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To Treat or Not to Treat Non–Small-Cell Lung Cancer Patients? Current Perspectives

To Treat or Not to Treat Non–Small-Cell Lung Cancer Patients? Current Perspectives

ABSTRACT: In the 1980s, the introduction of cisplatin (Platinol)-based chemotherapy prolonged survival and improved quality of life in patients with stage III and IV non–small-cell lung cancer. More recently, the use of five new chemotherapeutic agents—docetaxel (Taxotere), gemcitabine (Gemzar), irinotecan (Camptosar), paclitaxel (Taxol), and vinorelbine (Navelbine)—has further improved treatment results for non–small-cell lung cancer. In advanced disease, randomized trials have shown that combinations of these agents produce superior results to older cisplatin-based regimens. Although the new chemotherapeutic agents are more expensive than older drugs, calculations of costs per year of life gained have shown them to be cost-effective. The concurrent use of chemotherapy and chest radiotherapy for stage IIIB disease has produced improvements in survival and quality of life that outweigh increases in toxicity. Neoadjuvant chemotherapy plus surgery has improved survival in patients with stage IIIA disease and mediastinal lymph node involvement, and the role of neoadjuvant radiotherapy is being studied in this setting as well. Finally, trials of neoadjuvant strategies using new-agent combinations are also being conducted in patients with stage I and II non–small-cell lung cancer. [ONCOLOGY 13(Suppl 4):9-15,1999]

Introduction

The third most common cancer in the United
States, lung cancer, is the leading cancer killer of both men and
women.[1] Because of the low cure rate (14%), lung cancer kills more
individuals than cancers of the breast, prostate, colorectum, and
ovary combined.[1] Less than 25% of lung cancer patients present with
stages I and II, and nearly all patients die with disseminated
systemic disease. Thus, improved systemic therapies are critical to
improving the cure rate.

Great pessimism developed regarding the role of chemotherapy in
non–small-cell lung cancer, largely because alkylating
agent–based chemotherapy produced low response rates and
considerable toxicity. Moreover, these drugs worsened survival at all
stages, even when used as postoperative adjuvant therapy.[2]

The treatment of lung cancer improved considerably in the 1980s, when
cisplatin (Platinol)-based chemotherapy was shown to prolong survival
and improve quality of life in patients with stage III and IV
non–small-cell lung cancer as shown by randomized trials and
meta-analyses of these randomized trials.[2,3] In resectable
non–small-cell lung cancer, postoperative cisplatin-based
chemotherapy improved 5-year survival rates by 5% (a value of
borderline significance given the small number of patients enrolled
in these trials).[2]

In the 1990s, a renewed optimism has emerged with the introduction of
five new chemotherapeutic agents, each of which produces higher
response rates and longer survival than cisplatin.[4]

Therapy for Stage IV

At least one-third of all non–small-cell lung cancer patients
present with metastatic disease, and the vast majority of patients
will develop metastases during their course. The prognosis for
patients with metastatic disease is dismal, with median survivals of
about 4 months and 1-year survival rates below 15% when best
supportive care (including radiotherapy but excluding chemotherapy)
is the only therapy.[2]

Randomized trials and meta-analyses of these trials showed that
cisplatin-based chemotherapy significantly improves survival in these
patients, although the improvements are modest.[2] The median
survival is improved by an average of 10 weeks and the 1-year
survival rate is increased by 10%.[2] Although there has been limited
study of this issue, available data suggest that cisplatin-based
therapy also improves quality of life as assessed by patients,
despite the drug’s toxicity.[3]

These data were derived primarily from studies restricted to patients
with good performance status. Since response rates are lower and
toxicity rates are higher in patients with poor performance status,
the role of chemotherapy in poor performance status is unproven.

During the 1990s at least five new chemotherapeutic agents were
tested in 100 or more advanced-stage non–small-cell lung cancer
patients and were shown to produce responses in more than 20% of
those patients.[4] Results from these studies are summarized in Table
1
where they are compared to results with cisplatin alone.[5]

The survival results from these studies were as striking as the
response-rate results. The average median survivals in these studies
ranged from 33 weeks to 41 weeks, and the 1-year survival rates
ranged from 24% to 52%. These results can be contrasted with a median
survival of 4 months and 1-year survival rates of 10% to 15% with
best supportive care.

Randomized trials are necessary to confirm results from phase II
studies. Results from randomized studies comparing new single agents
to other therapies are summarized in Table
2
.[6-10] The original Eastern Cooperative Oncology Group (ECOG)
study of paclitaxel (Taxol) showed that it was superior to both
merbarone and piroxantrone with respect to both response and
survival.[6] Vinorelbine (Navelbine) was compared to fluorouracil

(5-FU)/leucovorin and was shown to be superior with respect to
response, time to progression, and survival.[7] Single-agent
vinorelbine was also compared to the combination of vinorelbine plus
cisplatin.[8] As shown in Table 2,
the combination proved superior to single-agent vinorelbine with
respect to both response and survival.

Single-agent gemcitabine (Gemzar) was compared to a standard two-drug
combination consisting of etoposide plus cisplatin in two randomized
trials.[9-10] In both studies, gemcitabine produced response rates
and survival that were equivalent to the standard two-drug
combination, but gemcitabine produced significantly less toxicity (Table
2
).

The activity of these new chemotherapeutic agents led to phase II
studies in which they were combined with cisplatin. The results of
these phase II studies are summarized in Table
3
.[3] Each combination produced response rates exceeding 35%,
whereas single-agent response rates were always less than 26%. A
comparison of Table 1 and Table
3
shows less striking differences with respect to median
survival and 1-year survival rates although the combination results
were always superior.

