Docetaxel (Taxotere) has shown activity both as a single-agent and in combination with multiple other cytotoxic agents in the front-line therapy of advanced, metastatic non-small-cell lung cancer (NSCLC). A randomized, phase III trial demonstrated a survival advantage for docetaxel over best supportive care in the front-line setting, with docetaxel achieving a 2-year survival of 12% vs 0% for best supportive care. Combinations of docetaxel with the platinum agents have been the most extensively studied in the front-line setting and have produced notably high response rates and encouraging median survivals.
ABSTRACT: Docetaxel (Taxotere) has shown activity both as a single-agent and in combination with multiple other cytotoxic agents in the front-line therapy of advanced, metastatic non-small-cell lung cancer (NSCLC). A randomized, phase III trial demonstrated a survival advantage for docetaxel over best supportive care in the front-line setting, with docetaxel achieving a 2-year survival of 12% vs 0% for best supportive care. Combinations of docetaxel with the platinum agents have been the most extensively studied in the front-line setting and have produced notably high response rates and encouraging median survivals. When compared to the paclitaxel/cisplatinum combination in a large, phase III randomized trial, the combination of docetaxel and cisplatin resulted in similar response, median survival, and 1-year survival rates. Another randomized phase III trial compared docetaxel/platinum combinations to the US Food and Drug Administration (FDA)-approved vinorelbine (Navelbine)/cisplatin regimen. The docetaxel/cisplatin combination produced a superior overall survival, 2-year survival, and overall response rates compared to vinorelbine/cisplatin. The combination of docetaxel and carboplatin (Paraplatin) demonstrated similar survival and response, and was associated with quality-of-life benefits over the vinorelbine/cisplatin arm. Docetaxel has been successfully combined with gemcitabine in multiple trials with impressive response and survival rates, and an acceptable toxicity profile. A large phase IIb trial demonstrated therapeutic equivalence and lesser toxicities for the docetaxel/gemcitabine combination compared to the combination of docetaxel and cisplatin. The docetaxel/gemcitabine combination therefore represents a viable nonplatinum regimen for first-line treatment of NSCLC. Other combinations that have been tested include docetaxel with vinorelbine, and docetaxel with irinotecan (CPT-11, Camptosar). Docetaxel is active in NSCLC and should be investigated further in combination with novel molecularly targeted drugs such as tyrosine kinase inhibitors, and farnesyl transferase inhibitors. [ONCOLOGY 16(Suppl 6):53-62, 2002]
Lung cancer is by far the leading cause ofcancer-related death. In 2002, an estimated 183,200 patients will be diagnosedwith lung cancer, and an estimated 161,400 deaths will occur. Much workremains to be done in this disease, which is associated with a 5-year survivalof only 15.8%, and a median survival for stage IV disease (even with enhancedcytotoxic therapies used in combination) ranging from 7.4 to 9.2 months.[1-6]However, it should be noted that over the past 15 years, combinationplatinum-based cytotoxic chemotherapy has resulted in a doubling of the mediansurvival rate among stage IV NSCLC patients, from approximately 4 to8 months. Furthermore, an almost threefold increase in the 1-year survivalrate (from 11% to 14% up to 30% to 35%) and meaningful 2-year survival rateshave been demonstrated in several randomized trials.
Docetaxel (Taxotere) has demonstrated modest but very real survival andquality-of-life advantages when used in the second-line NSCLC setting; it couldultimately produce a more meaningful survival advantage in early- tointermediate-stage disease.[8,9] This theory was evaluated in a phase II trialconducted by the Southwestern Oncology Group (SWOG) in which patients receiveddocetaxel after completing concurrent chemoradiation therapy with cisplatin andetoposide. The patients, all of whom had stage IIIB NSCLC without a malignantpleural effusion, demonstrated a median overall survival of 27 months and a3-year survival of 37%. The results of this phase IImulti-institutional, cooperative group study highlight the fact that agents thathave activity in advanced, refractory cancers often show significantly moreactivity in earlier stages of disease. Therefore, docetaxel should beinvestigated as a single agent and in combination with other cytotoxic agents,as a building block to improve upon the results now possible in the treatment ofpatients with NSCLC.
Numerous phase I and II trials have shown that single-agent docetaxel isactive in the treatment of incurable or metastatic NSCLC in chemotherapy-naivepatients. A combined overall response rate of 27% was documented in six phase IItrials of docetaxel, 100 mg/m² every 3 weeks, in this patient population, with amedian response duration of 6 months, a median overall survival of 9.2 months,and a 1-year survival of 39%. Lower doses of docetaxel have also beeninvestigated in phase II trials in the front-line therapy of NSCLC. Docetaxel at75 mg/m² and 60 mg/m² every 3 weeks resulted in overall response rates of 25%and 19%, respectively, and median survivals of 10 and 9.2 months.[12,13]
Based on these findings, Roszkowski et al conducted a randomized, open-labelphase III trial in 207 patients with either unresectable or metastatic NSCLC whowere treated with docetaxel plus best supportive care (BSC) or BSC alone.Patients in the chemotherapy arm received docetaxel at 100 mg/m² as a 1-hourintravenous infusion every 21 days until evidence of disease progression,the estimated maximal benefits from treatment were obtained, or unacceptabletoxicity. The study was conducted with 2-to-1 randomization; 137 patientsreceived docetaxel and 73 received BSC.
Overall survival was significantly longer for the docetaxel plus BSC arm ascompared to the BSC alone arm (P = .026). The 2-year survival in the docetaxelplus BSC arm was 12%, whereas none of the patients in the BSC arm survivedlonger than 20 months. The overall response rate in the patients whoreceived a minimum of two cycles of docetaxel was 19.7%. Time to diseaseprogression was significantly better in the docetaxel plus BSC arm vs the BSCalone arm at 12.6 weeks vs 8.9 weeks, respectively (P < .001).Quality-of-life tests revealed the superiority of the docetaxel arm (P = .0401).Additionally, requirements for narcotic analgesics and palliative radiationtherapy were significantly lower in the docetaxel plus BSC arm vs the BSC alonearm, in spite of the fact that 16% of the BSC arm went on to receivechemotherapy.
Weekly Docetaxel Regimen
A trial of single-agent docetaxel as a weekly regimen in the treatment ofpatients with NSCLC has been reported by Hainsworth et al. Docetaxel wasadministered at 36 mg/m²/wk for 6 consecutive weeks of an 8-week cycle to39 elderly or poor performance status patients with chemotherapy-naive NSCLC. Anoverall response rate of 18% was demonstrated, with one complete response andsix partial responses. The median survival was 5 months, with an estimated 1year survival rate of 27% in this group of elderly patients. Similar to findingsfrom other studies of weekly docetaxel administration, hematologic toxicitieswere greatly reduced. Grade 3 leukopenia was noted in only three patients, withnone developing grade 4 myelosuppression.
