Oncologist. The. Taxane-Platinum Combinations in Advanced Non-Small Cell Lung Cancer: A Review JAMES R. RIGAS LEARNING OBJECTIVES ABSTRACT

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1 The Oncologist Taxane-Platinum Combinations in Advanced Non-Small Cell Lung Cancer: A Review JAMES R. RIGAS Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, New Hampshire, USA Key Words. Chemotherapy Docetaxel Paclitaxel Doublets Non-small cell lung cancer LEARNING OBJECTIVES After completing this course, the reader will be able to: 1. Describe the rationale for and use of taxanes in NSCLC. 2. Identify key efficacy findings from the four large randomized trials assessing platinum-taxane combinations in advanced NSCLC. 3. Discuss adverse event and quality-of-life results from four large randomized trials assessing platinum-taxane combinations in advanced NSCLC. CME Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com ABSTRACT Platinum-based chemotherapy is the treatment of choice for patients with non-small cell lung cancer (NSCLC). As a result of their single-agent activities and synergistic effects, taxane-platinum combinations are often used as first-line therapy for this disease. Four large, multicenter, randomized phase III clinical trials (the TAX 326 trial, the Southwest Oncology Group 959 trial, the Italian Lung Cancer Project, and the Eastern Cooperative Oncology Group 1594 trial) have compared taxane-platinum combinations (docetaxel and paclitaxel) with other platinum combinations (vinorelbine and gemcitabine) in chemotherapy-naïve patients with good performance status scores and advanced disease. The end points for these large randomized clinical trials were survival, response rate, adverse events, and quality of life (QOL). Of the taxane-platinum combinations tested, docetaxel-cisplatin was the only platinum combination to yield survival and response rates superior to another platinum combination. In adverse event terms, the taxane-platinum combination of paclitaxel-carboplatin demonstrated less grade 3 or 4 neutropenia and lower rates of febrile neutropenia than other taxane-platinum combinations but higher rates of irreversible grade 3 or 4 peripheral neuropathy than any of the other taxane-platinum combinations. Additional differences emerged when QOL data were evaluated. The docetaxel-platinum combination demonstrated broad QOL benefits for patients receiving this combination, and this benefit was not observed with the other platinum or taxane-platinum combinations. As our use of these taxane-platinum combinations expands, these differences in survival, response rate, adverse events, and QOL will permit us to better balance our treatment goals for all patients with all stages of NSCLC. The Oncologist 24;9(suppl 2):16-22 INTRODUCTION Although surgery may be curative in early-stage disease, in excess of 7% of patients with non-small cell lung cancer (NSCLC) have advanced disease at diagnosis and are not surgical candidates [1]. Patients with advanced disease managed with best supportive care (BSC) alone have a Correspondence: James R. Rigas, M.D., Comprehensive Thoracic Oncology Program, Norris Cotton Cancer Center, Dartmouth Medical School, One Medical Center Drive, Lebanon, New Hampshire 3756, USA. Telephone: ; Fax: ; james.r.rigas@dartmouth.edu Received March 9, 24; accepted for publication March 22, 24. AlphaMed Press /24/$12./ The Oncologist 24;9(suppl 2):

2 Rigas 17 median survival time of only 5 months [2-4] and a 1-year survival rate of approximately 1% [1]. Various chemotherapy regimens have been evaluated in an attempt to improve on the outcomes achieved with BSC. In an analysis of more than 2,5 patients with advanced NSCLC enrolled in Southwest Oncology Group (SWOG) protocols between 1975 and 1988, cisplatin was identified as an independent prognostic variable (after adjustment for year of accrual and all prognostic variables) predicting superior survival [5]. In the 199s, platinum compounds were combined with newer third-generation chemotherapy agents, such as vinorelbine and gemcitabine, and the