The issue of treating elderly patients with chemotherapy is of
great clinical relevance today.[1-3] In the United States and Europe, the
leading cause of cancer death in men and women is lung cancer. The large
majority of lung cancer patients are more than 55 years old, and the number of
patients over the age of 65 has grown considerably in the course of the past
decade. When incidence rates are calculated for age specificity, lung cancer
rates escalate to more than 500,000 persons for those 70 to 85 years of
Age itself is not one of the definitive prognostic factors of
lung cancer. Because untreated lung cancer patients have an extremely poor
prognosis, the question of which treatment patients should receive should not be
based on age. Older patients should be offered the same general treatment as
younger, healthier patients. This general principle should apply to all
treatment modalities: surgery, radiotherapy, and chemotherapy.[7-9] At the same
time, daily contact with older patients shows that standard recommendations for
the proper dose and application time are often difficult to fulfill and must be
modified for the elderly.
Many older patients have additional complex medical problems,
including chronic obstructive airway disease, congestive heart failure, and
decreased renal function, which must be considered. In addition to the problems
of comorbidity, poor performance status, and polypharmacy, specific mental,
emotional, and social-economic conditions are often found in the elderly and
differ from their younger counterparts. There are, for example, many cases of
cognitive and emotional disturbances, family dysfunctions, limited access to
clinic and hospital care, confused reactions to complex medical schedules, and
less motivation to withstand the ordeal of aggressive treatmentall of which
may adversely influence cancer treatment and result in inadequate treatment
Of all the treatment modalities, the use of chemotherapy in the
elderly has remained the most controversial.[10-12] The skepticism often
expressed is related to (1) the perception of chemotherapy’s limited
benefit in general; (2) older data suggesting that chemotherapy is of benefit
mainly to patients younger than 70 years and that the recommended therapy should
be platinum-based combination chemotherapy; (3) the potential for increased
toxicity in the elderly; (4) the small number of studies dedicated to the
elderly and the fact that the elderly were, in the past, frequently excluded
from clinical studies; (5) preselection as a major problem in interpreting data
from retrospective reviews; and (6) the widespread reluctance to treat elderly
patients in the same way that younger patients are treated. With the general
improvements in cytotoxic therapy over the past few years, new possibilities are
being opened to elderly patients for more individualized treatment, which is
easier to adapt to the specific age group and general condition of the patients
The new generation of chemotherapeutic agents largely
responsible for these positive changes belong pharmacologically to the
antimetabolites, the topoisomerase I inhibitors, and the antitubulins. These new
agents show great single-agent efficacy in both first- and second-line therapy,
and are therefore especially attractive for use as single agents in the older
population. Furthermore, the toxicity profile of these new drugs differs from
that found in traditional chemotherapy and is generally found to be better
tolerated. In addition, these drugs can be administered flexibly in various
schedules and dosages, thus opening new options for platinum-free combination
chemotherapy, for chemoradiotherapy regimens, as well as for the application of
cytotoxic drugs on an outpatient basis.
Among the new drugs with probably the greatest impact on the
treatment of elderly patients are the classical antitubulin vinorelbine
(Navelbine), the antimetabolite gemcitabine (Gemzar), and the taxane docetaxel
(Taxotere).[15-19] This has been demonstrated in a number of nonrandomized
studies, in a few randomized trials, and in several retrospective analyses.
Vinorelbine was probably the first new agent tested in
nonrandomized and randomized trials in elderly patients with non-small-cell
lung cancer.[20-24] One milestone was the study of the elderly done by the
Elderly Lung Cancer Vinorelbine Italian Study Group, which has become known as
the ELVIS trial. Here, elderly patients over the age of 70 were randomized
to either single-agent vinorelbine or best supportive care alone. A
statistically significant survival advantage was seen in patients receiving
vinorelbine (Figure 1). This trial clearly established the potential benefit of
single-agent therapy for the elderly population. Vinorelbine is, therefore,
widely considered to be more or less the "standard arm" for upcoming
comparative studies, especially for testing the value of new agents in elderly
patients with non-small-cell lung cancer.
Another agent that has proven to be active and well tolerated in
non-small-cell lung cancer patients is gemcitabine. Gemcitabine is a
novel deoxycytidine analog with structural similarities to cytosine arabinoside.
Gemcitabine was the first cytotoxic drug registered for use in the palliation of
tumor-induced symptoms and was shown to be effective as a single agent in
both first- and second-line therapy.
When administered once weekly on days 1, 8, and 15 of a 28-day
cycle at a dose of 800-1,250 mg/m2, gemcitabine showed an objective response
rate of 20% to 26% in chemotherapeutically nonpretreated patients. The median
duration of response ranged from 3.3 to 12.7 months, and the overall median
survival time was 8.1 to 9.4 months. Single-agent gemcitabine was shown to be
especially effective in reducing tumor-induced dyspnea, pain, and hemoptysis. It
was also well tolerated by elderly patients. In the majority of cases,
gemcitabine promises a better quality of life; in one-third of the cases, it
leads to an improvement in performance status. Gemcitabine has also proven to be
superior to best supportive care in advanced non-small-cell lung cancer.
A specific review of single-agent gemcitabine investigations in
patients over 65 years old enrolled in four phase II trials has recently been
published. In these studies, 250 patients were under the age of 65 and 105
patients were 65 or older. Baseline patient characteristics for gender,
performance status, stage of disease, and histology did not differ significantly
between the age groups. There were no statistically significant differences for
the overall response rates, which showed 16% for the younger and 24% for the
older patients, respectively (Table 1).