As a result of these findings, and in particular in light of the absence ofgrade 3/4 neutropenia or neuropathy, many community physicians favor using aweekly schedule of docetaxel administration. Further testing remains to becompleted to determine whether response rates and survival are equivalent to theevery-3-week regimen. As will be discussed below, the use of docetaxel on aweekly schedule also offers attractive options for the development ofcombination regimens.
Docetaxel and Cisplatin
Based on docetaxel’s single-agent activity as first- and second-linetherapy of NSCLC, and because the platinum compounds have long been a staple offront-line therapy for NSCLC, the next logical step was to combine docetaxelwith cisplatin or carboplatin (Paraplatin). The lack of cross-resistance and thelargely nonoverlapping toxicity profile of docetaxel and the platinum agentsprovided additional rationale to investigate the combinations.
Several phase I trials of docetaxel and cisplatin have established thetoxicity profile and activity of the combination in advanced NSCLC.[16-18] Thetwo maximum tolerated doses achieved were either docetaxel at 100 mg/m²administered as a 1-hour infusion followed by cisplatin at 75 mg/m² 3-hourinfusion or docetaxel at 75 mg/m² as a 1-hour infusion followed by cisplatin at100 mg/m² as a 3-hour infusion with cycles repeated every 3 weeks. Manyphase II trials have used doses of 75 mg/m² of each of the two compoundsadministered at 3-week intervals; however, other regimens have also beenexplored, as discussed below.
The Zalcberg et al TrialZalcberg treated a total of 47 chemo-naivepatients with the combination of docetaxel at 75 mg/m² followed by cisplatin at75 mg/m². Premedications included ondansetron (Zofran), dexamethasone,promethazine, and standard hyperhydration with magnesium supplementation. Of the47 patients (72% male) enrolled, two-thirds had metastatic disease and 85% had agood performance status (World Health Organization [WHO] 0 or 1). All 47patients were assessable for toxicity and 37 were evaluable for response, with 3patients ineligible for enrollment and 8 discontinuing treatment due tosignificant toxicity.
Among assessable patients, the overall response rate was 38.9% (95%confidence interval [CI]: 23.1% to 56.5%). An additional 36.1% had stabledisease and 25% had disease progression. Based on an intent-to-treat analysis,the objective response rate was 29.8%, with a median survival of 9.6 months andan estimated 1-year survival of 33%. The most significant toxicities seenincluded grade 3/4 nausea (26%), hypertension (15%), diarrhea (15%), anddyspnea (13%). However, only one patient (1.2%) experienced grade 3 neurosensorytoxicity after completing eight cycles of therapy. Other grade 3/4 toxicitiesincluded hypomagnesemia (24%), febrile neutropenia (13%), and neutropenicinfections (11%), leading to two treatment-related deaths. The authors concludedthat docetaxel/cisplatin is active and feasible as a front-line therapy forNSCLC, with a favorable response rate, an acceptable toxicity profile, and goodmedian and 1-year survivals.
The Le Chevalier et al Trial
Le Chevalier et al evaluated docetaxel, 75 mg/m², plus cisplatin, 100 mg/m², administered every 3 weeks for threecycles and then every 6 weeks in 51 chemotherapy-naive patients with locallyadvanced or metastatic (80%) NSCLC, including 37% with bone involvement. Thepatient population was largely male (92%), with a median age of 54 years, and amedian WHO performance status of 1. Patients received a median of four treatmentcycles (range: 1 to 9), with more than 90% receiving full doses of both drugs asplanned per protocol.
An overall response rate of 33% (95% CI: 19.6%-49.6%), was demonstratedamong the 42 evaluable patients, 14 of whom responded. The median responseduration was 7.3 months, with a median survival of 8.4 months and a 1-yearsurvival of 35%. Neutropenia was the predominant toxicity, occurring inapproximately two-thirds of patients, with febrile neutropenia reported in sevenpatients (14%) and sepsis in one. Nonhematologic toxicities included grade 3vomiting (14%), although neuromotor and neurosensory deficits were infrequent,with grade 3 neuromotor and neurosensory toxicities occurring in onepatient each (2%).
The authors concluded that the results were encouraging, given the poorprognostic factors of the patient population, but questioned whether cisplatinadded to the efficacy of single-agent docetaxel, given its impressive cumulativephase II response rate of 27% in a similar patient population.
The Belani et al Trial
The third multicenter trial was conducted byBelani et al, who tested a combination of docetaxel at 75 mg/m² and cisplatin at75 mg/m² every 3 weeks in 47 patients with stage IIIB or IV NSCLC. Among the40 patients evaluable for response, 1 achieved a complete response and 14achieved a partial response, for an overall response rate of 37.5%(intent-to-treat response rate: 32%). The median duration of response was 34.6weeks. The median duration of survival was 11.3 months, and the median time toprogression was 18.9 weeks. As demonstrated previously, grade 3/4 neutropeniawas predominant, reported in 74.4% of patients and in 55.4% of cycles. Theincidence of febrile neutropenia was 12.8%. Nonhematologic toxicities includedasthenia in 14.9% of patients. Other grade 3/4 toxicities included nausea (20%),vomiting (12.5%), neurosensory effects (15%), neuromotor effects (12.5%),diarrhea (10%), and infection (7.5%). The Belani trial was the third phase IItrial to demonstrate the substantial activity of the docetaxel/cisplatincombination.
The Georgoulias et al Trial
The fourth phase II trial of thedocetaxel/cisplatin combination was conducted by Georgoulias et al, whoperformed a multicenter investigation of the regimen in 53 chemotherapy-naivepatients with stage IIIB/IV NSCLC. Eligible patients received docetaxel at 100 mg/m²on day 1 and cisplatin at 80 mg/m² on day 2 every 21 days. Prophylacticgranulocyte colony-stimulating factor (G-CSF, Neupogen), 150 µg/m², wasadministered on days 3 to 13. An overall response rate of 45% wasdocumented, with 1 complete response and 23 partial responses. The median timeto progression was 36 weeks, and the median survival was 48 weeks. The 1-yearsurvival rate of 48% was notable.
