Gemcitabine (Gemzar), paclitaxel (Taxol), docetaxel (Taxotere), and vinorelbine (Navelbine) are among the most active agents for the treatment of non-small-cell lung cancer and are generally more active than platinum
ABSTRACT: Gemcitabine (Gemzar), paclitaxel (Taxol), docetaxel (Taxotere), and vinorelbine (Navelbine) are among the most active agents for the treatment of non-small-cell lung cancer and are generally more active than platinum compounds. When combined with a platinum compound, these agents have produced the best survival outcomes seen to date in non-small-cell lung cancer. More than 100 clinical trials have defined and expanded the role of gemcitabine, which has been combined with each of these agents to create novel combinations. Several new nonplatinum-based combinations compare favorably with platinum-based combinations with respect to toxicity and efficacy. Moreover, changing the schedule of gemcitabine administration from days 1, 8, and 15 every 4 weeks to days 1 and 8 every 3 weeks seems to allow greater dose intensity with less severe toxicity and slightly greater efficacy. Coadministration of docetaxel, paclitaxel, or vinorelbine with gemcitabine on days 1 and 8 every 3 weeks is a promising approach. In addition to a lower incidence of severe neutropenia, docetaxel, paclitaxel, and vinorelbine protect against gemcitabine-associated thrombocytopenia. [ONCOLOGY 15(Suppl 6):18-25, 2001]
Gemcitabine (Gemzar), docetaxel (Taxotere), paclitaxel(Taxol), and vinorelbine (Navelbine) are among the most active agents for thetreatment of non-small-cell lung cancer (NSCLC). Each has been shown toproduce objective responses in approximately 20% of previously untreatedpatients with advanced or metastatic disease and to improve survival whencompared with best supportive care. When combined with a platinum compound,these agents have, to date, produced the best survival outcomes in non-small-celllung cancer and represent the new standard of care for good performance statusin patients with advanced or metastatic disease.
These new agents generally appear to be more active thanplatinum compounds. Gemcitabine, in particular, appears to be at the head of theclass with respect to activity and patient tolerance. More than 500 patientswere treated in six phase II clinical trials with gemcitabine 1.0-1.2 g/m2 ondays 1, 8, and 15 every 4 weeks. Reported objective response rates are in therange of 21% to 26%.[1-6] Fewer than 7% of these patients suffered any grade 4toxicity.
Three randomized clinical trials have shown that single-agentgemcitabine can produce response rates and survival outcomes equivalent to thecombination regimens of cisplatin (Platinol)/etoposide[7,8] orcisplatin/vindesine (Eldisine). However, gemcitabine has considerably lesstoxicity and greater benefit with respect to improved quality of life andperformance of daily activities. Therefore, investigators have hypothesized thatgemcitabine could be combined with one of the other new agents to create novelnonplatinum doublet combinations with efficacy and/or toxicity profiles superiorto that of standard platinum-containing combinations. This article summarizesthe efforts to date that explore gemcitabine combined with docetaxel,paclitaxel, or vinorelbine.
Gemcitabine with docetaxel was the first combination examined.In the initial two studies, docetaxel was added on day 1 or 15 to a standard day1, 8, and 15 schedule of gemcitabine. Treatment was recycled every 28 days.
Pawinski et al reported the results of 30 courses oftreatment in 11 patients (10 of whom had received prior chemotherapy) with avariety of tumor types. On the 28-day schedule, gemcitabine 800 mg/m2 wasadministered on days 1, 8, and 15 with docetaxel 85 mg/m2 on day 1. Grade 3/4neutropenia occurred in 18 of the 30 courses (60%), including febrileneutropenia in 2 of the 11 patients. Grade 3/4 thrombocytopenia occurred in 5 ofthe 30 courses (17%), and grade 3 dermatitis or increased liver function tests(LFTs) occurred in one patient each. Six of the 11 patients required attenuationof the docetaxel dose. The authors concluded that it was not feasible to carrythis dose and schedule forward to expanded phase II or phase III trials.
Similarly, Spiridonidis et al explored escalating doses ofdocetaxel on day 1 or day 15 of a day 1, 8, and 15 schedule of gemcitabine 800mg/m2 every 28 days in 40 patients (39 with prior chemotherapy) with a varietyof tumor types. Dose-limiting toxicity consisted primarily of grade 4neutropenia in 40% of patients, febrile neutropenia in 7.5%, grade 3/4thrombocytopenia in 22.5%, grade 3 asthenia in 17.5%, grade 3 flu-like symptomsin 10%, and grade 3 fluid retention in 7.5%. The maximum tolerated dose fordocetaxel was higher when it was given on day 1 compared to day 15: 100 mg/m2 vs75 mg/m2, respectively. Furthermore, successful delivery of the planned dose ofdocetaxel was 98% vs 74% for the two schedules, respectively.
