Gemcitabine for the Treatment of Non-Small-Cell Lung Cancer

ABSTRACT: Platinum-based chemotherapy regimens have been the mainstay of treatment for non-small-cell lung cancer because they improve survival. Although there is no standard platinum-based regimen, combination regimens with newer agents (eg, gemcitabine [Gemzar], paclitaxel [Taxol], and vinorelbine [Navelbine]) are superior to platinum alone or in combination with older agents (eg, etoposide). Four phase III clinical studies published in full demonstrate the favorable activity and toxicity profile of gemcitabine in combination with cisplatin (Platinol) for the treatment of patients with stage IIIB or IV non-small-cell lung cancer. These studies show overall response rates of approximately 30% to 60% with gemcitabine regimens vs overall response rates of 11% with cisplatin alone, 22% with cisplatin plus etoposide, 25% with cisplatin plus vinorelbine, and 40% with cisplatin plus mitomycin and ifosfamide (Ifex). Median survival time with gemcitabine regimens ranged from 8.1 to 9.8 months. Thrombocytopenia and anemia are the principal toxicities with gemcitabine regimens. Because of the favorable results with gemcitabine regimens, this drug is being evaluated in combination with carboplatin (Paraplatin) in newly diagnosed patients with stage IIIB or IV disease and good performance status, or as single-agent therapy in patients with poor performance status. [ONCOLOGY 15(Suppl 6):33-39, 2001]

Introduction

During the past 3 decades, extensive experience has been gainedin the treatment of patients with stage III or IV lung cancer. A total of 42phase III trials were initiated by the National Cancer Institute between 1973and 1994 and included 9,161 patients. A meta-analysis of these North Americantrials included 32 of the 42 trials, for a total of 5,820 patients, and dividedthe trials into two time frames: 1973 to 1983 and 1984 to 1994.[1] Whilethe percentage of women enrolled in clinical trials of lung cancer treatment wasunchanged between the two time frames (27% and 28%), there was a significantincrease in the median number of patients per treatment arm (77 vs 130; P <.001). Five trials found a median prolongation of survival of 2 months (range:0.7 to 2.7 months). In both time frames, median survival time was greater withcisplatin (Platinol)-based regimens: 1973 to 1983, 5.7 vs 4.4 months (P <.001); 1984 to 1994, 6.0 vs 4.4 months (P < .37). Many of the trials wereunderpowered to show a significant improvement in median survival time. Forexample, a study with 130 patients per treatment arm has 70% power to detect animprovement in median survival time from 6 to 8 months.

Based on North American andworldwide experience, platinum-based regimens have been the mainstay of chemotherapy regimens for non-small-celllung cancer for several decades. These regimens significantly reduce the risk ofdeath, increase median survival, and improve 1-year survival.[1,2] There is no standard platinum-based regimen, but combination regimenswith newer agents, such as gemcitabine [Gemzar], paclitaxel [Taxol], andvinorelbine [Navelbine], are superior to platinum alone or in combination witholder agents such as etoposide and vindesine [Eldisine].[3] The focus of thisarticle is the experience with platinum-based regimens that include gemcitabine,a deoxycitidine analog. Four phase III clinical trials of gemcitabine for thetreatment of non-small-cell lung cancer have been published in full.[4-7]These trials and the recently reported Eastern Cooperative Oncology Group (ECOG)E1594 trial, which demonstrated the activity of gemcitabine, are discussed.

Gemcitabine/Cisplatin

Approval by the US Food and Drug Administration (FDA) ofgemcitabine for use in non-small-cell lung cancer was based on a study thatcompared cisplatin/gemcitabine with cisplatin [Platinol] alone in approximately260 patients per treatment arm.[4] The study randomized 522 assessable patients(mean age: 62 to 63 years) who had not received prior treatment for non-small-celllung cancer to either cisplatin/gemcitabine or cisplatin alone administered on a28-day schedule. The treatment groups were well balanced with respect to diseaseseverity: 18 of 68 patients in the cisplatin/gemcitabine group and 17 of 61 inthe cisplatin group had stage IIIA/IIIB disease, respectively, and the numbersof patients with stage IV disease were 174 vs 184 (cisplatin/gemcitabine vscisplatin).

