Advances in Treatment of Inoperable NSCLC: Gemcitabine Doublets—A Promising Alternative

Advances in Treatment of Inoperable NSCLC: Gemcitabine Doublets—A Promising Alternative

ABSTRACT: Gemcitabine (Gemzar) was originally approved for use in combination with cisplatin (Platinol) for the treatment of advanced non–small-cell lung cancer (NSCLC). Research began to focus on combining gemcitabine with newer drugs, such as carboplatin (Paraplatin), vinorelbine (Navelbine), the taxanes, and the camptothecins, when it became clear that these agents had potentially increased efficacy and fewer side effects than the standard treatment. This article will briefly review the original experience with the gemcitabine/cisplatin doublet and then examine the experience to date with non–cisplatin-based gemcitabine doublet combinations in the treatment of advanced NSCLC. [ONCOLOGY 14(Suppl 4):7-14, 2000]


In the last decade, it has become clear that the
use of effective systemic chemotherapy can improve patient survival,
quality of life, and performance status compared with best supportive
care for selected patients with advanced-stage non–small-cell
lung cancer (NSCLC). Single-agent therapy with active drugs has been
shown to produce response rates of 25% to 30%, reduce tumor burden,
alleviate symptoms of disease, such as dyspnea and hemoptysis, and
improve survival.[1-3]

Combination chemotherapy appears to provide even better control,
yielding response rates of 30% to 40% and extending median survival
to 6 to 12 months vs 4 to 8 months without chemotherapy.[4-12]
Cisplatin (Platinol)-based combination regimens are considered the
treatment of choice for NSCLC.[12] However, the availability of
several new drugs that are active against NSCLC and also quite well
tolerated has broadened the options for treatment.

Gemcitabine (Gemzar) is a particularly notable member of this new
group of chemotherapeutic agents. With a database of more than 800
patients enrolled in phase II clinical trials, single-agent
gemcitabine is one of the most widely studied drugs for the treatment
of NSCLC. Externally validated response rates achieved with
single-agent gemcitabine range from 20% to 26%.[13] One-year survival
rates as high as 40% have been reported with gemcitabine chemotherapy
in select patient groups.[13-18] Potentially important interactions
of gemcitabine and radiation have also been recognized.[19-20]

Single-Agent Gemcitabine in NSCLC

In lung cancer patients, single-agent gemcitabine is usually
administered at doses of 1,000 mg/m² to 1,250 mg/m² on days
1, 8, and 15 of an q28-day schedule.[14-16] Among the studies of
single-agent gemcitabine, results have been notably consistent, with
an aggregate response rate of approximately 21% and median survivals
of 7 to 9.4 months. Two small studies included higher doses of
gemcitabine (up to 1,700 mg/m²[21] and 2,800 mg/m²[22]),
with little to suggest added benefit. In many cases, gemcitabine
therapy improved disease-related symptoms. The toxicity profile was
very acceptable.

In two small randomized studies, [17,18] gemcitabine produced
survival rates that were essentially identical to platinum-based
combination chemotherapy. Perng and coworkers treated 53 chemonaive
patients with inoperable stage III (N = 14) or IV (N = 39) NSCLC with
either gemcitabine 1,250 mg/m² on days 1, 8, and 15 (N = 27) or
cisplatin (80 mg/m² on day 1) plus etoposide (80 mg/m² on
days 1, 2, and 3) (N = 26). Response rates were 19.2% for patients
receiving the gemcitabine regimen and 20.8% for patients given the
cisplatin/etoposide regimen.[17] The median survival rate among
patients receiving gemcitabine was 37 weeks compared with 48 weeks on
the cisplatin combination. The 1-year survival rate in the
gemcitabine arm was close to 40%.

Similarly, European investigators assessed the same regimens, except
that cisplatin and etoposide were both administered at 100
mg/m².[18] Again, the response and median survival rates were
very similar between groups. Thus, single-agent gemcitabine appears
to produce activity comparable to etoposide/cisplatin combination
chemotherapy in the treatment of NSCLC.

Gemcitabine Plus Cisplatin

Phase II Trials

The combination of gemcitabine 1,000 mg/m² on days 1, 8, and 15
and cisplatin 100 mg/m² on either day 1, 2, or 15 has been
evaluated in numerous phase II trials. Five selected phase II trials
involving several hundred patients are representative.[23-27] All
five studies involved untreated patients with stage III or IV NSCLC,
although the ratio of patients with stage III vs IV disease varied
widely. For instance, investigators in South Africa included 50
patients in their trial, among whom only 38% had stage IV disease.[26]

In comparison, 54% of patients in the Italian Lung Cancer Project
(ILCP) trial,[24] and 81% of patients in the study by Sandler and
colleagues had stage IV NSCLC.[25] This heterogeneity of disease
stage, combined with slight differences in scheduling, may have been
responsible for the reported spectrum of response and survival
outcomes.[28] Response rates in these five trials ranged from 42% to
54%. Median survival ranged from 8.4 months to 14.3 months (Table
). The major toxicity was reversible myelosuppression of short duration.