Despite the use of prophylactic G-CSF, grade 3/4 neutropenia developed in 43%of patients and resulted in febrile neutropenia in 28%. There were two septicdeaths reported in this study. Nonhematologic toxicities included grade 3fatigue (13%), grade 3/4 diarrhea (11%), grade 3 neurotoxicity (9%), and grade3/4 mucositis (7.5%). The authors concluded that although thedocetaxel/cisplatin combination was highly active at the doses used in thisstudy, the incidence of hematologic toxicity was high despite the prophylacticuse of G-CSF.
Several other trials of the docetaxel/cisplatin combination have beenreported in abstract form, with overall response rates ranging from 47% to52%.[23-25] As a result of the encouraging response rates, time to progression,and median survival rates consistently demonstrated in phase II studies, thedocetaxel/cisplatin combination has been investigated in large, phase IIIrandomized trials, the results of which will be discussed below.
Docetaxel and Carboplatin
Carboplatin is considered to be a less toxic analog of cisplatin withmarginal but consistent activity in NSCLC. Therefore, carboplatin has beencombined with docetaxel in several studies.[26-31] A phase I, pharmacokineticstudy by Belani recommended doses for further evaluation of the combination ofcarboplatin at an area under the concentration-time curve (AUC) of 6 plusdocetaxel at 90 mg/m² with G-CSF support, or docetaxel at 80 mg/m² without G-CSFsupport. Belani conducted a multi-institutional phase II trial of docetaxelat 80 mg/m² plus carboplatin at an AUC of 6 without G-CSF support.
The Belani et al Trial
A total of 33 patients were enrolled, eight withstage IIIB and 25 with stage IV chemotherapy-naive NSCLC. One complete and11 partial responses were observed, for an objective response rate of 43% (95%CI: 24%-63%) among 28 evaluable patients and a 36% response rate (95% CI: 20%-55%)in the intent-to-treat population. Median duration of response was 5.5 months,median survival was 13.9, and the 1-year survival was 52%. The most commontoxicities were hematologic, with grade 4 neutropenia occurring in 79% ofpatients and febrile neutropenia in 15% of cycles. No episodes of grade 3/4infection were reported. Nonhematologic toxicities included asthenia (24%) andmyalgia (12%); however, no episodes of grade 3/4 neurologic toxicities werereported.
The same regimen of docetaxel at 80 mg/m² and carboplatin at an AUC of 6every 3 weeks was investigated by Harvey et al. The investigators alsoadministered ciprofloxacin (Cipro) at 500 mg/d on days 5 to 15. The studyenrolled 20 previously untreated patients with NSCLC. An overall response rateof 55% was demonstrated, with two complete responses and nine partial responses.At 1 year, 58% of patients were alive. Grade 3/4 toxicities included neutropenia(32%), thrombocytopenia (4%), and anemia (4%).
The Schuette et al Trial
Schuette and colleagues conducted a phase IIinvestigation of the docetaxel/carboplatin combination using a different dosingregimen. A total of 30 chemotherapy-naive patients with stage IIIB/IV NSCLCwere treated with docetaxel at 90 mg/m² over 1 hour followed by carboplatinat an AUC of 5 mg/mL/min (Calvert’s formula) every 3 weeks for a total of sixcycles. An objective response rate of 30% was achieved, with two completeresponses and seven partial responses. An additional 47% of patientsdemonstrated stable disease. The median time to progression was 24 weeks, andmedian survival, 57 weeks. An impressive 1-year survival rate of 56% wasreported. Myelosuppresssion was the predominant toxicity, with grade 3/4granulocytopenia reported in 35% of cycles and 77% of patients; however,neutropenic fever did not occur. With the exception of nail disorders(grade 3/4 in 27%), the other nonhematologic toxicities were grade 1/2 inseverity.
The Jahanzeb et al Trial
Jahanzeb and colleagues chose to investigate aconservative dosing regimen of docetaxel and carboplatin in 25 previouslyuntreated stage IIIB/IV NSCLC patients. Patients received docetaxel at 60 mg/m²and carboplatin at an AUC of 6 once every 3 weeks. An overall responserate of 35% was reported for the 20 evaluable patients, with one complete andsix partial responses. An additional eight patients (40%) demonstrated stabledisease. On an intent-to-treat basis, median survival was 45 weeks. Grade 3/4neutropenia was reported in 69% of cycles. Nonhematologic toxicities includedgrade 3 fatigue, nausea, anorexia, and weakness in one patient each.
The Arcenas et al Trial
Arcenas et al conducted a single-institutionstudy of docetaxel, 65 mg/m², and carboplatin at an AUC of 6 every 3 weeksin 20 male patients with previously untreated NSCLC. An overall responserate of 45% was demonstrated, with nine patients achieving a partial response,and five additional patients demonstrating stable disease. Median survival was12 months. Grade 4 neutropenia was reported in 50% of patients, andneutropenic fever occurred in 15%. Of nonhematologic toxicities, grade 1diarrhea occurred in seven patients (35%).
Phase III Randomized Trials
Based on the cumulative phase I and II data on the platinum agents incombination with docetaxel, two large phase III comparative trials have now beencompleted.
The ECOG 1594 Trial
Schiller reported the results of the EasternCooperative Oncology Group (ECOG) 1594 trial, one of the largest comparativetrials in metastatic lung cancer, which randomized 1,207 patients to one of fourplatinum-based doublet regimens: paclitaxel, 135 mg/m² by 24-hour infusion,followed by cisplatin, 75 mg/m² (arm A); gemcitabine (Gemzar), 1,000 mg/m² ondays 1, 8, and 15, followed by cisplatin, 100 mg/m² by 3-hour infusion onday 1 (arm B); docetaxel, 75 mg/m² by 1-hour infusion followed bycisplatin, 75 mg/m² by 1-hour infusion (arm C); and paclitaxel, 225 mg/m² by3-hour infusion, followed by carboplatin at an AUC of 6 (arm D).
Eligible patients were required to have measurable or evaluable disease andstage IIIB or IV NSCLC. The original eligibility requirement of a performancestatus (PS) of 0-2 was later amended to patients with a PS 0/1 because of thepoor outcome among patients with a PS of 2. The groups were well matched forknown prognostic factors, and the number of ineligible patients was similaracross all four arms. Compared to arm A (control), none of the other three armsshowed statistical superiority or inferiority in terms of response (19%), mediansurvival (7.9 months; 95% CI: 7.3-8.5 months), and 1-year survival rate (33%,95% CI: 30%-36%). Interestingly, toxicity varied by arm, with thegemcitabine arm (the only arm to contain 100 mg/m² of cisplatin), having thehighest degree of grade 3/4 nausea, vomiting, and renal failure.