Objective responses were reported in four of seven patients withpreviously treated breast cancer and in 9 of 21 patients with previously treatedNSCLC (43% response rate, 95% confidence interval [CI]: 22% to 66%), includingobjective regressions in brain metastases in four patients. Similar to thePawinski study, dose-limiting myelotoxicity most often occurred on or near day15 of this schedule, frequently requiring dose attenuations or omissions in theplanned day 15 dose of gemcitabine.
Because of the frequent need to reduce or omit day 15 treatmentin these 28-day schedules, investigators began to explore 21-day schedules inwhich gemcitabine could be given on days 1 and 8 with docetaxel on day 1 or 8 (Table1).
Greek Lung CancerCooperative Group Study
Georgoulias et al reported the results of a Greek LungCancer Cooperative Group study that explored this new schedule in 52 patientswith previously untreated NSCLC. Gemcitabine 900 mg/m2 was administered on days1 and 8 combined with docetaxel 100 mg/m2 on day 8. Granulocytecolony-stimulating factor (G-CSF [Neupogen]) was added to the regimen at 150µg/m2 on days 9 to 15. Data from 251 courses of treatment indicated thattoxicity was relatively mild with grade 3/4 neutropenia, thrombocytopenia, oranemia in 20%, 8%, and 10% of patients, respectively, and febrile neutropenia in8%. Grade 2 or 3 asthenia was reported in 17% and 2% of patients, respectively;fluid retention was ≤ grade 2 in 19% of patients.
Gemcitabine and docetaxel dose intensities were maintained at600 mg/m2/wk and 33 mg/m2/wk, respectively (100% of planned dose intensity), andonly 14 of 251 treatment courses were delayed secondary to toxicity. Objectiveresponses were observed in 19 patients (36.5% response rate, 95% CI: 21.5% to46.4%). The median response duration was 5.0 months, time to tumor progression7.0 months, and survival 8.5 months; 1-year survival was 42%.
Similar Results From Two Studies
Two additional studies exploring this 21-day schedule soonfollowed. Rubio et al reported the results of a study by Argentinianinvestigators using gemcitabine 1,000 mg/m2 on days 1 and 8 combined withdocetaxel 75 mg/m2 on day 8 in 18 NSCLC patients. Hematologic toxicity wasmoderate with grade 3/4 neutropenia and thrombocytopenia occurring in 39% and 0%of courses, respectively. Objective responses were observed in 31% of patients.
Similar results were reported by Rebattu et al withgemcitabine 1,000 mg/m2 on days 1 and 8 combined with docetaxel 85mg/m2 on day8 in 36 NSCLC patients. Grade 3/4 neutropenia and thrombocytopenia occurred in50% and 5%, respectively, of courses. Objective responses were documented in 30%of evaluable patients.
Higher Dose Intensity
The rationale of changing from a day 1, 8, and 15 every-4-weekschedule to a day 1 and 8 every-3-week schedule in gemcitabine-based studiesrecently received support from a randomized trial by Soto Parra et al. Inthis study, patients received cisplatin 70 mg/m2 on day 2 of either schedulewith gemcitabine 1,000 mg/m2.
The relative dose intensity (calculated as mg/m2/wk) ofgemcitabine was higher with the 3-week schedule than with the 4-week schedule589mg/m2/wk compared to 564 mg/m2/wk, respectively. The lower dose intensity of the4-week schedule resulted from forced reductions or omissions of gemcitabinedosing on day 8 or 15 of the schedule in 17% and 80% of courses, respectively.In spite of the higher dose intensity of the 3-week schedule, grade 3/4neutropenia, thrombocytopenia, and nonhematologic toxicity was significantlylower than with the 4-week schedule. Furthermore, the response rate was higherwith the 3-week compared with the 4-week schedule (55% vs 40%, respectively),although the difference was not statistically significant.
The Greek Lung Cancer Study Group was the first to compare anew gemcitabine/docetaxel combination to a platinum-based combination,cisplatin/docetaxel (Table 2). A total of 347 patients with advanced ormetastatic NSCLC were randomized and treated on the every-3-week schedule. Thefirst group (180 patients) received cisplatin 80 mg/m2 on day 2 combined withdocetaxel 100 mg/m2 on day 1; the second group (167 patients) receivedgemcitabine 1,100 mg/m2 on days 1 and 8 combined with docetaxel 100mg/m2 on day8. To decrease the severity of granulocytopenia expected with these moderatelyintensive treatments, G-CSF was administered on days 3 to 9 of theplatinum-based regimen and on days 9 to 15 of the gemcitabine-based regimen.
