Superiority of Sequential Versus Concurrent Administration of Paclitaxel with Etoposide in Advanced Non-Small Cell Lung Cancer: Comparison of Two Phase II Trials’

Vol. 4, 2723-2728, November 1998 Clinical Cancer Research 2723

Superiority of Sequential versus Concurrent Administration of Paclitaxel with Etoposide in Advanced Non-Small Cell Lung Cancer: Comparison of Two Phase II Trials’

Enriqueta Felip, Bartomeu Massuti, complete responses and seven partial responses, for an over- Carlos Camps, Dolores Benito, Dolores Isla, all response rate of 37.5% (95% confidence interval, 21- 58%). In conclusion, toxicity and antitumor activity of the Jose Luis Gonz#{225}lez-Larriba, paclitaxel/etoposide combination may be sequence depend- M. Paz L#{243}pez-Cabrerizo, Oscar Salamanca, ent. Our findings suggest that etoposide followed by pacli- Jos#{233}Puerto-Pica, Aifredo Moyano, Jos#{233}Baselga, taxel is well tolerated and has greater activity in NSCLC and Rafael Rosell2 than concurrent administration. Medical Oncology Department, Hospital General Vail d’Hebron, 08035 Barcelona [E. F., J. B.]; Hospital General de Alicante, 03010 INTRODUCTION Alicante [B. M.]; Hospital General de Valencia, 46014 Valencia The treatment of patients with metastatic or locally ad- [C. C.]; Bristol-Myers Squibb Company, 28040 Madrid [D. B., 0. SI; Hospital ClInico Universitario de Zaragoza, 50009 Zaragoza [D. I.]; vanced NSCLC3 remains unsatisfactory (1 , 2). Chemotherapy Hospital ClInico San Carlos, 28040 Madrid [J. L. G-L.]; Hospital trials in NSCLC have often focused on platinum-based chemo- Germans Trias y Pujol, 08916 Badalona, Barcelona [M. P. L-C., therapy, although such regimens have led to only marginal R. R.]; Hospital Infanta Cristina, 06080 Badajoz [J. P-P.] and Hospital improvements in survival (2-7). ln the past few years, several Ram#{243}nyCajal, 28034 Madrid [A. M.], Spain new chemotherapy agents have demonstrated activity in advanced NSCLC. Paclitaxel (Taxol#{174}; Bristol-Myers Squibb ABSTRACT Company, Princeton, NJ) is a novel chemotherapeutic agent that Paclitaxel and etoposide are two chemotherapy agents enhances microtubule assembly, inhibits the depolyrnerization with broad cytotoxic activity and different mechanisms of of tubulin, and has been shown to have promising preclinical action and resistance. Preclinical studies of their combined activity in NSCLC (8, 9). In several published trials. single- cytotoxicity have yielded conflicting results. We performed agent paclitaxel has been reported to have significant activity in two sequential Phase II trials using different sequence NSCLC as first-line therapy, with response rates between 21% schedules of paclitaxel and etoposide as first-line treatment and 36% and 1-year survival rates of -40% (10-12). This level in advanced non-small cell lung cancer (NSCLC). Forty-four of antitumor activity is at least similar to previously available patients with stage 11113 or LV NSCLC were included be- agents, and in addition, paclitaxel can be given in combination tween July 1995 and September 1996. All patients received with other active agents in NSCLC such as carboplatin, cispla- etoposide at 100 mg/m2, given as an i.v. infusion on days 1, tin, and etoposide. The combination of paclitaxel and cisplatin 2, and 3. The first 20 patients (part A) also received pacli- or carboplatin has been tested previously (13-16). Nonetheless, taxel at 175 mg/m2 as a 3-h infusion on day 1, immediately platinum-containing regimens are associated with substantial prior to etoposide. The subsequent 24 patients (part B) were toxicity, and therefore, newer combinations with better toxicity given the same paclitaxel dose, but on day 4. Grade 3-4 profiles and greater efficacy are needed. This trial was designed granulocytopenia was seen in 70% of the patients in part A to explore the combination of paclitaxel and etoposide in advanced NSCLC. Etoposide (VePesid; Bristol-Myers Squibb and in 37% of those in part B (P = 0.04). Twenty-five % of the courses in part A and 4% of the courses in part B were Company) is a topoisomerase II inhibitor that, as a single agent associated with granulocyte nadir 5OO/d (P = 0.00006). administered either p.o. or i.v., has demonstrated activity in No responses were observed in part A, although disease was NSCLC with response rates of 10-15% ( 17). Our rationale for stabilized in 14 patients (70%). In part B, there were two studying paclitaxel in combination with etoposide was based on several observations: both drugs are active in NSCLC, each drug has a different mechanism of action, and both drugs have a toxicity profile that makes them suitable to be studied in combination. Recent preclinical studies have highlighted the prob- Received 5/1/98; revised 8/7/98; accepted 8/10/98. lem posed by the combined cytotoxicity of these two agents (18, part The costs of publication of this article were defrayed in by the 19). Perez et a!. (19) evaluated the effects of paclitaxelietopo- payment of page charges. This article must therefore be hereby marked side scheduling in cell growth inhibition in lung human cancer advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. cell lines, reporting that little antagonism was observed when I The authors participated in this study on behalf of the Spanish Lung Cancer Group. This work was supported in part by a grant from Bristol-Myers Squibb Company. 2 To whom requests for reprints should be addressed, at Hospital Ger- mans Trias i Pujol, Medical Oncology Service, Box 72, 08916 Bada- :; The abbreviations used are: NSCLC, non-small cell lung cancer; ANC, lona, Barcelona, Spain. Phone: 34-93-4650409; Fax: 34-93-3954206; absolute neutrophil count; CBC. complete blood cell; PR, partial re- E-mail: [email protected]. sponse; SD, stable disease; Cl, confidence interval.