The Taxotere 326 Study Group Trial
The second, and largest, randomizedphase III trial was presented by Fossella on behalf of the Taxotere 326 StudyGroup. The study randomized 1,218 patients with advanced or recurrent NSCLCpatients to one of three arms: (1) docetaxel, 75 mg/m², plus cisplatin, 75 mg/m², on day 1 every 3 weeks (arm A); (2) docetaxel, 75mg/m², followed bycarboplatin at an AUC of 6 on day 1, every 3 weeks (arm B); and (3)cisplatin, 100 mg/m² on day 1, with vinorelbine (Navelbine), 25 mg/m²on days 1, 8, 15, and 22, repeated every 4 weeks (arm C). Each docetaxelarm was independently compared with the control arm of vinorelbine/cisplatin (Figure1).
Results demonstrated an overall survival advantage for thedocetaxel/cisplatin combination (arm A), compared with cisplatin/vinorelbine(arm C) (Table 1). The 2-year overall survival was 21% for thedocetaxel/cisplatin arm compared to 14% for the cisplatin/vinorelbine arm (P =.044). Intent-to-treat response rates were also superior in thedocetaxel/cisplatin arm compared to cisplatin/vinorelbine at 32% vs 25%, astatistically significant result (P = .029). A trend toward improved 2-yearsurvival was noted for the docetaxel/carboplatin arm (arm B) compared to thecisplatin/vinorelbine arm (arm C) at 18% vs 14%, respectively; however, thefindings did not reach statistical significance. Overall survival and responserates achieved with docetaxel/carboplatin were similar to those reported forcisplatin/vinorelbine.
A comparison of the major toxicities showed a statistically higher incidenceof some grade 3/4 toxicities in the cisplatin/vinorelbine arm, compared to thedocetaxel-containing arms. Although grade 3/4 hematologic toxicities includingneutropenia, febrile neutropenia, and infection occurred in a similar proportionof patients in all three arms, a higher incidence of grade 3/4 anemia wasreported for patients treated with cisplatin/vinorelbine vs the docetaxeltreatment arms. A higher incidence of grade 3/4 nausea and vomiting was alsoreported for the cisplatin/vinorelbine arm compared to both of thedocetaxel-containing arms.
Evaluation of quality-of-life (QOL) measures including global QOL, globalhealth status, pain, weight loss of 10% or more, and Karnofsky performance status wererecorded throughout the study and compared to baseline. Findings revealedsignificant benefits for the docetaxel/carboplatin arm over thecisplatin/vinorelbine arm.
Building on the earlier phase II studies, these two large phase III studiessuggest that the combination of docetaxel and cisplatin is among the most activecombinations as front-line therapy for NSCLC. The docetaxel/carboplatincombination also yields acceptable toxicities with equivalent response andoverall survival rates, and a quality-of-life advantage over thevinorelbine/cisplatin combination.
Combination Docetaxel and Gemcitabine
Gemcitabine is a deoxycytadine antimetabolite, closely related to cytarabine,that is capable of inhibiting DNA synthesis through inhibition of DNApolymerase. Myelosuppression is the dose-limiting toxicity of gemcitabine,with nonhematologic toxicities including nausea and vomiting, elevated hepaticenzymes, and a less common flu-like syndrome. Gemcitabine has been paired withdocetaxel as the most frequently tested nonplatinum-based combination inNSCLC. Numerous studies evaluating this combination in varying schedules and forvarious tumor types have been reported.[35-46] The opportunity for a non-platinum-containingregimen has spurred great interest in this combination in both the first- andsecond-line NSCLC settings. A summary of several of the studies, with a focus onthose conducted for first-line therapy of NSCLC is reviewed below.
The Sarah Cannon Cancer Center Trial
The docetaxel/gemcitabinecombination has been evaluated in weekly, biweekly, and alternating-weekschedules in cycles lasting 3, 4, and 8 weeks. Investigators from the SarahCannon Cancer Center tested weekly combinations of gemcitabine and docetaxel inchemotherapy-naive elderly or poor performance status patients. Treatmentconsisted of docetaxel, 30 mg/m², and gemcitabine, 800 mg/m², withboth agents administered weekly on days 1, 8, and 15 and repeated every 4 weeks.
The results demonstrate an overall response rate of 27% (14 partialresponses, 2 complete responses) and stable disease or a minor response in 46%.The median survival reported to date is 7.5 months. Therapy was well tolerated,with grade 3/4 toxicities including leukopenia and thrombocytopenia (11% each),asthenia (14%), nausea and vomiting (9%), myalgia (5%), and neuropathy (2%). Arandomized comparison of a weekly schedule of the docetaxel/gemcitabinecombination vs weekly docetaxel in this patient population is planned by thesame investigators.
The Neubauer et al Trial
Neubauer and colleagues evaluated a weeklyregimen of docetaxel, 36 mg/m², administered on days 1, 8, 15, and 22, andgemcitabine, 900 mg/m², on days 1, 8, 22, and 29 of an 8-week cycle.Treatment consisted of three 8-week cycles. Of 41 evaluable patients, 24%achieved a partial response, with an estimated 1-year survival of 30%. Grade 3/4toxicities included neutropenia (18%), leukopenia (19%), nausea (6%),thrombocytopenia (4%), and febrile neutropenia (4%).
Phase I Trials
Phase I trials utilizing the 3-weekly schedule includestudies by Jensen and Bhargava. In 23 mostly chemotherapy-naivepatients, the maximum tolerated dose of docetaxel was 80 mg/m² on day 1 andof gemcitabine, 800 mg/m² on days 1 and 8 every 3 weeks. Bhargavaadministered docetaxel at 30 to 40 mg/m²/wk and gemcitabine at 800 to1,250 mg/m²/wk in a phase I trial in 34 patients. The maximum tolerateddose was 40 mg/m² docetaxel with 1,000 mg/m² gemcitabine, eachadministered on days 1 and 8 every 3 weeks in chemotherapy-naive patients. Ofeight evaluable NSCLC patients, two (25%) achieved a partial response.
Trial Exploring 2-Week Permutation
Two-week permutations of thedocetaxel/gemcitabine combination have been explored in three trials.[42-44]This approach attempts to minimize myelosuppression by taking into considerationthe brief duration of leukopenia seen on day 7 following infusion of docetaxel,and allows for maximal escalation of the gemcitabine dose. Eckardt reached themaximum tolerated dose of docetaxel at 75 mg/m² and gemcitabine at 3,000 mg/m²with each agent administered on day 1 and day 15 of a 3-week cycle. Althoughhematologic toxicity was mild, significant asthenia was seen in 11 of 16patients at the time of this report, with 6 having at least grade 3toxicity.