A comparison of the toxicities of the cisplatin/docetaxel vsgemcitabine/docetaxel regimens revealed a higher rate of grade 3/4 neutropeniawith the former (34% vs 20%, respectively, P = .03) but a higher incidence offebrile neutropenia with the latter (29% vs 17%, respectively, P = .004). Therewere no significant differences between the two regimens with respect to grade3/4 thrombocytopenia (2% vs 4%, respectively), anemia (6% vs 4%, respectively),or fatigue (30% vs 33%, respectively).
Furthermore, analysis of therapeutic end points revealed nostatistically significant differences in response rates (31% vs 34%), mediantime to progression (8 months each), median survival (12 months vs 11 months),or 1-year survival (46% vs 41%). Although firm conclusions cannot be reachedfrom this randomized phase II trial, it is the first trial to demonstrate that anonplatinum-based regimen (gemcitabine/docetaxel) may be equivalent to aplatinum-based regimen with respect to efficacy.
Several groups of investigators have explored gemcitabinecombined with docetaxel or paclitaxel given together every 2 weeks.[18,19]However, the extraordinarily high doses of gemcitabine achievable with thisunconventional schedule (2,500-3,000 mg/m2) strongly implies a fundamentalchange in the drug’s pharmacodynamic properties. Unfortunately, there is notsufficient information to conclude that its efficacy in non-small-cell lungcancer is not also significantly changed by this novel schedule.
Four groups have investigated gemcitabine/paclitaxelcombinations (Table 3).
Androulakis et al was the first to report the results of aphase II trial with gemcitabine 900 mg/m2 on days 1 and 8 every 3 weeks combinedwith paclitaxel 175 mg/m2 on day 8 in 49 patients previously treated withcisplatin or docetaxel for recurrent NSCLC. Hematologic toxicity was mild withgrade 3/4 neutropenia or thrombocytopenia in only 12% and 2% of patients,respectively. Dose-limiting toxicity consisted of grade 2/3 asthenia (51%) orneuropathy (32%), respectively. Objective responses were reported in 18% ofpatients in this salvage setting.
Giaccone and colleagues investigated gemcitabine 1,000 mg/m2on days 1 and 8 every 3 weeks with paclitaxel in doses ranging from 150 to 200mg/m2 on day 1 in 49 previously untreated patients with NSCLC. Grade 4neutropenia or thrombocytopenia occurred in only 12% and 3.5%, respectively, ofpatients while objective responses were observed in 24%.
More recently, Monnier et al and Auerbach et al reportedthe preliminary results of their studies with gemcitabine 1,000 mg/m2 on days 1and 8 every 3 weeks with paclitaxel to 200 mg/m2 (Monnier) or 175mg/m2(Auerbach) on day 1 in 40 and 20 patients, respectively, with previouslyuntreated NSCLC. Toxicity data were reported in the Monnier study with grade 4neutropenia occurring in only 5% of patients and grade 4 thrombocytopenia inonly 1%. Objective responses were reported in 35% and 47% of these two studies,respectively.
Kosmidis et al were the first to report the results of arandomized clinical trial comparing the nonplatinum combination ofgemcitabine/paclitaxel to a standard second-generation platinum-based regimen,carboplatin (Paraplatin)/paclitaxel, in patients with previously untreatedadvanced or metastatic NSCLC (Table 4).
Patients were randomized to receive either paclitaxel 200 mg/m2on day 1 with gemcitabine 1 g/m2 on days 1 and 8 every 3 weeks or paclitaxel 200mg/m2 on day 1 with carboplatin at an area under the concentration-time curve(AUC) of 6 every 3 weeks. There were no statistically significant differencesbetween the two arms of the trial with respect to grade 3/4 neutropenia (10.5%vs 9.6%), thrombocytopenia (1.2% each), or anemia (1.9% vs 3.6%) or grade 3neuropathy (6.2% vs 5.4%). Although the results favored the nonplatinum regimen,there were no statistically significant differences in efficacy end pointsbetween gemcitabine/paclitaxel or carboplatin/paclitaxel with respect to(respectively) response rate (36.5% vs 28.7%), median time to tumor progression(7.2 months vs 6.9 months), median survival (12.3 months vs 10.7 months), or1-year survival (51.3% vs 41.3%).
This, therefore, represented the second randomized clinicaltrial that demonstrated that nonplatinum combinations of novel agents canproduce toxicity and survival results at least equal to the results previouslyachievable only with standard platinum-based regimens.
