the eligible subjects.
It is clear that new approaches are required. These should include
prevention, screening and early detection, and novel treatments based
on our understanding of the biology and molecular biology of this
disease. Tobacco products kill more than 450,000 Americans each
year, and another 50,000 die of the effects of secondhand smoke. A
tobacco-free environment would greatly improve the health of our
society and would reduce the rates of death from coronary artery
disease, lung cancer, and chronic lung disease.8
Will the early detection of lung cancer decrease mortality from
the disease? In early studies, screening with radiography of the
chest or cytologic examination of sputum samples did not improve
survival, and thus screening for lung cancer fell out of favor.
However, several new approaches are noteworthy. One is the use of
spiral computed tomography (CT) at low doses of radiation.9,10
This procedure can detect nodules highly suggestive of lung cancer
in asymptomatic persons who are at high risk. In one study of 1000
such persons, 23 of 27 cancers (85 percent) detected with the use of
spiral CT were stage I cancers.9
Chest radiography alone detected only seven cancers in this group
(26 percent). Since most of the cancers that were detected with spiral
CT were early-stage tumors curable by surgery, this technique may
reduce mortality from lung cancer. However, because there still are
no data on mortality from lung cancer after screening with spiral
CT, this technique cannot currently be advocated for mass screening.
Studies of the molecular biology of lung cancer and lung-cancer
cell lines have increased our understanding of the multistep pathway
for the pathogenesis of lung cancer. Genetic alterations such as
mutant K-ras and TP53 genes are detectable on cytologic
examination of sputum and bronchial-lavage samples.11,12
The use of such molecular markers, combined with advances in
bronchoscopy (e.g., laser-induced fluorescence endoscopic
bronchoscopy), may make possible the detection of preinvasive and
invasive lung cancer and the identification of the site of the
lesions in persons at high risk.13
The detection of very early lesions in persons at risk would also
identify candidates for studies of chemoprevention. Prospective
trials are required to determine whether the use of these invasive
approaches in asymptomatic persons will reduce mortality from lung
cancer.
Another approach is chemoprevention in persons who are at risk.14
To date, several large, randomized trials of beta carotene, retinol,
and isotretinoin for the prevention of lung cancer have not produced
positive results. Indeed, in one trial of the combination of beta
carotene and retinol (the Carotene and Retinol Efficacy Trial),
there was a 28 percent increase in the incidence of lung cancer in
the subjects who received the supplements, along with a 17 percent
increase in overall mortality in this group.15
These results are disappointing, but as we learn more about the
molecular carcinogenesis of lung cancer, more specific sites for
chemoprevention can be identified and targeted.
Chemotherapy in advanced lung cancer has reached a plateau; there
are few differences among various combinations of drugs. However,
there are now several reports of the use of biologic agents with
unique mechanisms of action in this disease. Epidermal growth factor
receptor is overexpressed in most cases of non–small-cell lung
cancer.16
Of the many strategies that have been developed to target this
receptor, the two most extensively evaluated are monoclonal
antibodies against the extracellular domain of the receptor (e.g.,
trastuzumab [Herceptin]) and inhibition of the tyrosine kinase
region of the receptor. Two tyrosine kinase inhibitors, ZD1839 and
OSI-774, have antitumor activity in advanced non–small-cell lung
cancer, even in patients in whom previous chemotherapy has failed.17,18
These and other novel biologic agents entering phase 1 and phase 2
trials offer the best hope for the future therapy of lung cancer.
Confirmation of the activity of such agents in advanced disease
would open the possibility of using them in early-stage disease,
either as adjuvant therapy or in combination therapy. All physicians
caring for patients with lung cancer should, in the absence of
contraindications, consider inviting their patients to participate in
these ongoing, pivotal trials.
The current treatment of advanced small-cell and non–small-cell
lung cancer with combination chemotherapy is nonspecific, nonselective,
and toxic. New combinations of chemotherapy are not likely to make
substantial improvements in survival. However, prevention, early
detection, and the use of specific biologic targets offer optimism
and hope that mortality from this disease may be reduced.
Desmond N. Carney, M.D., Ph.D.
Mater Misericordiae Hospital
Dublin 7, Ireland
References
Edward E.
Rylander, M.D.
Diplomat American
Board of Family Practice.
Diplomat American
Board of Palliative Medicine.