Of interest is the fact that the group under age 65 had a median
survival of 8 months and a 1-year survival rate of 27%, whereas the older
population had a median survival of 9.1 months and a 36% 1-year survival rate.
Gemcitabine was well tolerated and toxicities were similar for both age groups (Table
2). The number of cycles associated with dose reductions and/or dose
omissions and the mean number of treatment cycles administered were also
similar. The feasibility and effectiveness of single-agent gemcitabine in
patients older than 70 years of age has recently been confirmed by a number of
Because of their mild side-effect profiles, the new drugs are
also good candidates for combination chemotherapy. The question of whether the
addition of gemcitabine to vinorelbine improves survival and the quality of life
among elderly patients has recently been addressed in a randomized study of the
Southern Italy Co-Operative Oncology Group and the Inter-Regional Association
for the Study of Lung Cancer Italy. A total of 120 patients 70 years of age
or older with advanced non-small-cell lung cancer were randomized. In the
vinorelbine/gemcitabine group, median survival was 7 months, and the 1-year
survival rate was 30% compared with 2.5 months and 13% for single-agent
vinorelbine. This difference was statistically significant. The combination
therapy was also associated with a clear delay in symptom and quality-of-life
deterioration (Table 3).
Another important ongoing clinical trial is the phase III MILES
trial (Multi-agent Italian Lung Cancer Elderly Trial), in which the combination
of gemcitabine and vinorelbine is being compared to single-agent vinorelbine and
single-agent gemcitabine. Patients are eligible if they are 70 years of age or
older and if they are diagnosed as having inoperable stage III or IV non-small-cell
lung cancer. The primary end point of the MILES study is survival, and more than
600 patients are to be enrolled. Preliminary response data from 98 patients who
received single-agent gemcitabine at 1,200 mg/m2 on days 1 and 8 every 3 weeks
(49 patients) or gemcitabine at 1,000 mg/m2 combined with vinorelbine at 25
mg/m2 on days 1 and 8 every 3 weeks (49 patients) were recently published.
The data showed that nine patients responded to single-agent gemcitabine (9
partial responses) and that another nine responded to gemcitabine/vinorelbine (8
partial responses, 1 complete response) giving an identical response rate of
18.4% (95% confidence interval [CI] = 8.8%-32.0%) for each treatment arm.
Our own experience with combination chemotherapy for elderly
patients having advanced non-small-cell lung cancer comes from a randomized,
two-arm phase II study, where gemcitabine and docetaxel were given
Patients were randomized either to gemcitabine at 1,000 mg/m2 on
days 1, 8, and 15, every 4 weeks or to docetaxel at 35 mg/m2 also given on days
1, 8, and 15 every 4 weeks for up to six cycles. In case of tumor progression
during or after completion of first-line therapy, treatment crossover was
planned (Table 4).
Patients were included only if they had documented non-small-cell
lung cancer either in stage IIIB disease with pleural effusion and/or
superclavicular lymph node involvement or in stage IV disease. Patients also had
no prior chemotherapy, no prior radiotherapy of measurable lesions, a
performance status of 0-2, adequate hematology and biochemistry, no clinical
evidence of brain metastases, and were 18 years of age or older, and gave
informed, written consent. About 25% of the patients enrolled were 70 years of
age or older.
The major pretreatment characteristics for the two age groups
were well balanced (Table 5). For patients who were assigned initially to
receive single-agent gemcitabine and then, in case of progression, were switched
to or planned to cross over to docetaxel, the 1-year survival rates were almost
identical (30%). The median survival rate was about 8 months between the two age
groups (Table 6).
In spite of the great skepticism about using platinum-based
chemotherapy for older and unfit patients, the investigation of therapy regimens
using new drugs in combination with cisplatin (Platinol) for the elderly
continues.[34-37] From a randomized phase III study of gemcitabine plus
cisplatin vs cisplatin, subset analyses of 260 patients treated with gemcitabine/cisplatin were
carried out by Nguyen for patients over 70 years of age. These results
showed that gemcitabine/cisplatin was as well tolerated in the elderly as in
younger patients. There were also no statistically significant differences in
tumor response, time to progression, and median survival (Table
The feasibility and efficacy of cisplatin-based chemotherapy in
elderly patients has lately been confirmed by a retrospective analysis using the
Eastern Cooperative Oncology Group (ECOG) 5592 database. Response, toxicity,
and survival for fit, elderly non-small-cell lung cancer patients were similar
to the rates shown by younger patients. The authors therefore concluded that
advanced age alone should not preclude appropriate platinum-based chemotherapy.
Chemotherapy for elderly patients with advanced non-small-cell
lung cancer continues to be a major unresolved clinical problem. The
availability of new chemotherapeutic agents, however, has increased the
chemotherapeutic treatment options for patients with non-small-cell lung
cancer in general, but even more so for the elderly.
For advanced disease, as the recently published results of
randomized studies indicate, single-agent therapy using new chemo- therapeutic
agents or their combinations may offer an appropriate alternative to a
platinum-based combination chemotherapy for elderly patients. Physiologically
fit elderly patients with early-stage non-small-cell lung cancer who are in
good clinical condition should not be excluded from the clinical investigation
of platinum-based two- or even three-drug combinations to determine their role
within multimodality treatment concepts.
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