taxanes docetaxel and paclitaxel. These combinations produced higher response rates and longer survival times than the older cisplatin or carboplatin combinations and, thus, have become the standard of palliative care for patients with advanced NSCLC and good performance status [1, 6]. Each combination, however, is characterized by a unique adverse-event profile, thus allowing for choices of chemotherapy for the individual patient. The development of the taxanes, paclitaxel and docetaxel, represents a significant advance in the treatment of solid tumors, particularly breast and lung cancers. Paclitaxel is a natural product isolated from the Pacific yew, whereas docetaxel is a semisynthetic taxane analogue of the European yew. Slight structural differences between the two agents result in a 25% greater aqueous solubility of docetaxel compared with paclitaxel [7]. Taxanes disrupt the cell cycle by binding to the highaffinity site of the β-tubulin subunit, thus stabilizing microtubules (i.e., promoting microtubule formation and preventing microtubule depolymerization) and causing mitotic arrest. Although they share a common mechanism of action, there are several differences in the pharmacokinetics and pharmacologic actions of the two taxanes. For example, the affinity of docetaxel for the tubulin-binding site is twice that of paclitaxel, and docetaxel is twice as efficient as paclitaxel at decreasing the critical tubulin concentration required for the formation of microtubules [7]. Because of its low aqueous solubility, the vehicle for paclitaxel is a purified polyoxyethylated castor oil, which has been implicated in paclitaxel toxicity [8, 9] and in the nonlinear pharmacokinetics of paclitaxel [1-12]. The vehicle used for docetaxel is polysorbate, and its pharmacokinetics are dose and schedule dependent [7]. In phase III clinical trials conducted in patients with advanced NSCLC, treatment with the combination of a platinum and a taxane extended the median survival time to 8-11 months and the 1-year survival rate to 31%-46% [13-16] and improved quality of life (QOL) [1]. A review of these studies is useful in assessing if the pharmacokinetic and pharmacologic differences between these agents are reflected in the efficacy, adverse-event profile, and QOL benefits of the taxanes in patients with advanced NSCLC. TAXANES IN NSCLC The preclinical development of paclitaxel has been primarily performed in the U.S., while docetaxel has been developed primarily in Europe. Both taxanes have activity as single agents and in combination in NSCLC and both offer survival and QOL advantages over best supportive care in randomized trials [2, 3]. Of note, docetaxel demonstrated incomplete cross-resistance to paclitaxel in vitro, and clinical data suggest that docetaxel may have activity as second-line therapy in paclitaxel- and platinum-pretreated NSCLC patients [17]. Moreover, the median and 1-year survival rates in patients treated with second-line docetaxel were superior to those achieved with best supportive care, and those benefits were achieved in conjunction with a positive impact on QOL [4, 18]. Based on these data, docetaxel was approved in the U.S. and Europe as second-line therapy for NSCLC after failure of a prior platinum-based chemotherapy [19], whereas this indication has not been granted for paclitaxel [2]. Both taxanes demonstrate radiosensitizing properties [21], and the taxanes have been evaluated as adjuvant and neoadjuvant therapy of NSCLC. In vitro data showing a synergistic effect between taxanes and platinums [22] led to studies combining the two in patients with NSCLC. The combination of a taxane with a platinum compound for the first-line therapy of NSCLC has been studied extensively. The results of several large phase III studies are reviewed below. PHASE III TRIALS ASSESSING PLATINUM-TAXANE COMBINATIONS FOR ADVANCED NSCLC Four large, multicenter, open-label, randomized clinical trials assessing platinum-taxane combinations in patients with advanced NSCLC are reviewed in Table 1 [13-16]. Patients enrolled in these