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 nonsmall-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(Drug information on cisplatin) (Platinol)-based combination regimens are considered the treatment of choice for NSCLC. However, the availability of several new drugs that are active against NSCLC and also quite well tolerated has broadened the options for treatment.
Gemcitabine(Drug information on 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%. 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]
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 and 2,800 mg/m²), 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(Drug information on 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. 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. 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.
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.
In comparison, 54% of patients in the Italian Lung Cancer Project (ILCP) trial, and 81% of patients in the study by Sandler and colleagues had stage IV NSCLC. This heterogeneity of disease stage, combined with slight differences in scheduling, may have been responsible for the reported spectrum of response and survival outcomes. Response rates in these five trials ranged from 42% to 54%. Median survival ranged from 8.4 months to 14.3 months (Table 1). 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. 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. 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(Drug information on mitomycin) (Mutamycin)/ifosfamide (Ifex)/cisplatin.
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(Drug information on 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 toxicitiesincluding alopecia, sensory neuropathy, and diarrheawere 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.