Since more frequent dosing schedules often improve the efficacyof phase-specific cytotoxic agents and the opportunity for enhanced interactionwith radiation therapy and other frequently dosed chemotherapeutic agents, therehas been great interest in exploring weekly administration schedules with thetaxanes.
Paclitaxel was the first taxane to be studied on a weeklyschedule. Loffler et al examined paclitaxel in doses ranging from 40 mg/m2to 90 mg/m2 given as a 1-hour intravenous infusion weekly for 6 weeks in 50previously treated patients with a variety of malignancies. Overall toxicity wasmild with no grade 4 hematologic or grade 3 nonhematologic toxicity. In fact, atthe maximum dose studied (90 mg/m2), grade 3 leukopenia was observed in only oneof 10 patients. Objective responses were documented in 15 of 50 patients (30%response rate).
Ackerley conducted a more formal phase I/II clinical trialof weekly paclitaxel given as a 3-hour infusion with doses from 100 mg/m2/wk to200 mg/m2/wk in 26 previously untreated patients with NSCLC. The goal of thisstudy was to define a maximum tolerated dose that could be maintained for 6consecutive weeks. Doses of 135-150 mg/m2/wk were maintained in all sixpatients and 175 mg/m2/wk was maintained in four. Dose-limiting toxicityconsisted primarily of neutropenia and cumulative neuropathy at the 200 mg/m2/wkdose level. Hematologic toxicity was mild at the lower recommended dose levels,and neuropathy occurred primarily after several weeks of treatment. Objectiveresponses were documented in 9 of 24 evaluable patients (38% response rate).
Docetaxel has also been studied on a weekly schedule. Peacock etal investigated docetaxel doses ranging from 20 mg/m2 to 52 mg/m2 weekly for6 consecutive weeks in 38 patients with advanced chemotherapy refractorymalignancies. Notably, 23 of the 38 patients had previously received paclitaxel.
Myelosuppression was not a dose-limiting toxicity at any of thedoses tested. Only five episodes of grade 3 leukopenia and no grade 4 leukopeniawere observed in over 280 courses of treatment. Dose-limiting toxicity consistedprimarily of grade 3 fatigue and asthenia, which was observed in all threepatients treated at 52 mg/m2/wk and in 2 of 10 patients treated at 43mg/m2/wk.Other grade 3 toxicities included severe dermatitis (acral erythema) at the 43mg/m2/wk dose level. At weekly doses as high as 36 mg/m2/wk, docetaxel wasextremely well tolerated with rare grade 3 or 4 toxicities even in previouslytreated patients. Although this group of patients had received priorchemotherapy, including paclitaxel, several objective responses were observed inpatients with breast cancer or non-Hodgkin’s lymphoma.
Because of the encouraging data with a weekly schedule ofpaclitaxel or docetaxel, several investigators have explored the combination ofweekly gemcitabine plus a taxane. Two groups have studied weeklygemcitabine/docetaxel.
Rizvi et al conducted a phase I study of gemcitabine 800-1,250mg/m2 combined with docetaxel 30-40 mg/m2 on days 1 and 8 every 3 weeks in 26patients with advanced cancers. Grade 3/4 neutropenia, observed in 7 of 26patients (27%), was the most common toxicity. However, all seven patients hadreceived two or more prior chemotherapy regimens whereas none of 11 previouslyuntreated patients experienced grade 3/4 neutropenia. No significanthepatotoxicity, fluid retention, or neuropathy was observed. Two objectiveresponses (partial responses) were documented in five patients with NSCLC,including one previously treated with cisplatin/etoposide and vinorelbine andone previously untreated.
A small pilot study was conducted at the Cedars-SinaiComprehensive Cancer Center in which we initially fixed the dose of gemcitabineat 1,000 mg/m2 and combined it with docetaxel in doses escalating from 30mg/m2to 35 mg/m2 to 40 mg/m2. No grade 3/4 hematologic toxicity or grade 2/4nonhematologic toxicity (except alopecia) was observed in 27 courses oftreatment (six patients) at the 30-35 mg/m2 dose level of docetaxel. Toxicityin 11 treatment courses (four patients) at the 40 mg/m2 dose level of docetaxelincluded grade 3 neutropenia in one course and grade 2 asthenia/fatigue in threecourses; mild leg edema occurred in one of the four patients.
Gemcitabine was increased to 1,200 mg/m2 with docetaxel 40mg/m2with no grade 4 hematologic or grade 3/4 nonhematologic toxicity observed inseven treatment courses administered to two patients. Patients were given 4 mgdexamethasone to take orally on the day before, day of, and day afterchemotherapy.