trials had stage IIIB or IV disease, were chemotherapy naïve, and had good performance status. TAX 326 Trial The TAX 326 trial was a multinational, phase III study of docetaxel plus carboplatin (DCb) or docetaxel plus cisplatin (DC) versus the reference regimen of vinorelbine plus cisplatin (VC) [13]. Enrollment required a Karnofsky performance status (KPS) of at least 7% and adequate organ function. Patients were randomized to one of three treatment groups (Table 1). Dexamethasone was administered to patients receiving docetaxel as prophylaxis against fluid retention and hypersensitivity reactions. Antiemetic

3 18 Review of Taxane-Platinum Combinations in Advanced NSCLC Table 1. Phase III trials assessing platinum-taxane combinations in patients with advanced NSCLC Study Treatment Cycle length (weeks) n TAX 326 [13] Vinorelbine, 25 mg/m 2 days 1, 8, 15, 22 Cisplatin, 1 mg/m 2 day Docetaxel, 75 mg/m 2 over 1 hour day 1 Cisplatin, 75 mg/m 2 day Docetaxel, 75 mg/m 2 over 1 hour day 1 Carboplatin, AUC 6 day SWOG 959 [14] ILCP [16] Vinorelbine, 25 mg/m 2 /week Cisplatin, 1 mg/m 2 day Paclitaxel, 225 mg/m 2 over 3 hours day 1 Carboplatin, AUC 6 day Vinorelbine, 25 mg/m 2 weekly 12, then every other week Cisplatin, 1 mg/m 2 day Paclitaxel, 225 mg/m 2 over 3 hours day 1 Carboplatin, AUC 6 day Gemcitabine, 1,25 mg/m 2 days 1, 8 Cisplatin, 75 mg/m 2 day ECOG 1594 [15] Paclitaxel, 135 mg/m 2 over 24 hours day 1 Cisplatin, 75 mg/m 2 day Paclitaxel, 225 mg/m 2 over 3 hours day 1 Carboplatin, AUC 6 day Gemcitabine, 1, mg/m 2 days 1, 8, 15 Cisplatin, 1 mg/m 2 day Docetaxel, 75 mg/m 2 over 1 hour day 1 Cisplatin, 75 mg/m 2 day Abbreviation: AUC = area under the concentration-time curve. prophylaxis was administered to all patients, and patients receiving cisplatin received hydration. The primary end point was overall survival, and the study was designed to compare each docetaxel arm with the vinorelbine arm; there was no intention of comparing the two docetaxel arms [13]. Baseline characteristics were well balanced across treatment groups. Approximately two-thirds of the patients in each treatment group had stage IV disease. The relative dose intensities were.94 and.93 for the two docetaxel groups and.78 for the vinorelbine group. In the pairwise comparison of DC versus VC, the overall survival times were 11.3 months versus 1.1 months, respectively (p =.44) (Table 2). The 1- and 2-year survival rates were 46% versus 41% and 21% versus 14% for DC versus VC, respectively. The overall response rates were 31.6% for DC and 24.5% for VC (p =.29). Median survival times and overall response rates were similar in the pairwise comparison of DC versus VC (Table 2) [13]. Patients in the docetaxel-containing groups had fewer grade 3 or 4 adverse events (41% and 4%) than those in the vinorelbine group (48%). There were no between-group differences in grade 3 or 4 neutropenia, thrombocytopenia, or infection. Grade 3 or 4 anemia, nausea, and vomiting were more common in patients receiving vinorelbine, and grade 3 or 4 diarrhea was more common with docetaxel. Vinorelbine was associated with more treatment delays due to hematologic toxicity, more hospitalizations due to adverse events, and a higher rate of discontinuations due to adverse events than docetaxel [13]. QOL instruments included the Lung Cancer Symptom Scale (LCSS) and the global QOL scale, EuroQOL. Patients treated with docetaxel reported consistently better global QOL scores than patients treated with vinorelbine, who generally reported deteriorating QOL. These differences were statistically significant for the DC versus the VC regimen when evaluated by EuroQOL (p =.16; Fig. 1) but not by the LCSS (p =.64) and for the DCb versus the VC regimen when evaluated by EuroQOL (p <.1; Fig. 1) and by the LCSS (p =.16). In addition, patients treated with docetaxel demonstrated improvements in clinical benefit parameters. Docetaxel was associated with less weight loss (p <.1 for both docetaxel groups versus VC) and less deterioration in KPS (p =.28 for DC and p <.1 for DCb) than vinorelbine [13, 23].