Grades 3/4 hematologic toxicities occurred more frequently inthe gemcitabine combination treatment group than in the cisplatin-alone group(25.4% vs 0.8%).[4] Neutropenia and thrombocytopenia were common: 57% and 50%,respectively, in the cisplatin/gemcitabine group vs 4.5% and 3.6% in thecisplatin group. Anemia (low hematocrit) was noted in 25% ofcisplatin/gemcitabine-treated patients and 6.5% of cisplatin-treated patients,while the incidence of febrile neutropenia was modest (4.6% and 0.8%). Theincidence of nonhematologic toxicities reflected primarily the cisplatincomponent and generally were comparable for the two treatment groups. Nausea andvomiting were reported by 27% and 23% of patients receivingcisplatin/gemcitabine and 21% and 19% of those receiving cisplatin, and renaltoxicity occurred in approximately 5% and 2% of these patients, respectively.Neurotoxicity was more common with cisplatin/gemcitabine: 17.5% vs 8.6% forcisplatin alone.

Response parameters all favored the cisplatin/gemcitabine arm (Table1).[4] The overall response rate for cisplatin/gemcitabine was 30.4% vs11.1% for cisplatin (P < .0001), and the median survival time was 9.1 vs 7.6months, respectively (P = .004). One-year survival was also notably higher forcisplatin/gemcitabine-treated patients, 39% vs 28%. The time to progressivedisease and the survival time significantly favored the cisplatin/gemcitabinecombination regimen over treatment with cisplatin alone (P = .0013 and P= .004,respectively) (Figure 1).

Gemcitabine/Cisplatin vsCisplatin/Etoposide

A second phase III, randomized trial was conducted in a similarpatient population (no prior treatment, stage IIIB or IV non-small-cell lungcancer).[5] This Spanish trial of 135 patients compared gemcitabine/cisplatinadministered in a 21-day schedule with cisplatin/etoposide in an every 28-dayschedule. The primary end point was overall response rate. Approximately 50% ofpatients (mean age: 58 to 59 years) in each group had stage IV disease.

Overall, toxicity was comparable for the two treatmentregimens.[5] The incidence of neutropenia was higher in etoposide- than ingemcitabine-treated patients (76% vs 64%), which corresponds to other studies ofetoposide-containing regimens, while the incidence of grade 3/4 thrombocytopeniawas greater with gemcitabine (56% vs 13%). Seven gemcitabine-treated patientsand 12 etoposide-treated patients developed febrile neutropenia. The incidenceof nausea and vomiting was similar in both treatment groups (39% vs 26%), whilegrade 3 alopecia was far more common with etoposide (13% vs 51%).

Response to treatment was greater with gemcitabine than withetoposide (Table 1).[5] The overall response rates were 40.6% and 21.9%(P =.02), and the time to progression was 6.9 vs 4.3 months (P = .01) forgemcitabine vs etoposide. A trend toward increased median survival time and1-year survival of 8.7 months and 32% was seen for gemcitabine, compared with7.2 months and 26% for etoposide. The progression-free survival curvesignificantly favored gemcitabine, and the survival curve favored gemcitabine,although not significantly. The authors concluded that compared withetoposide/cisplatin, the gemcitabine-containing regimen provided a significantlyhigher response rate and a delay in disease progression, without impairingquality of life.

Gemcitabine/Cisplatin vs Cisplatin Triplet

An Italian phase III trial, which included 307 patients withstage IIIB or IV non-small-cell lung cancer who had not received previoustreatment, randomly assigned patients to either gemcitabine plus cisplatin ormitomycin (Mutamycin) plus ifosfamide (Ifex) plus cisplatin. Both regimens wereadministered on a 28-day schedule.[6] The majority of patients (mean age: 60 to62 years) in each treatment group had stage IV disease (123, gemcitabine; 120,triplet regimen).