Four groups have studied weekly gemcitabine and paclitaxel.Einhorn et al reported preliminary results in 31 patients with a variety ofmalignancies. Gemcitabine was given in doses ranging from 600 mg/m2 to 1,000mg/m2 combined with paclitaxel in doses ranging from 60 mg/m2 to 130mg/m2/3 hon days 1, 8, and 15 every 4 weeks Overall the regimen was well tolerated.Cumulative neurotoxicity was dose-limiting at a paclitaxel dose level of 135mg/m2/wk and was mild to moderate below that level. Grade 4 neutropenia wasobserved in three patients (10%), and there was one episode of neutropenicfever.
Subsequently, the recommended phase II dose level of gemcitabine1,000 mg/m2/wk combined with paclitaxel 110 mg/m2/wk on 3 out of every 4 weekswas studied by the Hoosier Oncology Group in 42 previously untreated NSCLCpatients. Grade 3/4 neutropenia occurred in 43% of patients and threepatients died unexpectedly from febrile neutropenia. An additional patient diedof pulmonary toxicity. Although the overall response rate was 37%, the 1-yearsurvival was only 26%, primarily due to the unexpectedly high toxic death rate.Poor patient selection was cited as a possible contributing factor to thesediscouraging results.
DePas et al, reporting for an Italian/Swiss group, conducteda phase I/II trial of gemcitabine 800-2,000 mg/m2/wk and paclitaxel 60-100mg/m2/wk on 3 consecutive weeks out of every 4 weeks in 30 NSCLC patients.Hematologic toxicity was very mild with grade 3/4 neutropenia occurring only atthe highest dose level studied and overall in only 10% of patients. Theobjective response rate was 43%.
We conducted another small pilot study at Cedar-SinaiComprehensive Cancer center. Gemcitabine 800 mg/m2/wk to 1,200 mg/m2/wk andpaclitaxel 80 mg/m2/wk to 120 mg/m2/wk for 2 out of every 3 weeks was given to11 NSCLC patients. Grade 3/4 neutropenia occurred in 27% of patients and grade 3neuropathy was observed in only one patient in the first three treatment cycles.There was no grade 3/4 thrombocytopenia; five patients (45%) achieved a partialresponse.
Based on the above experience with weekly gemcitabine/taxanecombinations, we initiated a randomized phase II trial of weeklygemcitabine/docetaxel vs weekly gemcitabine/paclitaxel in patients with advancedor metastatic NSCLC among a group of primarily community-based medicaloncologists called the American Clinical Oncology Research Network (ACORN) (Figure1). Gemcitabine 1,200 mg/m2 on days 1 and 8 every 3 weeks is given inboth arms of the study.
In arm A, patients receive docetaxel 40 mg/m2 and in arm B theyreceive paclitaxel 120 mg/m2 on the same days as gemcitabine. Patients arestratified according to stage (IIIB vs IV), sex, performance status (PS 0-1 vs2), and weight loss (£ 5% vs > 5% prior weight loss) prior to randomization.Quality of life and differences in response rate and toxicity, with a specialemphasis on taxane-associated asthenia and neuropathy and the impact ofactivities of daily living, are the primary study end points. Time to tumorprogression and survival are secondary end points.
To date, 51 patients have been entered into the study, 25 on armA and 26 on arm B, and have received 188 courses of treatment. Toxicities in thefirst two cycles of treatment have been mild with grade 4 neutropenia in four(16%) patients on arm A and in two (8%) patients on arm B. Grade 3/4asthenia/fatigue has occurred in four (16%) patients on arm A and in two (8%)patients on arm B. Grade 3/4 neuropathy has occurred in three (12%) patients onarm B. Preliminary response rates are 44% and 35% on arms A and B, respectively.The study is targeted to accrue at least 75 evaluable patients per arm (total150 patients).
One of the most widely explored nonplatinum combinations isweekly gemcitabine and vinorelbine. Seven phase II trials examined both drugsadministered on days 1, 8, and 15 every 4 weeks.[33-39] Gemcitabine 1,000 mg/m2and vinorelbine 25 mg/m2 were the most commonly used doses. Myelosuppression wasthe most common dose-limiting toxicity, with grade 3/4 neutropenia occurring in10% to 50% of patients. Other adverse effects included fevers, myalgias,thromboses, and grade 1-3 elevated LFTs in 5% to 15% of patients. The nearabsence of alopecia is especially notable. Objective response rates varied from19% to 70% with most in the 20% to 30% range.