4 Rigas 19 Table 2. Efficacy, toxicity, and QOL results of phase III trials assessing platinum-taxane combinations in patients with advanced NSCLC Efficacy Overall survival 1-year survival 2-year survival Overall response Overall Study/treatment (months) rate (%) rate (%) rate (%) toxicity QOL TAX 326 [13] Vinorelbine + cisplatin VC > DC DC > VC Docetaxel + cisplatin 11.3 a b Vinorelbine + cisplatin VC > DCb DCb > VC Docetaxel + carboplatin SWOG 959 [14] Vinorelbine + cisplatin V > PCb PCb = VC Paclitaxel + carboplatin ILCP [16] Vinorelbine + cisplatin NR 3 VC > GC = PCb PCb < VC = GC Paclitaxel + carboplatin NR 32 Gemcitabine + cisplatin NR 3 ECOG 1594 [15] Paclitaxel + cisplatin PC = PCb = GC = DC NR Paclitaxel + carboplatin Gemcitabine + cisplatin Docetaxel + cisplatin a p =.44 b p =.29 Abbreviations: NR = not reported SWOG 959 Trial The SWOG 959 trial was a multicenter, randomized, phase III study comparing paclitaxel plus carboplatin (PCb) with VC (Table 1). The dose and schedule of VC was identical to that used in the TAX 326 trial. Enrollment required a PS score of or 1. Patients treated with cisplatin underwent hydration and received antiemetics. Patients treated with carboplatin received dexamethasone, diphenhydramine, and ranitidine or cimetidine. The primary outcome measure was overall survival [14]. The majority of patients were male (69%) and had stage IV disease (89%). The objective response rates were similar in both treatment groups: 28% for patients in the VC arm and 25% for patients in the PCb arm (Table 2). Median survival was also similar, at 8.1 months for VC and 8.6 months for PCb. The VC regimen was associated with more serious toxicities and a lower dose intensity. Significantly more patients treated with VC experienced grade 3 or 4 leukopenia, neutropenia, nausea, and vomiting, and significantly more patients treated with PCb experienced grade 3 or 4 Mean change from baseline 1 5 Better DC + CIS VC + CIS -5 Worse Baseline score ~ 72 p =.16* *Longitudinal analysis Weeks *Bars represent ± a unit of standard error. Mean change from baseline 15 DC + Carbo VC + CIS 1 Better 5-5 Worse p = Weeks Bars represent ± a unit of standard error. Figure 1. TAX 326 Trial: EuroQOL assessments of DC and DCb versus VC.

5 2 Review of Taxane-Platinum Combinations in Advanced NSCLC sensory neuropathy. Discontinuation due to toxicity was more common in the VC arm (p =.1) [14]. QOL was measured with the Functional Assessment of Cancer Therapy-Lung instrument. There were no statistically significant between-group differences in QOL at either 13 or 25 weeks. QOL was categorized as improved, stable, or declined. Approximately 4% of patients in each group reported a decline in QOL, while improvements in QOL were reported in 38% of patients in the VC group, compared with 28% in the PCb group [14]. ITALIAN LUNG CANCER PROJECT The Italian Lung Cancer Project (ILCP) compared three platinum-based doublets: VC, PCb, and gemcitabine plus cisplatin (GC) (Table 1). Eligible patients had Eastern Cooperative Oncology Group (ECOG) PS scores of -2. The primary outcome measure was objective response rate. Patient and tumor characteristics were similar across treatment groups. Eighty-one percent of patients had stage IV disease, and nearly 17% of patients had metastases to the brain [16]. There were no statistically significant between-group differences in objective response rates, which were 3%, 32%, and 3% for patients treated with VC, PCb, and GC, respectively, or in the overall survival time or 1-year survival rate (Table 2) [16]. VC was generally associated with more adverse events than the other two regimens. Grade 3 or 4 neutropenia, anemia, nausea and vomiting, and constipation were more common with VC, while grade 3 or 4 thrombocytopenia was more common with PCb and GC. Grade 3 or 4 alopecia was more common with PCb. Dose intensity was 9% or greater for all drugs except vinorelbine, which had a dose intensity of 77% [16]. QOL was measured using the European Organization for Research and Treatment of Cancer