Overall, the results of these studies revealed the
gemcitabine/cisplatin combination to be an effective regimen,
producing favorable response rates and survival. Results of these
phase II studies led to the initiation of pivotal randomized phase
III trials of the cisplatin/gemcitabine combination.[29,30]

Phase III Trials

The Hoosier Oncology Group trial compared gemcitabine/cisplatin vs
cisplatin alone in 522 patients with previously untreated, locally
advanced or metastatic NSCLC.[29] Patients received either 100
mg/m² cisplatin on day 1 of a 28-day cycle (N = 262) or
cisplatin 100 mg/m² on day 1 plus gemcitabine 1,000 mg/m²
on days 1, 8, and 15 repeated q28 days (N = 260).

Response to the combination proved to be significantly superior to
that of cisplatin alone: 30.4% vs 11.1% (P < .0001).
Furthermore, there was a statistically significant advantage for the
combination in terms of median response duration (5.6 months vs 3.7
months, P = .0013) and overall survival (P = .004).

Cardenal and colleagues in Spain compared the activity of an q3-week
gemcitabine/cisplatin regimen with standard etoposide/cisplatin in
the treatment of 135 patients with advanced NSCLC.[30] Regimens of
either cis-platin 100 mg/m² on day 1 plus gemcitabine 1,250
mg/m² on days 1 and 8 or cisplatin 100 mg/m² on day 1 plus
etoposide 100 mg/m² on days 1, 2, and 3 were administered on an
q21-day schedule. The overall response rate for gemcitabine/cisplatin
was statistically superior to that for etoposide/cisplatin (40.6% vs
21.9%; P = .02). In addition, time-to-disease progression was
significantly greater with gemcitabine/cisplatin (6.9 months vs 4.3
months; P = .01). Median survival time was 8.7 months with
gemcitabine/cisplatin and 7.2 months with etoposide/cisplatin (P
= .18).

This trial supports the current widespread use of the
better-tolerated 21-day schedule of gemcitabine/cisplatin, which
again demonstrated an improved response rate and time-to-disease
progression vs standard cisplatin/etoposide therapy.

The Italian Lung Cancer Project investigators tested the 4-week
gemcita-bine/cisplatin regimen against the three-drug combination of
mitomycin (Mutamycin)/ifosfamide (Ifex)/cisplatin.[31]

In this study, 307 patients with stage IIIB/IV NSCLC were randomly
assigned to an q28-day treatment with either gemcitabine 1,000
mg/m² on days 1, 8, and 15 plus cisplatin 100 mg/m² on day
2 or mitomycin 6 mg/m²/ ifosfamide 3,000 mg/m² /mesna on
day 1 plus cisplatin 100 mg/m² on day 2.

Although there was no statistically significant difference in overall
median survival (8.6 vs 9.6 months, P = .877), median time to
progression (5.0 vs 4.8 months) or median time-to-treatment failure
(4.0 vs 3.7 months), an improved response rate was observed in the
gemcitabine/cisplatin arm (P = .029). This confirms the
substantial activity of gemcitabine/cisplatin in patients with
metastatic or poor prognosis stage IIIB disease. Toxicity was
comparable in the two arms.

Figure 1 illustrates the 1-year
survival advantages of gemcitabine/cisplatin (21- and 28-day
schedules) relative to cisplatin/etoposide or cisplatin alone. This
benefit was associated with equivalent or improved quality-of-life
parameters for the gemcitabine-based therapy compared with the other
regimens. The gemcitabine/cisplatin regimen also had a tolerable
safety profile. The predominant toxicity was acute myelosuppression,
generally marked by a short nadir and little clinical impact. Rates
of febrile neutropenia and bleeding requiring transfusion were low,
and hematologic toxicities generally resolved quickly.

 Although thrombocytopenia was a frequent cause for dose
reductions, full recovery generally occurred within the cycle period.
This was true on both the 21-day and 28-day schedules. Other
toxicities—including alopecia, sensory neuropathy, and
diarrhea—were mild and transient. Overall, the
gemcitabine/cisplatin regimen fared well in phase III comparisons,
and was deemed to warrant further consideration in the treatment of
advanced NSCLC.


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