paclitaxel and etoposide were given concurrently, although syn- of <5004a1 for 7 days or a platelet nadir of <50,000/pA for ergisrn was observed when paclitaxel followed etoposide expo- 7 days, and it was reduced two steps (1 10 mg/rn2) in the event

sure. The evidence that sequence-dependent effects of pacli- of febrile neutropenia. The etoposide dose was reduced to 75% taxel/etoposide may be crucial in synergism or antagonism if the neutrophil nadir was <500/pA or the platelet nadir was between the two drugs prompted us to combine paclitaxel and <50,000/pl. If, on day 21, neutrophil count was < 1,500/pi or etoposide in two sequential Phase II trials. In the first Phase II the platelet count was < l00,000/pJ, treatment was delayed 1 study (part A), paclitaxel and etoposide were administered con- week or until recovery. The use of hematopoietic growth factor currently, whereas in the second (part B), etoposide preceded was restricted to patients who developed neutropenic fever. For paclitaxel administration. nonhernatological toxicities, the following criteria were considered for dose reductions: the paclitaxel dose level was reduced one step in the presence of grade 2 stomatitis and two steps for PATIENTS AND METHODS grade 3 neuropathy, and paclitaxel was withheld if grade 4 Patient Eligibility. Entry criteria for these two sequential neuropathy occurred. Phase II studies were identical. All patients had histologically Scans or films of indicator lesions were performed for confirmed stage IIIB or IV NSCLC and were chemotherapy response evaluation after three cycles of therapy or sooner, if the naive. Prior radiotherapy was allowed. provided that measurable patient appeared to have disease progression. Standard Eastern lesions were outside the radiotherapy treatment field. All par- Cooperative Oncology Group criteria for solid tumor response ticipants were required to have age of 18 years, an Eastern were used to evaluate response. All patients received a total of Cooperative Oncology Group performance status of 2, a life six cycles of treatment, unless there was evidence of progressive expectancy of >3 months, and adequate hematological (ANC of disease. On completion of 6 cycles, patients who had complete 2,000/i.l and platelet count of > l00,000/xl), hepatic (total response or PR continued therapy up to a maximum of 10 bilirubin level of 2 mg/dl), and renal (creatinine concentration cycles. Toxicity from treatment was graded according to stand- of < 1 .5 mg/dl) function. Written informed consent was ob- ard WHO criteria. Following completion of treatment, patients tamed from all patients, and the protocol was approved by the were evaluated every 3 months up to 2 years and then every 6 institutional ethics committees of the participating centers. Pa- months. tients were excluded from the trial for any of the following: In part A, 20 eligible patients were to be included. If one or history of prior malignancies, pregnancy, history of atrial or more objective responses were observed, an additional 15 eli- ventricular arrhythmias or congestive heart failure, documented gible patients were to be accrued. Such a design has a 98% myocardial infarction in the preceding 6 months, history of power to detect an objective response rate of 20% after accrual second- or third-degree heart block, preexisting motor or sen- of the first 20 patients. Part A of