QLC-C3-LC13 instrument. After two cycles of treatment, the instrument favored PCb (versus VC) for role functioning, fatigue, nausea and vomiting, and anorexia and favored VC (versus PCb) for peripheral neuropathy and alopecia. After four cycles of treatment, the instrument favored GC (versus VC) for peripheral neuropathy and VC (versus PCb) for pain, peripheral neuropathy, and alopecia [16]. ECOG 1594 TRIAL The ECOG 1594 trial tested three regimens for advanced NSCLC against paclitaxel plus cisplatin (PC): GC, DC, and PCb (Table 1). Initially, patients with ECOG PS scores of -2 were enrolled, but the protocol was amended after enrollment of 66 patients who had PS scores of 2 to include patients with PS scores of or 1 only. This decision was made because of a high rate of serious adverse events in patients with PS scores of 2. Overall survival was the primary efficacy end point. Most patients had stage IV disease (87%), and 13% had brain metastases [15]. There were no significant between-group differences in overall survival times, 1- or 2-year survival rates, or objective response rates (Table 2). Grade 3 or 4 toxicities were fairly evenly distributed among treatments. Compared with PC, grade 3 or 4 thrombocytopenia, anemia, and renal toxicity were more common with GC, and febrile neutropenia was less common. Hypersensitivity reactions were more common with DC than with PC. Crossover and QOL data were not reported in this study [15]. DISCUSSION Taxane-platinum combinations form the mainstay of treatment for patients with advanced NSCLC in many parts of the world. There were four key end points in these randomized trials for determining the relative merits of these regimens: survival, response rate, adverse event profile, and QOL. The relative merits of each of these end points may vary depending on the stages of NSCLC being treated (i.e., advanced NSCLC QOL and minimizing adverse events versus earlier-stage NSCLC survival and response rates and minimizing long-term cumulative adverse events). The phase III studies reviewed here demonstrate a benefit of the DC doublet in terms of all these end points. First, in terms of survival, in the largest prospective phase III study evaluating the efficacy of a taxane-platinum combination in advanced NSCLC, Fossella and colleagues [13] reported that DC was modestly superior to VC, with the median survival being about 1 month longer in patients treated with docetaxel. Overall, 1-year and 2-year survival rates were highest in the DC arm of this trial compared with the other trials reviewed here. Moreover, between-group differences in the 2-year survival rates favoring the docetaxel arms were most notable in the TAX 326 trial [13]. Second, in terms of response rate, the DC arm of the TAX 326 trial was the only study treatment among the platinum doublets evaluated in these phase III trials to show an advantage relative to the control regimens, with an overall response rate of 32%, versus 24% for VC. The PCb regimen evaluated in the SWOG trial and ILCP showed similar overall response rates to those of VC and GC [14, 16]. In the ECOG 1594 trial, the only direct comparison of similar regimens, response rates and survival times were similar between patients treated with cisplatin plus either docetaxel or paclitaxel [15]. Differences in trial design, patient characteristics, and treatment delivery between this trial and the TAX 326 trial likely account for the outcome variations observed with the taxane-platinum regimen between these trials. The size of the trials varied, with the