Rigas et al treated 41 patients in a phase I study of docetaxel, 35 to 65mg/m², and gemcitabine, 2,000 to 4,000 mg/m², with both agents administered ondays 1 and 15 of an every-3-week cycle. Dose-limiting febrile neutropenia andfatigue were seen with docetaxel at 65 mg/m² and gemcitabine at 4,000 mg/m² inpreviously treated patients. As a result, these doses were recommended forfurther investigation in chemotherapy-naive patients.
Denes et al compared two every-other-week dose schedules of gemcitabineand docetaxel in order to build on preclinical and in vitro work. In the firstschedule, docetaxel was given immediately before gemcitabine, and in the secondschedule, a 24-hour interval separated their administration. The recommendedphase II doses for patients were docetaxel, 100 mg/m², plus gemcitabine, 3,000 mg/m², without an interval on day 1, every 2 weeks. The recommended doses forthe schedule containing a 24-hour interval were docetaxel, 75 mg/m² on day 1,followed by gemcitabine, 1,000 mg/m² on day 2.
Georgoulias et al treated 51 chemotherapy-naive patients with docetaxel, 100 mg/m²on day 8 and gemcitabine at 900 mg/m² on days 1 and 8, with G-CSF (150 mg/m² subcutaneously) daily from days 9 to 15. Treatment was repeated every3 weeks. A partial response was seen in 19 patients, for an overall responserate of 37.5% (95% CI: 24%-50%); stable disease and progressive disease wereobserved in 16 patients each (31.4%). Median response duration was 5 months andmedian time to tumor progression was 6 months. Median survival in this study wasan encouraging 13 months, with the actuarial 1-year survival at 50.7%.
Grade 3/4 neutropenia developed in four patients (8%), and all werecomplicated with fever, but there were no treatment-related deaths.Nonhematologic toxicities included grade 3/4 diarrhea (6%), grade 2/3neurotoxicity (8%), grade 2/3 asthenia (20%), and grade 2/3 edema (20%).
The Georgoulias et al Trial
Based on these encouraging phase II data,Georgoulias et al went on to conduct a large, randomized phase IIb trial ofdocetaxel and gemcitabine vs docetaxel and cisplatin (Figure2). A total of441 patients with stage IIIB or IV NSCLC were randomized to receivedocetaxel, 100 mg/m² on day 1, and cisplatin, 80 mg/m² on day 2, orgemcitabine, 1,100 mg/m² on days 1 and 8, and docetaxel, 100 mg/m² on day8. All patients received G-CSF (150 µg/m²). The objective response rates weresimilar in the two groups, with an overall response rate of 35% (95% CI:28%-41%) for docetaxel/cisplatin and a response rate of 33% (95% CI: 27%-40%)for docetaxel/gemcitabine (Table 2). No difference in median, actuarial, 1- or2-year survivals between the two arms was demonstrated, with 1-year survival at42% vs 39% for docetaxel/cisplatin and docetaxel/gemcitabine (P = .807),respectively, and 2-year survival at 8% for both arms (P = .941).Median survival was also similar between the two arms, at 10 months fordocetaxel/cisplatin and 9.5 months for docetaxel/gemcitabine (P = .980).
A significant difference in grade 3/4 toxicities was reported, with ahigher incidence of neutropenia (P = .01), nausea/vomiting (P = .001), anddiarrhea (P = .001) for the docetaxel/cisplatin arm (Table3). The toxicityprofile for the noncisplatin docetaxel/gemcitabine regimen thus appears to besuperior. Interestingly, the incidence of febrile neutropenia was not differentbetween the two arms with 29 patients (14%) in the docetaxel/cisplatin arm and23 patients (11%) in the docetaxel/gemcitabine arm developing febrileneutropenia.
This large, phase IIb study demonstrated that the median response rate,overall survival, and 1- and 2-year survival for the non-platinum-containingdocetaxel/gemcitabine arm were equivalent to the cisplatin/docetaxel arm. Thesuperior toxicity profile suggests that the non-platinum-baseddocetaxel/gemcitabine regimen may be among the most desirable combinations forthe treatment of NSCLC, and deserves further investigation.
Combination Docetaxel and Vinorelbine
Perhaps no docetaxel-containing regimen has been more controversial than thecombination with vinorelbine. Extensive preclinical evidence suggests additiveand/or synergistic interactions between docetaxel and vinorelbine in a varietyof common solid tumors. In the treatment of NSCLC, several trials havedemonstrated the safety and efficacy of the combination, whereas other trialshave resulted in excessive toxicity.
The Miller et al Trial
Miller et al treated 27 patients with NSCLC on anevery-2-week schedule of vinorelbine given as an intravenous push followedimmediately by a 1-hour intravenous infusion of docetaxel. Vinorelbine wasdose-escalated from 15 mg/m² to 45 mg/m² and docetaxel from 50 mg/m² to 60 mg/m²with both drugs administered every 2 weeks. In total, 209 treatmentcycles were administered with concomitant prophylactic corticosteroids andG-CSF. Only four cycles were associated with febrile neutropenia (1.9% out ofthe 209 cycles), with documented bacteremia occurring in three patients (fourepisodes in the absence of neutropenia). Symptomatic onycholysis was observed inthree patients, but clinically significant peripheral neuropathy and fluidretention were rare. Confirmed partial responses were noted in 10 evaluablepatients for a response rate of 37% (95% CI: 20%-57%).
Miller et al conducted a follow-up phase II trial of docetaxel andvinorelbine in 35 chemotherapy-naive patients. In this trial, vinorelbine at45 mg/m² was followed immediately by docetaxel at 60 mg/m² , with both drugsadministered every 2 weeks in conjunction with prophylatic corticosteroids,G-CSF, and ciprofloxacin. A median dose of vinorelbine at 450 mg/m² anddocetaxel at 600 mg/m² was delivered. The major objective response rate was 51%(95% CI: 34%-68%). Median cumulative follow-up in this trial was 14 months,with a predicted median survival time of 14 months, 1-year survival rate of 60%,and projected 2-year survival rate of approximately 30%. Grade 3/4toxicity included febrile neutropenia in 14% of patients and in 1.3% oftreatment courses. No dose-limiting neurotoxicity occurred; rather, the majortoxicities included symptomatic onycholysis and excessive lacrimation afterseveral months of therapy.
The high activity with the appearance of progressive late toxicities seenwith chronic therapy led the authors to propose that this regimen be reservedfor settings requiring briefer, fixed periods of treatment, such as induction orpostoperative treatment for a limited number of cycles.