Randomized trials to confirm these results are now appearing in the
literature and are summarized in Table
4
. The results of these studies suggest that survival is
improved when combinations of vinorelbine plus cisplatin,[11]
gemcitabine plus cisplatin (Eli Lilly, unpublished data), and
paclitaxel plus cisplatin,[12,13] are compared to cisplatin alone or
etoposide plus cisplatin. As in the phase II studies, the increases
in response rates are somewhat more striking than the increases in
survival. Nonetheless, the median survival exceeded 35 weeks and the
1-year survival rates exceeded 30% in all groups receiving a new drug
plus cisplatin.

The costs of these new chemotherapeutic agents are higher than the
costs of chemotherapeutic agents no longer under patent protection.
Because survival is prolonged by chemotherapy, the costs of
chemotherapy per year of life gained can be calculated. Such
calculations have been published by Evans and his coworkers from
Canada and are summarized in Table 5.[14]

An earlier study from Canada showed that patients treated with
outpatient chemotherapy incurred lower costs than patients given best
supportive care (including radiotherapy).[15] The costs were lower
because the chemotherapy-treated patients received less radiotherapy
and spent fewer days in the hospital. These results were confirmed in
a more recent Canadian[14] study. This led to lower costs for
patients receiving etoposide plus cisplatin, compared to best
supportive care.

The new chemotherapeutic agents are associated with higher costs than
etoposide/cisplatin therapy, as indicated in Table
5
. The costs per year of life gained are under $20,000 (in 1995
Canadian dollars) for each of these therapies. Costs of this
magnitude are generally deemed to be cost-effective in the medical
community and are considerably lower than commonly used procedures
such as organ or marrow transplantation, dialysis, or mammography.

In summary, there is now convincing evidence that chemotherapy can
relieve symptoms, improve quality of life, and prolong survival at
acceptable medical costs in patients with advanced non–small-cell
lung cancer. Newer drug combinations appear to be superior to older
cisplatin-based combinations.

Therapy for Stage IIIB

For many years, radiation therapy was the standard treatment for
stage IIIB non–small-cell lung cancer. The recognition that
cisplatin had radiosensitizing properties and could be given safely
before, after, or with chest radiotherapy led to randomized trials
comparing radiotherapy alone to combined chemotherapy and
radiotherapy in stage IIIB non–small-cell lung cancer. These
randomized trials and meta-analyses of these trials established that
the combined-therapy approaches significantly prolonged survival.[2]
On average, the median survival was improved by about 4 months.[2,16]
The long-term survival was also extended, with two- to threefold
improvements in 5-year survival rates.[2,16]

Several approaches to combining the modalities were studied including
sequential approaches[16], alternating approaches[17], and concurrent
approaches.[18,19] Each of these approaches was superior to
radiotherapy alone in randomized trials, and the meta-analyses were
unable to show whether one of these approaches was preferred over
others.[2] Table 6 summarizes
the results of some of the randomized trials.

More recently, a randomized trial comparing the sequential and
concurrent approaches was completed (Table
6
).[20] The study showed that the concurrent administration of
mitomycin (Mutamycin), vinblastine, and cisplatin chemotherapy (MVP)
and chest radiotherapy (56 Gy) produced a higher response rate (84%
vs 66%) and longer survival compared to a sequential approach. There
was more toxicity in the concurrent arm, but the authors concluded
that the improvements in efficacy outweighed the increases in toxicity.

The addition of chemotherapy to chest radiotherapy also improves
quality of life as assessed by patients. In a phase III study
conducted in the United Kingdom, patients were randomized to receive
chest radiotherapy (56 Gy) and best supportive care measures or chest
radiotherapy and chemotherapy with mitomycin, ifosfamide (Ifex), and
cisplatin. Survival was significantly longer in patients receiving
the combined modality (median, 13 vs 9.9 months).[3] The
quality-of-life score, whereby a lower score represented better
quality of life, was 287 in the combined modality arm vs 394 in the
radiotherapy arm (P = .0002).

Since all of the new chemotherapeutic agents have radiosensitizing
properties in vitro,[4,21] it is logical to combine these agents with
chest radiotherapy. The most extensive experience with this
combination involves paclitaxel. Phase II studies evaluating chest
radiotherapy with paclitaxel alone or with paclitaxel and other
agents are summarized in Table 7.[22-26]

Choy and coworkers studied the weekly administration of concurrent
chest radiotherapy and paclitaxel alone[22] or paclitaxel and
carboplatin (Paraplatin).[23] They reported that these combined
approaches produced exciting preliminary results with acceptable
toxicity. Belani and coworkers also evaluated concurrent radiotherapy
with paclitaxel and carboplatin.[24] They, too, reported extremely
favorable survival results with acceptable toxicity.

Curran et al studied paclitaxel in combination with carboplatin given
alone for two cycles and then followed by concurrent radiotherapy
with the same paclitaxel combination given at 3-week intervals.[25]
This trial had impressive survival results with acceptable toxicity.
Finally, Greco et al used a three-drug combination of paclitaxel,
cisplatin, and etoposide given at 3-week intervals and combined with
chest radiotherapy.[26] They reported an 82% response rate, a 1-year
survival of 65%, and acceptable toxicity.

It appears that the simultaneous delivery of gemcitabine and
radiotherapy is extremely dangerous, producing marked increases in
normal tissue toxicity.[4] Several patients experienced toxic deaths
when near-full doses of gemcitabine were given weekly with chest
radiotherapy. Phase I studies are now evaluating very low doses of
weekly gemcitabine (200 to 300 mg/m²) with chest radiotherapy.
Fewer results are available for docetaxel (Taxotere), vinorelbine,
and irinotecan (Camptosar) combined with radiotherapy. Further study
of these combinations will be required before standard
recommendations can be made.

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