6 Rigas 21 A Adverse events grade 3/4 neutropenia B Adverse events febrile neutropenia ) p < p <.5 11 Patients (%) Vin + Cis Tax + Cis Tax + Carbo Vin + Cis Pac + Carbo Gem + Cis Pac + Cis Pac + Carbo Gem + Cis Tax + Cis Vin + Cis Pac + Carbo Tax 326 ILCP ECOG 1594 SWOG 959 Patients (%) T+C T+Cb 1.5 P+C G+C 4 4 P+C P+Cb G+C T+C P+C Tax 326 ILCP ECOG 1594 SWOG 959 C Patients (%) Adverse events grade 3/4 peripheral neuropathy p < p < T+Cb G+C Tax 326 ILCP ECOG 1594 SWOG 959 T+C P+Cb P+C P+Cb G+C T+C P+Cb Figure 2. Selected grade 3 or 4 toxicities reported in large phase III clinical trials: A) neutropenia, B) febrile neutropenia, and C) peripheral neuropathy. TAX 326 trial including approximately 1 more patients in each treatment arm than the ECOG trial. There were differences in patient characteristics between the trials in terms of stage of disease and proportion of patients with brain metastases. Also, there were differences in treatment delivery between the two trials. Finally, the use of subsequent lines of chemotherapy, which was not reported in the ECOG trial, may have obscured potential differences among the treatments. Analysis of adverse events among the four phase III trials also revealed differentiating features. A common manageable adverse event for the taxane-platinum combinations has been neutropenia. Throughout the studies, lower rates of grade 3 or 4 neutropenia were reported with the PCb combination, most notably demonstrated in the SWOG trial (Fig. 2A). In addition, the clinically important myelosuppressive end point of febrile neutropenia appears to be less common with PCb, which is particularly evident in the ECOG 1594 trial where the difference between the paclitaxel 24-hour infusion and 3-hour infusion arms was statistically significant (p <.5) (Fig. 2B) [15]. Docetaxel distinguishes itself with a low incidence of irreversible grade 3 or 4 peripheral neuropathy when used in combination with carboplatin (1%); the incidence with the PCb combination was much higher at 7%-13% (Fig. 2C). Finally, health-related QOL studies have become an important end point of advanced palliative cancer therapy trials. They assess subjective perceptions of positive and negative aspects of physical, emotional, social, and cognitive functions affected by the disease and its treatment. QOL assessments are particularly important in advanced NSCLC because of the substantial symptomatic burden of this disease. In fact, it has been argued by some that the therapeutic index in advanced disease is too narrow to warrant subjecting patients to the unpleasant side effects of treatment [24]. As assessed in these trials, docetaxel-platinum combinations appear to offer a QOL advantage among newer platinum doublets. In the TAX 326 trial, DC or DCb was superior to VC. In fact, patients treated with docetaxel consistently reported improvements in global QOL, while vinorelbine-treated patients consistently reported deteriorating QOL [13]. In the ILCP, VC was favored on several scales when compared with PCb [16]. The ECOG 1594 trial did not report QOL [15], and the SWOG 959 trial reported similar QOL in patients treated with VC and with PCb [14], but fewer patients treated with PCb reported improved QOL (28%) compared with patients treated with VC (38%). With their benefits in the key end points of survival, response rate, adverse event profile, and QOL in ran-

7 22 Review of Taxane-Platinum Combinations in Advanced NSCLC domized trials of advanced NSCLC, docetaxel and docetaxel-based regimens are logical for further evaluation in earlier-stage NSCLC. Growing evidence indicates that adjuvant treatment with a cisplatin-based regimen is a valid treatment option for good performance status patients with resected disease, and it is speculated that the addition of docetaxel to cisplatin will result in an incremental benefit. Docetaxel is also commonly used as part of a combined modality regimen in locally or regionally advanced disease, with notable results as consolidation therapy. Moreover, its use as induction therapy for inoperable locally advanced disease is under rigorous investigation, focusing on the optimal integration into current treatment strategies. In conclusion, docetaxel has markedly impacted the treatment of advanced NSCLC and continued evaluation in earlier-stage disease is warranted. ACKNOWLEDGMENT J.R.R. has received grant/research support from Amgen, Aventis, Bristol Myers Squibb, GlaxoSmithKline, Ortho Biotech, Pfizer, OSI, Roche, Merck, Ligand, Genentech, and Abbott and is a consultant for Amgen, Bayer, and GlaxoSmithKline. REFERENCES 1 Proceedings of the European Consensus Conference on Medical Treatment of Non-Small Cell Lung Cancer. Lung Cancer 22;38(suppl 3):S1-S85. 