The incidence of grade 3/4 hematologic toxicities was similar inboth groups, although a higher proportion of patients in the gemcitabine groupexperienced thrombocytopenia (64% vs 28%; P < .001).[6] Neutropenia occurredin 40% and 33% of patients receiving the gemcitabine and triplet regimen,respectively; the occurrence of febrile neutropenia was rare (1% vs 0%). Nonhematologic toxicities occurred with similar incidence in both treatmentgroups, except alopecia which had a threefold higher incidence in the tripletregimen group (12% vs 39%; P < . 001).

The overall response rate to the gemcitabine regimen (59%) washigher than with the triplet regimen (40%; Table1).[6] The time to progressionwas similar in both groups (5.0 vs 4.8 mo) as was the 1-year survival (33% vs34%). There were no differences between the two regimens in the progression-freesurvival and survival curves. The results of this study are noteworthy in that,in previous studies, the mitomycin, ifosfamide, and cisplatin regimen was shownto be superior to supportive care and doublet regimens.The study provides further support of the benefit of gemcitabine/cisplatin inthe treatment of non-small-cell lung cancer.

Gemcitabine, Cisplatin, Vinorelbine

An ongoing, phase III Italian study, though underpowered, hasprovided some interesting preliminary results (Table1). The study is comparingthe triplet regimen of gemcitabine, cisplatin, and vinorelbine withgemcitabine/cisplatin; a third treatment arm, cisplatin/vinorelbine, wasdiscontinued due to a markedly higher incidence of neutropenia.[7] Sixtypatients (mean age: 60 to 62 years) with stage IIIB or IV non-small-cell lungcancer who had not been previously treated were randomized to each treatment. Ahigher proportion of patients had stage IV disease (57% to 60%), and themajority of patients had a performance status of 1.

Occurrences of grade 3/4 hematologic toxicities were comparablefor the three treatment groups with the exception of neutropenia.[7] Treatmentregimens containing gemcitabine were associated with a 40% to 45% incidence ofneutropenia, whereas the cisplatin/vinorelbine regimen was associated with a 75%incidence. Thrombocytopenia did not differ markedly among groups: 30% forgemcitabine/cisplatin, 17% for gemcitabine/cisplatin/vinorelbine, and 20% forcisplatin/vinorelbine. Fatigue was common with all three regimens (10%, 14%,15%).

Response to the gemcitabine-containing regimens was superior tothe cisplatin/vinorelbine regimen: 30% with gemcitabine doublet (95% confidenceinterval [CI] = 19%-43%) and 47% with gemcitabine triplet regimens (95% CI =34% to 60%) vs 25% with cisplatin/vinorelbine (95% CI = 15% to 38%) (see Table1) as was the 1-year survival rate (40% and 45% vs 34%).[7] Median survival timewas 42 and 51 weeks with the gemcitabine regimens compared with 35 weeks for thecisplatin/vinorelbine regimen. In patients with stage IV non-small-cell lungcancer, the median survival time also favored the gemcitabine regimens: 34 and47 weeks vs 27 weeks for the cisplatin/vinorelbine regimen. Both the mediansurvival time and the 1-year survival rate for the gemcitabine/cisplatin regimenobserved in this study are comparable to those achieved in the ECOG E1594clinical study discussed below.[8]

ECOG E1594 Phase III Study

The ECOG E1594 study evaluated four doublet regimens commonlyused for the treatment of non-small-cell lung cancer.[8] Patients werestratified by stage of disease (IIIB vs IV), performance status 0 to 1 vs 2,weight loss (< 5% vs ³ 5%), andwhether they had metastases to the central nervous system. They were thenrandomized to one of four treatments: cisplatin/paclitaxel (the referencetreatment arm), cisplatin/gemcitabine, cisplatin/docetaxel (Taxotere), orcarboplatin (Paraplatin)/paclitaxel (Figure 2). At an interim analysis afterapproximately 100 patients with a performance status of 2 had been treated,enrollment of performance status 2 patients, and hence stratification byperformance status, was suspended due to excessive toxicity with all fourtreatment regimens in these patients.

Nearly 1,200 patients (approximately 300 per treatment arm) wereenrolled in the E1594 study, and the treatment groups were comparable withrespect to prognostic factors.[8] The mean age of patients ranged from 61.6 to63.9 years with a slight preponderance of males (61% to 64%), and the majorityof patients had stage IV non-small-cell lung cancer (84% to 87%). Patientswith stage IIIB disease had malignant pleural effusions. Approximately 12% to14% of patients in each group had metastases to the central nervous system thatwere controlled by radiation therapy and/or surgery. The median number of weeksof treatment in all four arms was 12.