Similar to the experience with gemcitabine/taxane combinations,alteration to a day 1 and 8 every-3-week schedule resulted in increased doseintensity (calculated on a mg/m2/wk basis) and less severe toxicity. At leastseven phase II trials examined both drugs administered on days 1 and 8 every 3weeks.[40-46] In most studies, the dose of gemcitabine could be increased to1,200 mg/m2; in three of the seven studies, the dose of vinorelbine wasincreased from 25 mg/m2 to 30 mg/m2.
Myelosuppression remained the most common dose-limiting toxicitybut appeared to be less than that seen on the days 1, 8, and 15 every-4-weekschedule. Grade 3/4 neutropenia occurred in 8% to 37% of patients. Fevers,myalgias, thromboses, and grade 1-3 elevated LFTs continued to occur in 5% to15% of patients; alopecia was uncommon. Objective response rates also appearedto be slightly higher than with the 4-week schedule, ranging from 27% to 41%.
More than 100 clinical trials conducted by investigatorsworldwide over the past 8 years have served to define and expand the role ofgemcitabine in the treatment of non-small-cell lung cancer. Clearly, it is oneof the most active and best tolerated drugs for the treatment of this disease.Its moderate toxicity profile has allowed it to be combined with cisplatin,carboplatin, and the other new active agents docetaxel, paclitaxel, andvinorelbine.
Gemcitabine combined with cisplatin or carboplatin ranks among the most active platinum-based combinations inNSCLC. Several new nonplatinum gemcitabine-based combinations reviewed herecompare very favorably to platinum-based combinations with respect to toxicityand efficacy. Changing the schedule of administration of gemcitabine from days1, 8, and 15 every 4 weeks to days 1 and 8 every 3 weeks appears to allowgreater dose intensity with less severe toxicity and slightly greater efficacy.
Coadministration of docetaxel, paclitaxel, or vinorelbinecombined with gemcitabine on days 1 and 8 every 3 weeks is a very promisingapproach. In addition to a lower incidence of severe neutropenia, these threeagents protect against gemcitabine-associated thrombocytopenia. Interestingly,paclitaxel given weekly with gemcitabine may produce less neurotoxicity thanwhen it is given every 3 weeks with carboplatin.
Additional clinical trials are needed to better define doses andschedules of administration and to confirm these promising preliminaryobservations. However, data presented in this review suggest thatgemcitabine-based combinations are emerging as a new standard for the treatmentof non-small-cell lung cancer.
1. Abratt RP, Bezwoda WR, Falkson G, et al: Efficacy and safetyprofile of gemcitabine in non-small-cell lung cancer: A phase II study. J ClinOncol 12:1535-1540, 1994.
2. Anderson H, Lund B, Bach F, et al: Single-agent activity ofweekly gemcitabine in advanced non-small-cell lung cancer: A phase II study. JClin Oncol 12:1821-1826, 1994.
3. Gatzemeier U, Shepherd FA, LeChevalier T, et al: Activity ofgemcitabine in patients with non-small-cell lung cancer: A multicentre,extended phase II study. Eur J Cancer 32A:243-248, 1996.
4. Fukuoka M, Takada M, Yokoyama A, et al: Phase II studies ofgemcitabine for non-small-cell lung cancer in Japan. Seminars in Oncol24(suppl 7):42-46, 1997.
5. Yokoyama A, Nakai Y, Yoneda S, et al: Activity of gemcitabinein the treatment of patients with non-small-cell lung cancer: A multicenterphase II study. Anti-Cancer Drugs 8:574-581, 1997.
6. Anderson H, Hopwood P, Stephens RJ, et al: Gemcitabine plusbest supportive care vs best supportive care in inoperable non-small-cell lungcancer: A randomized trial with quality of life as the primary outcome. UK NSCLCGemcitabine Group. Br J Cancer 83:447-453, 2000.
7. Manegold C, Bergman B, Chemaissani A, et al: Single-agentgemcitabine vs cisplatin/etoposide: Early results of a randomized phase II studyin locally advanced or metastatic non-small-cell lung cancer. Ann Oncol8:525-529, 1997.
8. Perng RP, Chen YM, Ming-Liu J, et al: Gemcitabine vs thecombination of cisplatin and etoposide in patients with inoperable non-small-celllung cancer in a phase II randomized study. J Clin Oncol 15:2097-2102, 1997.
9. Vansteenkiste J, Vandebroek J, Nackaerts K, et al:Gemcitabine monotherapy vs cisplatin-based chemotherapy in symptomatic advancedNSCLC: A prospective randomized comparison of symptom control. Lung Cancer29(suppl 1):48, 2000.