the trial was, in fact, terminated sory neuropathy greater than grade II according to WHO crite- after the accrual of 20 patients because no response was ob- na, and history of sensitivity to cremophor. Patients with brain served. To have comparable sample size in part B, which was metastases were also excluded. conducted subsequently, it was decided that a similar number of Before protocol enrollment, all patients underwent a com- patients should be accrued. plete history and physical examination. Laboratory evaluation Overall response rate was calculated for all patients en- included a CBC count, electrolytes, liver function tests, urea, tered, with no attempt to exclude patients whose response was creatinine, and urinalysis. Electrocardiography. chest X-ray, and not evaluated or who had early progression. Progression-free computed tomographic scan of chest and upper abdomen were survival was measured from the commencement of chemother- performed on all patients; additional imaging studies were per- apy treatment to the date of progression, relapse, or death formed if they were clinically indicated or to measure areas of without prior progression. Overall survival was measured from known disease. the commencement of chemotherapy treatment to the date of Drug Administration and Study Design. The two se- death. For responding patients, response duration was the inter- quential groups of patients received chemotherapy with pacli- val between the first documentation of response and relapse. taxel and etoposide. Patients in the first group were given Progression-free survival and overall survival were calculated etoposide (fixed dose of 100 mg/m2) on days 1, 2, and 3, using the Kaplan-Meier method. Patients’ characteristics, tumor administered by 30-mm infusion, preceded by paclitaxel (175 response rates, and treatment toxicities in the two parts of the mg/m2), given iv. over 3 h on day 1 . In the second group, the study were compared using the x2 test. The Mann-Whitney etoposide dose/schedule was the same as in part A, but pacli- nonparametric test was used to assess differences in the effects taxel (175 mg/rn2) was administered on day 4. Thirty mm before of the two sequences on nadir ANCs and platelet counts. the infusion of paclitaxel, patients received the following iv. injections: 20 mg of dexamethasone, 50 mg of diphenhydra- mine, and 300 mg of cimetidine, to avoid acute allergic reac- RESULTS tions. All patients were treated in an outpatient setting. Treat- Between July 1995 and September 1996, 44 patients were ment cycles in both groups were repeated every 2 1 days. On included in these two sequential studies, 20 patients in part A days 1 1 and 21, patients underwent a CBC count. The paclitaxel and 24 in part B. Table 1 shows the pretreatment characteristics dose was escalated to 200 mg/rn2 and, subsequently, to a max- of all patients. Prognostic factors were similar in the two groups. imum of 225 mg/rn2 if the neutrophil nadir was > 1,000/pA and Toxicity. Both treatment schedules were well tolerated, the platelet nadir was > 100,000/pi. Paclitaxel dose level was as shown in Table 2. In part A, a total of 94 courses of therapy reduced one step (135 mg/rn2) in the event of a neutrophil nadir were administered to 20 patients (median, 5.5 courses; range,

Table 1 Patient characteristics Table 2 Hematological and nonhematological toxicity”