The Kourousis et al Trial
Kourousis et al also tested docetaxel andvinorelbine in 46 chemotherapy-naive patients. They evaluated vinorelbine at 25 mg/m²on day 1 and docetaxel at 100 mg/m² on day 2 with cycles repeated every 3weeks. G-CSF was given to all patients on days 3 to 10. A total of 177 coursesof chemotherapy were administered. Responses included 4 complete responses(9.8%) and 11 partial responses (26.8%) among the 41 evaluable patients, for anoverall response rate of 36.6%. Stable and progressive disease occurred in 13patients each (31.7%). The median overall survival in this study was 5 months,and the 1-year survival was 24%. Median duration of response was 5 months, andmedian time to progression was 3 months.
Adverse events included grade 4 neutropenia in 15 patients, grade 3/4thrombocytopenia in 3 patients, grade 3 anemia in 2 patients, and grade 2and 3 neurotoxicity in 7 patients and 1 patient, respectively. In addition, twopatients complained of grade 3 asthenia. A total of 20 patients (43%) requiredhospitalization11 (24%) due to neutropenic fever (24%) and 9 (20%) due tononneutropenic pulmonary infections, with 2 deaths resulting from sepsis and 2deaths from cardiopulmonary insufficiency. The investigators concluded thatdespite the activity of this combination, the high incidence of complicatedneutropenia precludes its general use in patients with advanced NSCLC.
The Bennouna et al Trial
Bennouna et al conducted a phase II studyevaluating docetaxel, 75 mg/m² administered for 1-hour on day 1 followed byvinorelbine, 20 mg/m² administered over 15 to 30 minutes on days 1 and 5, withcycles repeated every 3 weeks. Of the 39 patients evaluated, 9 had a partialresponse, for an overall response rate of 23.1% (95% CI: 11.1%-39.3%) with amedian response duration of 20 weeks (95% CI: 17-30 weeks). Median survival inthis study was an encouraging 40 weeks, with a 1-year survival rate of 31% inthe intent-to-treat population. Grade 4 neutropenia occurred in 33 patients(92%), with 16 patients (41%) experiencing febrile neutropenia and 9 (23%)experiencing confluent stomatitis. Of the two deaths that occurred, one patientwas due to febrile neutropenia and the other due to septicemia.
Despite the fact that this combination was active, substantial toxicity wasseen. Notably, prophylactic G-CSF and/or antibiotics were not administered inthis study. The authors concluded that a new therapeutic schedule of thecombination should be identified for further investigation.
The University of Texas M. D. Anderson Cancer Center Trial
In a preliminary report from theUniversity of Texas M. D. Anderson Cancer Center, 84 patients with stageIIIB/IV NSCLC were treated with docetaxel and vinorelbine as first- orsecond-line therapy in a phase II trial. Doses used were vinorelbine at 25 mg/m²on days 1 and 8, and docetaxel at 75 mg/m² (previously untreated) or60 mg/m² (previously treated) on day 8 every 21 days. All patientsreceived prophylactic G-CSF, 5 µg/kg on days 2 to 6 and days 10 to 14 of everycycle.
At the time of this report, 7 of 37 (19%) chemotherapy-naive patients hadachieved a partial response, and an additional 15 patients (40%) had stabledisease. With a median follow-up of 33 weeks, the estimated 1-year survival was47%. Of 14 evaluable, previously treated patients, 1 (7%) achieved a partialresponse and 9 (64%) had stable disease. The estimated 1-year survival forpreviously treated patients is 10%. Grade 3/4 neutropenia and fever was seen in14% and 8% of chemotherapy-naive patients, and in 24% and 21% of previouslytreated patients, respectively.
In summary, the docetaxel and vinorelbine regimen is highly active, but acute(hematologic) and chronic (onycholysis and lacrimation) toxicities discourageroutine use of the combination as long-term therapy for NSCLC patients with poorperformance status. As previously stated, Miller et al have recommended that thedose-dense, 2-weekly combination of vinorelbine at 45 mg/m² followed bydocetaxel at 60 mg/m², or possibly a weekly regimen of the combination beconsidered for further investigation as a short-term regimen for induction orpostoperative chemotherapy.
Combination Docetaxel and Irinotecan
To date, a limited number of trials have tested the docetaxel and irinotecan(CPT-11, Camptosar) combination. At least one of these trials is noteworthy.Masuda et al conducted a phase I trial in 32 patients with stage IIIB/IVNSCLC who were treated at 4-week intervals with docetaxel and irinotecan.Docetaxel at 30 to 60 mg/m² was given on day 2 and irinotecan at 40 to 60 mg/m²was given on days 1, 8, and 15. The maximum tolerated doses ofdocetaxel/irinotecan were 50 mg/m², respectively, and 60 mg/m². Neutropeniaand diarrhea were the dose-limiting toxicities.
Among the 39 evaluable patients, 11 partial responses (37%) were seen. Anencouraging median survival time of 48 weeks and a 1-year survival of 44.9% werealso reported. The authors recommended docetaxel doses of 50 mg/m² on day 2, andirinotecan doses of 50 mg/m² on days 1,8, and 15 of an every 4-week cycle forfuture phase II investigation in patients with advanced NSCLC.
Clearly, single-agent docetaxel has demonstrated extensive activity in thetherapy of stage IIIB/IV NSCLC. In combination with cisplatin, carboplatin, orgemcitabine, this agent has shown extensive front-line activity with acceptabletoxicities in several randomized phase IIb and III trials. The largestrandomized trial in NSCLC that compared docetaxel/cisplatin anddocetaxel/carboplatin to the vinorelbine-cisplatin combination demonstrated asuperior 2-year survival rate favoring the docetaxel/cisplatin combination overthe FDA-approved combination of vinorelbine/cisplatin. Docetaxel/carboplatin wasactive and well tolerated, and demonstrated improved quality of life in thisstudy.
A large, randomized phase II study by Georgoulias demonstrated that thedocetaxel/gemcitabine combination was equally efficacious todocetaxel/cisplatin, with markedly less peripheral neuropathy, renal failure,nausea, vomiting, and neutropenia. Although docetaxel/vinorelbine is anextremely active regimen, the incidence of febrile neutropenia seen by all butone group of investigators casts doubt as to whether the combination can befurther developed for chronic therapy of stage IIIB/IV NSCLC. Additionalinvestigations of biweekly and weekly regimens in the neoadjuvant andpostoperative settings may determine a better schedule for thedocetaxel/vinorelbine combination in the therapy of NSCLC.