10. Pawinski A, Louwerens M, Tonelli D, et al: A phase I studyof taxotere and Gemzar in patients with advanced solid tumors (abstract 957).Proc Am Soc Clin Oncol 17:249a,1998.
11. Spiridonidis CH, Laufman LR, Jones JJ, et al: Weeklygemcitabine combined with monthly docetaxel in patients with advancedmalignanciesA phase I trial (abstract 795). Proc Am Soc Clin Oncol 17:206a,1998.
12. Spiridonidis CH, Laufman LR, Carman L, et al: Second-linechemotherapy with weekly gemcitabine and monthly docetaxel in patients with non-small-celllung cancer: A phase II study (abstract 1968). Proc Am Soc Clin Oncol 19:503a,2000.
13. Georgoulias V, Androulakis N, Kouroussis Ch, et al:Second-line treatment with paclitaxel and gemcitabine in patients with non-small-celllung cancer who failed cisplatin-based chemotherapy. Proc Am Soc Clin Oncol17:468a, 1998.
14. Rubio G, Blajman C, Capo A, et al: Docetaxel and gemcitabinein metastatic non-small-cell lung cancer. A phase II study. Preliminaryfeasibility report (abstract 2012). Proc Am Soc Clin Oncol 18:522a, 1999.
15. Rebattu P, Quantin X, Morere J, et al: A phase II study ofdocetaxel (D) and gemcitabine combination in patients with non-small-cell lungcancer (abstract 2124). Proc Am Soc Clin Oncol 19:539a, 2000.
16. Soto Parra HJ, Cavina R, Antonelli G, et al: Superiority of3-week vs 4-week schedule of cisplatin and gemcitabine: Results of a randomizedphase II study (abstract 2152). Proc Am Soc Clin Oncol 19:546a, 2000.
17. Georgoulias V, Papadakis E, Alexopoulos A, et al: Docetaxelplus cisplatin vs docetaxel plus gemcitabine chemotherapy in advanced non-small-celllung cancer: A preliminary analysis of a multicenter randomized phase II trial(abstract 1778). Proc Am Soc Clin Oncol 18:461a, 1999.
18. Eckardt JR, Schmidt AM, Needles BM, et al: A phase I studyof the combination of docetaxel and gemcitabine (abstract 920). Proc Am Soc ClinOncol 17:240a, 1998.
19. Giaccone G, Smit E, Laan D, et al: Phase I/II study ofpaclitaxel and gemcitabine in advanced non-small-cell lung cancer (abstract1869). Proc Am Soc Clin Oncol 17:486a, 1998.
20. Androulakis N, Kouroussis C, Kakolyris S, et al: Salvagetreatment with paclitaxel and gemcitabine for patients with non-small-celllung cancer after cisplatin- or docetaxel-based chemotherapy: A multicenterphase II study. Ann Oncol 9:1127-1130, 1998.
21. Giaccone G, Smit EF, van Meerbeeck JP, et al: A phase I-IIstudy of gemcitabine and paclitaxel in advanced non-small-cell lung cancer.Ann Oncol 11:109-112, 2000.
22. Monnier A, Douillard JY, Lerouge D, et al: Results of aphase II study with Taxol and Gemzar in metastatic non-small-cell lung cancer(abstract 2021). Proc Am Soc Clin Oncol 19:516a, 2000.
23. Auerbach M, Chaudry M, Richards P, et al: Phase II study ofgemcitabine and paclitaxel in metastatic non-small-cell lung cancer (abstract2052). Proc Am Soc Clin Oncol 19:522a, 2000.
24. Kosmidis PA, Bacoyiannis C, Mylonakis N, et al: A randomizedphase III trial of paclitaxel plus carboplatin vs paclitaxel plus gemcitabine inadvanced non-small-cell lung cancer. A preliminary analysis (abstract 1908).Proc Am Soc Clin Oncol 19:488a, 2000.
25. Loffler TM, Winnfried F, Lipke J, et al: Schedule- anddose-intensified paclitaxel as weekly 1-hour infusion in pretreated solidtumors: Results of a phase I/II trial. Semin Oncol 23(suppl 16):32-34, 1996.
26. Akerley W: Phase I/II trial of weekly paclitaxel in patientswith advanced lung cancer. Semin Oncol 23(suppl 16):55-58, 1996.
27. Peacock NW, Burris HA, Hainsworth JD, et al: Weeklydocetaxel in patients with advanced refractory malignancies: A phase I trial(abstract 727). Proc Am Soc Clin Oncol 17:189a, 1998.