2 Roszkowski K, Pluzanska A, Krzakowski M et al. A multicenter, randomized, phase III study of docetaxel plus best supportive care versus best supportive care in chemotherapy-naive patients with metastatic or non-resectable localized non-small cell lung cancer (NSCLC). Lung Cancer 2;27: Ranson M, Davidson N, Nicolson M et al. Randomized trial of paclitaxel plus supportive care versus supportive care for patients with advanced non-small-cell lung cancer. J Natl Cancer Inst 2;92: Shepherd FA, Dancey J, Ramlau R et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinumbased chemotherapy. J Clin Oncol 2;18: Albain KS, Crowley JJ, LeBlanc M et al. Survival determinants in extensive-stage non-small-cell lung cancer: the Southwest Oncology Group experience. J Clin Oncol 1991;9: Bunn PA Jr, Kelly K. New chemotherapeutic agents prolong survival and improve quality of life in non-small cell lung cancer: a review of the literature and future directions. Clin Cancer Res 1998;4: Lam YW, Chan CY, Kuhn JG. Pharmacokinetics and pharmacodynamics of the taxanes. J Clin Pharm Pract 1997;3: Rowinsky EK. On pushing the outer edge of the outer edge of paclitaxel s dosing envelope [editorial]. Clin Cancer Res 1999;5: Weiss RB, Donehower RC, Wiernik PH et al. Hypersensitivity reactions from taxol. J Clin Oncol 199;8: Sparreboom A, van Tellingen O, Nooijen WJ et al. Nonlinear pharmacokinetics of paclitaxel in mice results from the pharmaceutical vehicle Cremophor EL. Cancer Res 1996;56: Sparreboom A, van Zuylen L, Brouwer E et al. Cremophor EL-mediated alteration of paclitaxel distribution in human blood: clinical pharmacokinetic implications. Cancer Res 1999;59: van Tellingen O, Huizing MT, Panday VR et al. Cremophor EL causes (pseudo-) non-linear pharmacokinetics of paclitaxel in patients. Br J Cancer 1999;81: Fossella F, Pereira JR, von Pawel J et al. Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group. J Clin Oncol 23;21: Kelly K, Crowley J, Bunn PA Jr et al. Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non-smallcell lung cancer: a Southwest Oncology Group trial. J Clin Oncol 21;19: Schiller JH, Harrington D, Belani CP et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 22;346: Scagliotti GV, De Marinis F, Rinaldi M et al. Phase III randomized trial comparing three platinum-based doublets in advanced non-small-cell lung cancer. J Clin Oncol 22;2: Gandara DR, Vokes E, Green M et al. Activity of docetaxel in platinum-treated non-small-cell lung cancer: results of a phase II multicenter trial. J Clin Oncol 2;18: Shepherd FA, Fossella FV, Lynch T et al. Docetaxel (Taxotere) shows survival and quality-of-life benefits in the second-line treatment of non-small cell lung cancer: a review of two phase III trials. Semin Oncol 21;28(suppl 2): Taxotere (docetaxel) injection concentrate. Product information. Bridgewater, NJ: Aventis Pharmaceuticals Inc., Taxol (paclitaxel) injection. Product information. Princeton, NJ: Bristol-Myers Squibb Company, Calderoni A, Cerny T. Taxanes in lung cancer: a review with focus on the European experience. Crit Rev Oncol Hematol 21;38:

8 Rigas Jensen PB, Holm B, Sorensen M et al. In vitro cross-resistance and collateral sensitivity in seven resistant small-cell lung cancer cell lines: preclinical identification of suitable drug partners to taxotere, taxol, topotecan and gemcitabin. Br J Cancer 1997;75: Gralla RJ, Rodrigues J, Von Pawel J et al. Prospective analysis of quality of life (QOL) in a randomized multinational phase III study comparing docetaxel (D) plus either cisplatin (C) or carboplatin (Cb) with vinorelbine plus cisplatin (VC) in patients with advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 22;21:3a. 24 Bottomley A, Efficace F, Thomas R et al. Health-related quality of life in non-small-cell lung cancer: methodologic issues in randomized controlled trials. J Clin Oncol 23;21: