Gemcitabine and Cisplatin Combination in Early-Stage Non-Small-Cell Lung Cancer

Introduction

In non-small-cell lung cancer surgical resection is possible in only 20%
to 30% of all cases, mainly because of locally advanced disease and high
incidence of distant metastases. For early-stage resectable non-small-cell
lung cancer, 5-year survival is 60% for stage I, 40% for stage II, and 20% for
limited stage IIIA; in case of mediastinoscopy positive N2 disease, 5-year
survival drops to 5% to 10%. According to historical series, the 5-year survival
is 0% in unresectable, locally advanced, bulky stage IIIA or IIIB disease.[1,2]
The overall 5-year survival across all stages of non-small-cell lung cancer
ranges between 8% and 12% both in Europe and the United States, mainly because
of early dissemination of disease, which precludes the possibility of any
locoregional treatment (surgery or radiation therapy). Therefore, it seems quite
clear that the overwhelming majority of non-small-cell lung cancer patients
requires an effective systemic treatment to improve these dismal survival
figures.

A meta-analysis, conducted in 1995, of all randomized trials
focusing on the role of chemotherapy in non-small-cell lung cancer showed a
small but significant survival benefit in favor of cisplatin- (Platinol)-based
systemic chemotherapy across all stages.[3] The results of this meta-analysis
have stimulated the use of chemotherapy in addition to locoregional treatment in
the management of locally advanced non-small-cell lung cancer.

In the past 15 years, preoperative or neoadjuvant chemotherapy
has been widely employed in the treatment of stage IIIA disease in many phase II
trials and in some small phase III randomized studies.

Preoperative phase II chemotherapy studies, as exemplified by
the Memorial Sloan-Kettering and Toronto experiences with the MVP regimen
(mitomycin [Mutamycin], vinblastine, cisplatin) have shown improved survival
compared with historical controls, with median survival of 15.5 to 19 months and
5-year survival consistently around 18% vs 9% for historical controls.[4,5]

These favorable results have been validated by three small,
randomized trials which seem to indicate that neoadjuvant therapy in stage IIIA
improves survival. Unfortunately, the results cannot be considered conclusive
because of the premature interruption of these studies on the basis of interim
analysis data and a possible worse selection of patients in the control arm
which consisted of surgery alone. In the Pass et al trial (27 stage IIIA N2
patients), both median survival (28.7 months vs 15.5 months) and disease-free
survival (12.7 months vs 5.8 months) seem to favor the neoadjuvant chemotherapy
arm, but statistical significance was not reached.[6]

Two subsequent studies from M. D. Anderson Cancer Center and the
Spanish Lung Cancer Group showed a statistically significant improvement in
survival for those patients who received preoperative chemotherapy vs surgery
alone.[7,8] The design of these trials was very similar: induction chemotherapy
consisted of cyclophosphamide (Cytoxan, Neosar), etoposide, and cisplatin in the
M. D. Anderson experience, and mitomycin, ifosfamide (Ifex), and cisplatin in
the Spanish study. The survival advantage conferred by induction chemotherapy
was maintained after 3 and 5 years of follow-up.

New Agents in Neoadjuvant Chemotherapy

Until the early 1990s, the regimens used in phase II/III studies
as induction chemotherapy always consisted of the double or triple combinations
of cisplatin with old active drugs such as etoposide, mitomycin, vinca
alkaloids, and ifosfamide. During the 1990s, a number of new drugs with
different mechanisms of action showed important activity as single agents in non-small-cell
lung cancer: the nucleoside analog gemcitabine; the microtubulin inhibitors
paclitaxel, docetaxel (Taxotere), and vinorelbine (Navelbine); and the
topoisomerase I inhibitors irinotecan (CPT-11, Camptosar) and topotecan
(Hycamtin) showed response rates greater than 20%. In patients with metastatic
non-small-cell lung cancer, these new agents in combination with a platinum
compound (either cisplatin or carboplatin [Paraplatin]) have demonstrated
superior response rates and/or survival compared with cisplatin alone or older
platinum-based combinations.[9]

In particular, gemcitabine and cisplatin in combination have
revealed a strong synergism in preclinical models.[10] In three different large
randomized trials of advanced non-small-cell lung cancer, this new regimen has
shown a survival advantage vs cisplatin alone [11] and higher response rates
than etoposide/cisplatin[12] and the mitomycin/ifosfamide/cisplatin
combination.[13] On the basis of this activity in advanced disease, this regimen
has been tested in several phase II studies in the more favorable stage III non-small-cell
lung cancer as induction chemotherapy to surgery or radiotherapy.

In 1996, the EORTC initiated a phase II trial to define the
toxicity and activity of this new regimen as an induction treatment for patients
with stage III N2 non-small-cell lung cancer, within a large ongoing
randomized trial comparing surgery with radiotherapy after neoadjuvant
chemotherapy.[14] Forty-seven patients received gemcitabine 1,000 mg/m² on days
1 through 8 and 15 and cisplatin 100 mg/m² on day 2, every 4 weeks. Of the 47
eligible patients, 33 had objective responses (70.2%, 95% confidence interval
[CI] = 55.1%-82.7%) with three complete and 30 partial responses. Resections
were considered complete in 71% of these patients who underwent thoracotomy.
Median survival was 18.9 months, and 1-year survival was 69%. Grade 3/4
thrombocytopenia occurred in 60% of patients without any episodes of bleeding
and caused withholding of gemcitabine on day 15 in 48% of the courses.