Overall, the response to treatment and survival were comparableamong treatment groups (Table 2).[8] The response rate in the gemcitabine arm(20.8%) was equivalent to that in the paclitaxel reference arm (21.2%), whilethe response rates were somewhat lower, but not statistically different, in thedocetaxel (17.4%) and carboplatin (15.5%) arms. Response rates in this study aresomewhat lower than in other studies of these doublet regimens because of thestrict criterion for a confirmatory chest x-ray at 4 weeks to be considered atreatment responder. The time to progression of disease significantly favoredgemcitabine compared with the paclitaxel reference arm (4.5 vs 3.5 mo; P =.003). Overall survival at 1 and 2 years also tended to favor gemcitabine, butthere were no significant differences for any of the groups compared with thereference arm (Table 2).

There was more variation among the regimens with respect totoxicities (Table 3).[8] Grade 3/4 anemia and thrombocytopenia occurredsignificantly more often in the gemcitabine arm than in thereference arm. The higher incidence of hematologic toxicity in the gemcitabinearm may be due to the weekly doses of gemcitabine and more frequent monitoring(on days 1, 8, and 15 of the 28-day schedule). Gastrointestinal toxicities weresimilar among the three cisplatin-containing arms but occurred less frequentlyin the carboplatin-containing arm. Grade 3 sensory neurologic toxicity tended tooccur more often in the carboplatin and gemcitabine arms.

Infections requiring hospitalization were less frequent incomparator treatment arms, particularly the carboplatin-containing arm, than inthe reference treatment arm (cisplatin/paclitaxel), although the differenceswere not significant. Use of broad-spectrum antibiotics was also lower in thecarboplatin-containing arm. An analysis of the total, aggregate worst degree oftoxicity indicated fewer severe toxicities in the carboplatin-containingtreatment arm, which was not significant when compared with thecisplatin/paclitaxel reference arm.

In summary, the E1594 clinical trial found no differences in theprimary end point or in survival between the cisplatin/paclitaxel reference arm and eachof the comparator treatment arms. The time to progression of disease was,however, significantly improved with the gemcitabine regimen, while the overallresponse rate to carboplatin/paclitaxel was worse than with the referenceregimen, with the difference approaching statistical significance. Treatmentdecisions regarding use of one of these doublet regimens in patients with non-small-celllung cancer, therefore, depends on other considerations, includingcost-effectiveness, side effects and toxicities, and ease of administration.Other considerations may include the overall response rate and time toprogression of disease.

Evolving Treatment Strategies

While the overall response rate in the gemcitabine arm of theE1594 clinical trial was comparable to the reference treatment arm, the higherincidence of hematologic toxicities may have been related to its use incombination with cisplatin 100 mg/m², which is also hematotoxic, to the days 1,8, and 15 administration regimen in a 28-day schedule, or to both.Administration of gemcitabine at 1,000 mg/m² on days 1 and 8 of a 21-dayschedule,[9] gemcitabine at 1,000 mg/m² on days 1, 8, and 15 of a 28-dayschedule,[10] or gemcitabine at 1,200 mg/m² (with dose escalation) on days 1 and8 of a 28-day schedule[11] with carboplatin has been shown to result in a goodoverall response rate and to be well tolerated. 

Conclusions

In the United States, new regimens employing gemcitabine areemerging for the treatment of newly diagnosed patients with stage IIIB or IV non-small-celllung cancer (Figure 3). For patients with a good performance status, gemcitabineat 1,000 mg/m² on days 1 and 8 plus carboplatin dosed at an area under theconcentration-time curve (AUC) of 6 on day 1 of a 21-day schedule is beingevaluated. In patients with a poor performance status, single-agent gemcitabineat 1,000 to 1,250 mg/m² on days 1 and 8 in a 21-day schedule is being studied.Patients who relapse on either of the gemcitabine regimens would receivedocetaxel 75 mg/m² every 3 weeks.

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