Part A: Part B: etoposide -* Part A (n = 20): Part B (n = 24):

paclitaxel/etoposide paclitaxel paclitaxel/etoposide etoposide - paclitaxel

No. % No. % No. % No. %

No. of patients entered 20 24 Granulocytopenia No. of patients eligible 20 24 Grade 1-2 2 10 4 16 Age, yr Grade3 3 15 7 29 Median 62.5 62.5 Grade4 11 55 2 8 Range 40-74 31-70 Thrombocytopenia ECOG#{176}performance status Grade 1-2 3 15 0 2 10 1 4 Grade 3 18 90 18 75 Grade 4 2 5 21 Hemoglobin Histology Grade 1-2 1 1 55 14 58 Squamous cell 8 40 11 46 Grade 3 Adenocarcinoma 9 45 7 29 Grade 4 Large cell 3 15 6 25 Neutropenic fever 4 20 3 12 Stage Stomatitis IIIB 11 55 11 46 Grade2 2 8 IV 9 45 13 54 Grade3 2 8 Nausealemesis (4 ECOG, Eastern Cooperative Oncology Group. Grade2 2 13 4 17 Grade3 2 13 Neurological Grade2 6 38 7 29 1-8 courses). One patient died of toxicity (infection during Grade3 I 6 2 8 neutropenia) after the first cycle, and another patient refused Grade4 I 4 Alopecia further treatment after the second course of therapy. Granulo- Grade2 2 13 6 25 cytopenia was the principal toxicity observed with this regimen, Grade3 13 81 16 68 with grade 3-4 in 70% of patients. Febrile neutropenia occurred Myalgia/arthralgia in 4 of 20 patients (20%), and no thrombocytopenia or signifi- Grade2 5 31 3 13 Grade3 1 6 cant anemia was observed. In this group of patients, 20% required paclitaxel dose reduction, whereas 15% of the patients ‘4 Worst toxicity per patient; grades according to WHO. tolerated a dose escalation to 200 mg/rn2 and 35% of the patients reached 225 mg/rn2. Peripheral neuropathy was the most significant nonhematological toxicity noted in this study population (grade 2, 38%; grade 3, 6%). Myalgia and arthralgia (grade 2-3) nadir for concurrent paclitaxelletoposide courses was signifi- were reported in 37% of patients, and nausea and vomiting were cantly lower than the nadir for etoposide-first courses: 1400 uncommon. versus 20004d (P 0.005). Thirty-eight % of the courses in In part B, 24 patients received a total of 124 courses of part A and 24% of the courses in part B were associated with therapy (median, 5.5 courses; range, 1-10 courses). Treatment ANC nadirs of sil000/pA (P = 0.035), and 25% of the courses was withdrawn early from three patients: one patient died 10 in part A and 4% of courses in part B were associated with ANC days after starting the first cycle as a result of pulmonary nadirs of 500/p.l (P = 0.00006). Significantly more patients in embolus (not related to treatment), the second had early disease part A (14 of 20 patients) than in part B (9 of 24 patients) had progression, and the third was lost to follow-up evaluation after grade 3-4 granulocytopenia (P 0.04). In the first cycle of the second course of therapy. The main hematological toxicity chemotherapy, grade 4 granulocytopenia was observed in 35% was granulocytopenia, grade 3 in 29% of patients and grade 4 in of patients in part A (7 of 20 patients) and 6% of patients in part 8% of patients. Fever during neutropenia that required hospital- B (1 of 24 patients; P = 0.015). Febrile neutropenia during the first ization occurred in three patients ( 12%). Eight patients (33%) cycle of chemotherapy occurred in two patients (10%) in part A of developed grade 2 anemia, but no episodes of thrombocytopenia the study, whereas no such episodes were seen in part B. were observed. Twenty-five % of patients were escalated to the Response. Response data are summarized in Table 4. In 200 mg/rn2 paclitaxel dose level, and 38% were escalated to 225 part A, no objective responses were observed, although 14 mg/rn2. Dose reduction was required in five patients (21%). The patients had disease stabilization. For patients with SD, the incidence of peripheral neuropathy was cumulative, but this estimated median time to progression or death was 6.7 months toxicity was not severe, reaching grade 3-4 in only 12% of (95% CI, 2-11). The estimated median overall survival time for patients. Other nonhematological toxicities, including nausea all patients was 1 1.8 months (95% CI, 6-17), and the estimated and vomiting, mucositis, and arthralgia/myalgia, were infre- survival rate at 1 year was 48%. quent. In part B, 9 (37.5%) of the 24 patients enrolled achieved an The effects of drug sequencing on hematological toxicity objective response (95% CI, 21-58%); complete response was are listed in Table 3. There was no difference in the median observed in 2 patients (8%), and 7 patients (29%) had PR. At a pretreatment ANC for courses giving concurrent paclitaxel/ median follow-up time of 1 1 months, four of the nine patients etoposide or etoposide-first cycles. However, the median ANC who responded remained free of progression. Twenty-five % of