An area warranting further exploration of docetaxel is in combination withnovel targeted therapies, such as tyrosine kinase inhibitors and farnesyltransferase inhibitors. These agents have shown a low but definite response ratein NSCLC, and may well synergize with docetaxel given their common signaling andapoptotic pathways, in which both classes of agents are active. Severaltrials are currently evaluating combinations of docetaxel with either monoclonalantibodies to the epidermal growth factor receptor, or a farnesyl transferaseinhibitor, or a tyrosine kinase inhibitor. Combining these novel signaltransduction inhibitors with docetaxel, one of the most active agents inadvanced NSCLC, may lead to more durable responses in advanced-stage disease.
1. Jemal, A, Thomas A, Murray T, et al: Cancer statistics, 2002. CA Cancer JClin 52:23-47, 2002.
2. Minna J, Sekido Y, Fong K, et al: Cancer of the lung, in DeVita VT,Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology, 5thed, pp 849-911. Philadelphia, Lippincott, 1997.
3. Schottenfield D: Etiology and epidemiology of lung cancer, in Pass HI,Mitchell JB, Johnson DH, et al (eds): Lung Cancer Principles and Practice, 2nded, pp 367-388. Philadelphia, Lippincott Williams & Wilkins, 2000.
4. Rapp E, Pater JL, Willan A, et al: Chemotherapy can prolong survival inpatients with advanced non-small-cell lung cancerreport of a Canadianmulticenter randomized trial. J Clin Oncol 6:633-641, 1988.
5. Ganz PA, Figlin RA, Haskell CM, et al: Supportive care vs supportive careand combination chemotherapy in metastatic non-small-cell lung cancer. Doeschemotherapy make a difference? Cancer 63:1271-1278, 1989.
6. Cartei G, Cartei F, Cantone A, et al: Cisplatin-cyclophosphamide-mitomycincombination chemotherapy with supportive care vs supportive care alone fortreatment of metastatic non-small-cell lung cancer. J Natl Cancer Inst85:794-800, 1993.
7. Johnson DH: Treatment strategies for metastatic non-small-cell lungcancer. Clin Lung Cancer 1:34-41, 1999.
8. Shepherd F, Ramlau R, Mattson K, et al: Prospective randomized trial ofdocetaxel vs best supportive care in patients with non-small-cell lung cancerpreviously treated with platinum-based chemotherapy. J Clin Oncol18(10):2095-2103, 2000.
9. Fossella FV, DeVore R, Kerr R, et al: Randomized phase III trial ofdocetaxel vs vinorelbine or ifosfamide in patients with advanced non-small-celllung cancer previously treated platinum-based chemotherapy. J Clin Oncol18(12):2354-2362, 2000.
10. Gaspar L, Gandara D, Chansky K, et al: Consolidation docetaxel followingconcurrent chemoradiotherapy in pathologic stage IIIb non-small-cell lung cancer(NSCLC) (SWOG 9504): Patterns of failure and updated survival (abstract 1255).Proc Am Soc Clin Oncol 20:315a, 2001.
11. Rigas JR: Single-agent docetaxel in previously untreated non-small-celllung cancer. Oncology 11(suppl 7):17-21, 1997.
12. Miller VA, Rigas JR, Kris MG, et al: Phase II trial of a 75 mg/m² dose ofdocetaxel with prednisone premedication for patients with advancednon-small-cell lung cancer. Cancer 75:968-972, 1995.
13. Kunitoh H, Watanade K, Onoshi T, et al: Phase II trial of docetaxel inpreviously untreated advanced non-small-cell lung cancer: A Japanese cooperativestudy. J Clin Oncol 14:1649-1655, 1996.
14. Roszkowski K, Pluzanska A, Krzakowski M, et al: A multicenter,randomized, phase III study of docetaxel plus best supportive care vs bestsupportive care in chemotherapy-naïve patients with metastatic ornon-resectable localized non-small-cell lung cancer (NSCLC). Lung Cancer37(3):145-157, 2000.
15. Hainsworth JD, Burris HA, Litchy S, et al: Weekly docetaxel in thetreatment of elderly patients with advanced non-small-cell lung carcinoma. AMinnie Pearl Cancer Research Network phase II trial. Cancer 89(2):328-333, 2000.
16. Cole JT, Gralla RJ, Marques CB, et al: Phase I/II study of cisplatin anddocetaxel in non-small-cell lung cancer (abstract 1087). Proc Am Soc Clin Oncol14:357a, 1995.
17. Pronk LC, Schellens JHM, Planting AST, et al: Phase I and pharmacologicstudy of docetaxel and cisplatin in patients with advanced tumors. J Clin Oncol15:1071-1079, 1997.
18. Millward MH, Yalcberg J, Bishop JF, et al: Phase I trial of docetaxel andcisplatin in previously untreated patients with advanced non-small-cell lungcancer. J Clin Oncol 15:750-758, 1997.
19. Zalcberg J, Millward M, et al: Phase II study of docetaxel and cisplatinin advanced non-small-cell lung cancer. J Clin Oncol 16:1948-1953, 1998.
20. Le Chevalier T., Monnier A, Douillard JY, et al: Docetaxel (Taxotere)plus cisplatin: An active and well-tolerated combination in patients withadvanced non-small-cell lung cancer. Eur J Cancer 34:2032-2036, 1998.
21. Belani CP, Bonomi P, Dobbs TW, et al: Docetaxel and cisplatin in patientswith advanced non-small-cell lung cancer (NSCLC): A multicenter phase II trial.Clin Lung Cancer 1(2):144-150, 1999.
22. Georgoulias V, Androulakis N, Dimopoulos AM, et al: First-line treatmentof advanced non-small-cell lung cancer with docetaxel and cisplatin: Amulticenter phase II study. Ann Oncol 9:331-334, 1998.
23. Faderl B, von Pawel J, Wagner H, et al: Phase II study of docetaxel andcisplatin in a circadian timing as first-line chemotherapy in advancednon-small-cell lung cancer (abstract 1017). Eur J Cancer 35:256, 1999.
24. Cole JT, Gralla RJ, Rittenberg CN, et al: Defining the dose of docetaxel(Taxotere) in combination chemotherapy in non-small-cell lung cancer: Preservingefficacy with lower dose regimens (abstract 1671). Proc Am Soc Clin Oncol16:465a, 1997.
25. Androulakis N, Dimopoulos AM, Kourousis C, et al. First-line treatment ofadvanced non-small cell lung cancer (NSCLC) with docetaxel and cisplatin: Amulticenter pahse II study (abstract 1655). Proc Am Soc Clin Oncol 16:461a,1997.