28. Belani CP: Weekly paclitaxel and carboplatin in non-small-celllung cancer. Lung Cancer 29(suppl 2):128, 2000.
29. Rizvi NA, Spiridonidis CH, Davis TH, et al: Docetaxel andgemcitabine combinations in non-small-cell lung cancer. Semin Oncol 26(suppl 16):27-31, 1999.
30. Einhorn LH, Raghavan D, Kindler H, et al. A phase I trial ofgemcitabine plus paclitaxel combination therapy in patients with refractorysolid tumors (abstract 796). Proc Am Soc Clin Oncol 17:207a, 1998.
31. Bhatia S, Ng E, Ansari R, et al: A phase II study ofpaclitaxel (P) and gemcitabine in patients with advanced non-small-cell lungcancerA Hoosier Oncology Group study (abstract 2091). Proc Am Soc Clin Oncol19:532a, 2000.
32. DePas TM, Danesi R, Sessa C, et al: Phase I study ofgemcitabine and paclitaxel in chemonaive patients with advanced non-small-celllung cancer (abstract 2094). Proc Am Soc Clin Oncol 19:532a, 2000.
33. Pirker P, Krajnik G, Mohn-Staudner A, et al:Vinorelbine/gemcitabine in advanced non-small-cell lung cancer: Final resultsof an AASLC trial (abstract 2080). Proc Am Soc Clin Oncol 19:529a, 2000.
34. Chen YM, Whang-Peng J, Perng RP, et al: A multi-center phaseII study of gemcitabine and vinorelbine in patients with advanced stage IIIB-IVnon-small-cell lung cancer (abstract 1856). Proc Am Soc Clin Oncol 18:481a,1999.
35. Krajnik G, Wein W, Greil R, et al: Vinorelbine/gemcitabinein advanced non-small-cell lung cancer: A phase I trial. Eur J Cancer34:1977-1980, 1998.
36. Isokangas OP, Knuuttila A, Halme M, et al: Phase II study ofvinorelbine and gemcitabine for inoperable stage IIIB-IV non-small-cell lungcancer. Ann Oncol 10:1059-1063, 1999.
37. Barr F, Mirsky H, Clinthorne D, et al: A phase III study ofgemcitabine and vinorelbine salvage chemotherapy for taxanes resistant non-small-celllung cancer (abstract 1914). Proc Am Soc Clin Oncol 18:496a, 1999.
38. Herrero CC, Martinez EN, Jaime AB: Second-line treatmentwith gemcitabine and vinorelbine in non-small-cell lung cancer cisplatinfailures: A pilot study. Lung Cancer 27:47-53, 2000.
39. Hirsch V, Ayoub J, Cormier Y, et al: Phase II multicentertrial with gemcitabine and vinorelbine in patients with advanced (stage IIIB +IV) non-small-cell lung cancer (abstract 1961). Proc Am Soc Clin Oncol18:508a, 1999.
40. Gridelli C, Cigolari S, Bilancia D, et al: Phase II study ofgemcitabine and gemcitabine + vinorelbine in advanced NSCLC elderly patientswithin the phase III MILES (Multicenter Italian Lung Cancer in the ElderlyStudy) randomized trial (abstract 2092). Proc Am Soc Clin Oncol 19:532a, 2000.
41. Esteban E, Llano JLG, Vietez JM, et al: Phase I/II study ofgemcitabine plus vinorelbine in non-small-cell lung cancer (abstract 1855).Proc Am Soc Clin Oncol 17:482a, 1998.
42. Lorusso V, Mancarella S, Carpagnano F, et al: Gemcitabineplus vinorelbine in patients with stage IIIB-IV non-small-cell lung cancer. Aphase II study. Proc Am Soc Clin Oncol 17:470a, 1998.
43. Herbst RS, Lilenbaum R: Gemcitabine and vinorelbinecombinations in the treatment of non-small-cell lung cancer (NSCLC). SeminOncol 26(suppl 16):67-70, 1999.
44. Beretta GD, Michetti G, Belometti MO, et al: Gemcitabineplus vinorelbine in elderly or unfit patients with non-small-cell lung cancer.Br J Cancer 83:573-576, 2000.
45. Gridelli C, Frontini L, Perrone F, et al: Gemcitabine plusvinorelbine in advanced non-small-cell lung cancer: A phase II study of threedifferent doses. Br J Cancer 83:707-714, 2000.
46. Lilenbaum R, Schwartz MA, Cano R, et al: Gemcitabine andnavelbine in advanced non-small-cell lung cancer (abstract 1901). Proc Am SocClin Oncol 17:494a, 1998.