Table 3 Schedule-dependent hematological toxicity Table 4 Therapeut ic response

Paclitaxel Part A (n = 20): Part B (ii = 24): dose level No. of Neutrophil Platelet nadir, paclitaxel/etoposide etoposide-paclitaxel (mg/m2) Sequence” cycles nadir. median median No. % No. % All cycles P/E 94 1,400 245,000 E-P 124 2.000 268,000 ORR” 9 37.5 CR 110 P/E 4 500 197.000 2 8.3 E-*P 6 2,080 215,000 PR 7 29.2 135 P/E 12 800 172,500 SD 14 70 9 37.5 E-P 8 3.400 369,950 PD 4 20 4 16.6 175 P/E 29 1,300 230,500 NA 2 10 2 8.3

E-*P 46 1,630 216,500 ‘I ORR, overall response rate; CR, complete response; PD, progres- 200 P/F 21 1,900 303,000 sive disease; NA, not assessable. E-+P 37 1,500 239,000 225 P/E 28 1,200 263,000 E-P 27 2,550 310,000

‘A P/E, concurrent paclitaxel/etoposide; E-*P, etoposide followed by paclitaxel. sequence of paclitaxel plus doxorubicin, given as a 3-h infusion, had no effect on the tolerability of the combination. The lack of sequence dependence could be attributed to the administration of paclitaxel over 3 h, whereas the longer 24-h infusion may objective responders tolerated paclitaxel escalation to 225 mg/ have provoked pharmacokinetic interference. In a recent study rn2. SD was observed in nine patients (37.5%), and three of NSCLC patients, paclitaxel and carboplatin combination ( 1 2.5%) had progressive disease while receiving chemotherapy. showed no sequence-dependent toxicities or pharmacokinetic For patients with SD, the estimated median time to progression interactions (15). This may be explained by the fact that carbo- or death was 8.2 months (95% CI, 5-12). In part B of the study, platin does not modulate cytochrome P450, whereas the reduced the estimated median overall survival for all patients was 12.3 paclitaxel clearance in the cisplatin-paclitaxel sequence has months (95% CI, 7-17). been attributed to inhibition by cisplatin of cytochrome P450 enzymes. DISCUSSION In our study, based on the CBC counts performed on days Paclitaxel may play an increasing role in the treatment of 1 1 and 21 from the beginning of each chemotherapy cycle, NSCLC because it is an active chemotherapeutic agent that can granulocytopenia was worse in part A when paclitaxel preceded be used in combination. Available data suggest, however, that etoposide. Paclitaxel administration may well interfere with paclitaxel is a complex drug that both affects and is affected by etoposide pharmacokinetics because recent data suggest that the administration of other drugs (20-26). The primary objective of metabolism of both drugs is catalyzed by cytochrome P450 3A4, this study was to explore the toxicity and antitumor activity of which is found in the liver and gastrointestinal mucosa (27, 28). two different paclitaxel/etoposide sequences in patients with In a Phase I study, lung cancer patients were treated with advanced NSCLC. paclitaxel, given as a 3-h infusion (starting dose 100 mg/rn2), Our findings suggest that sequence is important because we and oral etoposide (100 mg on days 1-5; Ref. 29). Two admin- have observed different hematological toxicity in the two sched- istration schedules were used: schedule A, in which paclitaxel ules used. Sequence-dependent effects on toxicity have been was given on day 1, and schedule B, when it was administered reported with paclitaxel-based combinations. Rowinsky et al. on day 5. Higher paclitaxel dose level was achieved when (23) showed that the combination of paclitaxel and cisplatin paclitaxel was given at the beginning. Their results are different resulted in 30% higher paclitaxel levels when cisplatin preceded from ours; possible