26. Belani CP, Hadeed V, Ramanathan R, et al: Docetaxel and carboplatin: Aphase I and pharmacokinetic trial for advanced non-hematologic malignancies(abstract 771). Proc Am Soc Clin Oncol 16:220a, 1997.
27. Belani C, Einzig A, et al: Multicenter phase II trial of docetaxel andcarboplatin in patients with stage IIIB and IV non-small-cell lung cancer. AnnOncol 11:673-678, 2000.
28. Harvey J, Windsor K, Lasker J: A phase II study of docetaxel andcarboplain in patients with advanced non-small-cell lung cancer (NSCLC)(abstract 2000). Proc Am Soc Clin Oncol 19:511a, 2000.
29. Schuette W, Bork I, Wollschlager B, et al: Combination chemotherapy withdocetaxel and carboplatin for advanced non-small-lung cancer. Clin Drug Invest21:161-168, 2001.
30. Jahanzeb M, Sarna G, Hirsch R, et al: A multicenter phase II trial ofcarboplatin and docetaxel in previously untreated advanced non-small-cell lungcarcinoma (NSCLC) (abstract 2011). Proc Am Soc Clin Oncol 19:514a, 2000.
31. Arcenas A, Karkera D, Krasnow S: A phase II trial of carboplatin anddocetaxel for stage IIIb/IV non-small-cell lung cancer (abstract 2848). Proc AmSoc Clin Oncol 20: 2001.
32. Schiller JH, Harrington D, Belani C, et al: Comparison of fourchemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med346:92-98, 2002.
33. Fossella F: Multicenter, randomized phase III study of taxotere +cisplatin or taxotere + carboplatin vs vinorelbine plus cisplatin as first-linetherapy for advanced non-small-cell lung cancer (abstract 562). Eur J Cancer37(suppl 6):S154, 2001.
34. Budman D, Lichtman S: Investigational drugs, in: Perry MC (ed): TheChemotherapy Source Book, pp 479-555. Baltimore, Williams & Wilkins, 1997.
35. Spiridonidis CH, Laufman LR, Jones J, et al: Phase I study of docetaxeldose escalation in combination with fixed weekly gemcitabine in patients withadvanced malignancies. J Clin Oncol 16:3866-3873, 1998.
36. Pawinski A, Louwerens M, Tonelli D, et al: A phase I study of docetaxeland gemcitabine combination in chemotherapy-naïve patients with advanced ormetastatic non-small-cell lung cancer (abstract 957). Proc Am Soc Clin Oncol17:449a, 1998.
37. Spiridonidis CH, Laufman L, Jones J, et al: Phase I study of docetaxeldose-escalation in combination with fixed weekly gemcitabine in patients withadvanced malignancies. J Clin Oncol 16:3866-3873, 1998.
38. McKay CE, Hainsworth JD, Burris HA, et al: Weekly docetaxel/gemcitabinein the treatment of elderly patients (pts) with advanced non-small-cell lungcancer (NSCLC): A Minnie Pearl Cancer Research Network phase II trial (abstract2793). Proc Am Soc Clin Oncol 20:260b, 2001.
39. Neubauer M, Garfield D, Khan M, et al: Phase II trial of weekly docetaxel(Taxotere) plus gemcitabine (Gemzar) as first-line therapy for patients withadvanced non-small-cell lung cancer (abstract 2760). Proc Am Soc Clin Oncol20:252b, 2001.
40. Jensen NV, Hansen O, rose C, et al: Combination of docetaxel andgemcitabine in the treatment of advanced non-small-cell lung cancer (NSCLC)(abstract 1026). Proc Eur Cancer Conf 10:S258, 1999.
41. Bhargava P, Marshall JL, Fried K, et al: Phase I and pharmacokineticstudy of two sequences of gemcitabine and docetaxel administered weekly topatients with advanced cancer. Cancer Chemother Pharmacol 48:95-103, 2001.
42. Eckardt JR, Schmidt AM, Needles BM, et al: A phase I study of thecombination of docetaxel (D) and gemcitabine (G) (abstract 920). Proc Am SocClin Oncol 17:240a, 1998.
43. Rigas JR, Rothenberg ML, Davis TH, et al: Phase I clinical andpharmacokinetic study of docetaxel with two gemcitabine infusion schedules(abstract 870). Proc Am Soc Clin Oncol 18:226a, 1999.
44. Denes AE, Needles BM, Schmidr A, et al: A comparison of two schedules ofdocetaxel in combination with gemcitabine given every other week (abstract 828).Proc Am Soc Clin Oncol 19:212a, 2000.
45. Georgoulias V, Kouroussis C, et al: Front-line treatment of advancednon-small-cell lung cancer with docetaxel and gemcitabine: A multicenter phaseII trial. J Clin Oncol 17:914-920, 1999.
46. Georgoulias V, Papadakis E, Alexopoulos A, et al: Platinum-based andnon-platinum-based chemotherapy in advanced non-small-cell lung cancer: Arandomised multicentre trial. Lancet 357:1478-84, 2001.
47. Miller V, Ng K, et al: Phase I trial of docetaxel and vinorelbine inpatients with advanced non-small-cell lung carcinoma. Cancer 88:1045-1050, 2000.
48. Miller V, Krug L, et al: Phase II trial of docetaxel and vinorelbine inpatients with advanced non-small-cell lung cancer. J Clin Oncol 18:1346-1350,2000.
49. Kourousis C, Androulakis N, Kakolyris S, et al: First-line treatment ofadvanced non-small-cell lung carcinoma with docetaxel and vinorelbine. Cancer83:2083-2090, 1998.
50. Bennouna J, Monnier A, Riviere A, et al: A phase II study of docetaxeland vinorelbine combination chemotherapy in patients with advancednon-small-cell lung cancer. Eur J Cancer 36(9):1107-1112, 2000.
51. Papadimitrakopoulou V, Lozada JA, Henderson T, et al: A phase II study ofvinorelbine and docetaxel in the treatment of advanced non-small-cell lungcancer as front-line and second-line therapy (abstract 2789). Proc Am Soc ClinOncol 20:259b, 2001.
52. Masuda N, Shunichi N, Kudoh S, et al: Phase I and pharmacologic study ofdocetaxel and irinotecan in advanced non-small-cell lung cancer. J Clin Oncol18:2996-3003, 2000.
53. Khuri FR, Herbst RS, Fossella FV: Emerging therapies in non-small-celllung cancer. Ann Oncol 12(6):739-744, 2001.