Similar results have been reported in a series of small phase II
studies of gemcitabine and cisplatin as induction chemotherapy in stage III non-small-cell
lung cancer. In 1996, we started an Italian prospective phase II trial to
evaluate the safety and activity profile of a new, 3-week schedule of
gemcitabine and cisplatin as induction chemotherapy to surgery or radiotherapy
in stage IIIA/IIIB non-small-cell lung cancer. A total of 110 patients were
treated with gemcitabine 1,250 mg/m² on days 1-8 and cisplatin 80
mg/m² on day
2. Ninety males and 20 females were enrolled. The median age was 61 years
(range: 39-79) and all patients had 0 or 1 ECOG performance status (49 and 61,
respectively). Fifty-five patients had squamous carcinoma, 37 adenocarcinoma, 6
large cell carcinoma; and 12 unknown non-small-cell lung cancer. A median
number of four courses (range: 2-8) was given. Response assessment showed 69
partial responses (62%) and 3 pathologically confirmed complete responses (3%);
34 patients (31%) remained with stable disease and only 4 experienced
progression; 31 patients (28%) underwent thoracotomy and were completely
resected.

Treatment was well tolerated. Twenty-two patients experienced
World Health Organization (WHO) grade III neutropenia and 3 developed grade IV
neutropenia. WHO grade III and IV thrombocytopenia was recorded in 22 and 12
patients, respectively. No toxic deaths were observed.[15]

Neoadjuvant Chemotherapy
in Early Stages of
Non-Small-Cell Lung Cancer

In these studies, the activity of the gemcitabine/cisplatin
combination in stage III non-small-cell lung cancer is among the highest and
compares very favorably with the results of published phase II and III studies.

Response rates were in the range of 60% to 70%. Surgical
resection and pathologic downstaging of mediastinal lymph nodes occurred in more
than 50% of patients, despite significant initial tumor burden (most patients
had bulky N2 unresectable disease at the start of treatment).

These considerations indicated that the gemcitabine/cisplatin
combination is a very active induction chemotherapy and prompted Italian
investigators to evaluate its role in a more favorable setting, namely stage
I/II and selected IIIA resectable cases. Recently, in the United States and
Europe, neoadjuvant chemotherapy has been evaluated in early-stage non-small-cell
lung cancer, both in phase II and III studies. In a multicenter US phase II
trial of 94 patients with T2 N0, T1/2N1; and T3 N0/1 disease, investigators
delivered two cycles of carboplatin/paclitaxel followed by surgery and by three
additional cycles of chemotherapy.[16] Major responses occurred in 56% of cases;
4% of patients were completely resected.

In a randomized phase III study of 373 patients, Depierre et al
assessed the impact of neoadjuvant chemotherapy (two cycles of MIC regimen)
followed by surgery vs surgery alone, on survival in stage I/II and IIIA non-small-cell
lung cancer.[17] In a Cox regression model adjusted for stage, the effect of
preoperative chemotherapy was significantly favorable with a relative risk of
.77 (P = .05). Disease-free survival was significantly longer (P = .02) and the
risk of distant recurrence was significantly lower (P = .01) in the preoperative
chemotherapy arm.

After these trials, we designed a randomized study comparing
surgery vs induction chemotherapy with gemcitabine/cisplatin followed by surgery
in early-stage patients. Overall survival will be the main end point of this
trial, which is currently ongoing in Italy.

New Drugs in Combined-Modality Treatment

The 1995 meta-analysis showed that chemotherapy improves
survival when added to radiotherapy for patients with unresectable stage III non-small-cell
lung cancer.[3] These data have been recently confirmed by two consecutive
prospective trials from the Cancer and Leukemia Group B (CALGB) and Radiation
Therapy Oncology Group (RTOG), both reporting a survival advantage in favor of
sequential chemoradiotherapy vs radiotherapy alone.[18,19] Concurrent
cisplatin-based chemoradiotherapy vs sequential radiotherapy alone has also been evaluated in phase III
trials with promising results: Furuse et al showed that median and long-term
survival were clearly superior in the concurrent arm of split-course thoracic
radiotherapy and MVP chemotherapy vs the sequential arm of MVP before thoracic
radiotherapy.[20]

Recently, new drugs have been evaluated by the CALGB in a
randomized phase III study exploring sequential and concurrent chemoradiotherapy
in unresectable stage III non-small-cell lung cancer. This study was designed
to investigate three new combinations plus cisplatin/radiotherapy combinations:
cisplatin/gemcitabine, cisplatin/paclitaxel, and cisplatin/vinorelbine. Each
combination was given initially as induction chemotherapy for two cycles and
then concurrently with radiotherapy. The results of this study are very
promising, with a median survival of 18 months, 1-year survival of 66%, and an
acceptable toxicity profile.[21]

Conclusions

The new gemcitabine/cisplatin regimen has been extensively
evaluated in advanced non-small-cell lung cancer in phase II and phase III
randomized trials with a response rate ranging between 21% and 40% and a median
survival of approximately 9 months. These data place this combination among the
most active regimens in non-small-cell lung cancer and suggest the importance
of a thorough evaluation in more favorable disease stages. The ongoing trials in
the neoadjuvant setting and in the sequential or concurrent approach with
radiotherapy in early non-small-cell lung cancer will contribute to define the
role of this regimen in the combined treatment of non-small-cell lung cancer.