explanations are the concurrent administra- paclitaxel. The clinical significance of this finding is that pa- tion of paclitaxel and etoposide in both schedules in their trial tients who received cisplatin before paclitaxel have more mci- and the known variability in bioavailability of the oral route in dence of neutropenia than those receiving this combination in etoposide administration. the reverse order. In a Phase I trial, paclitaxel/cyclophospha- Sequencing of drug delivery can be extremely important in mide combination was evaluated, and neutropenia was more multidrug chemotherapy if one or more of the agents impose severe when paclitaxel was administered first. In this study, cell cycle blocks or exhibit cell cycle-specific cytotoxicity (30- pharmacokinetic studies have failed to demonstrate any alter- 32). In vitro preclinical studies have reported cytotoxic interac- ations in standard pharmacokinetic parameters (24). Holmes et tions between paclitaxel and etoposide when they were given in al. (25) investigated paclitaxel administered over 24 h followed human NSCLC cell lines (18, 19). Sequential schedule of eto- by doxorubicin in previously untreated patients with metastatic poside followed by paclitaxel seems more appropriate because breast cancer. Due to severe problems with mucositis and febrile etoposide promotes accumulation of cells in the premitotic neutropenia, the sequence of drugs was reversed, resulting in phases of cell cycle and paclitaxel stabilizes the microtubules better tolerance. The pharmacological studies indicated that against depolymerization, leading to arrest in the G2 and M doxorubicin clearance was reduced by -30% in courses in phases of the cell cycle. Although the currently reported study which paclitaxel was administered first. Other clinical studies was not a randomized trial and definitive conclusions should not have reported no link between paclitaxel schedule and toxicity. be drawn, a clear impact of sequencing on antiturnor activity In metastatic breast cancer, Gianni et a!. (26) found that the was observed. When paclitaxel and etoposide were administered

at the same time, no objective responses were observed, as individual patients from 52 randomized clinical trials. Br. Med. J., 311: compared with the schedule of etoposide followed by paclitaxel, 899-909, 1995. which achieved a 37.5% response rate. Regardless of lack of 2. Rosell, R., Abad-Esteve, A., Moreno, I., Barnadas, A., Carles, J., response in part A, the median survival duration of 1 1 .8 months Fernandez, C., Ribelles, N., and Culubret, N. A randomized study of two vindesine plus cisplatin-containing regimens with the addition of mito- and the estimated 1-year survival rate of 48% is superior to mycin C or ifosfamide in patients with advanced non-small cell lung published supportive care arms (1). Some thoughts on survival cancer. Cancer (Phila.), 65: 1692-1699, 1990. should be kept in mind: 55% of patients included were classified 3. Rosell, R., Carles, J., Ariza, A., Moreno, I., Ribelles, N., Solano, V., as stage IIIB, and some patients received second-line chemo- Pellicer, I., Barnadas, A., and Abad, A. A Phase II study of days 1 and therapy. Furthermore, the fact that paclitaxel is an inhibitor of 8 cisplatin and recombinant cn-2B interferon in advanced non-small cell angiogenesis would help explain some of the prolonged stable lung cancer. Cancer (Phila.), 67: 2448-2453, 1991. responses seen in our patients (33, 34). In a recently published 4. Kris, M. G., Gralla, R. J.. Wertheim, M. S., Kelsen, D. P., O’Connell, Phase I trial, 24 previously untreated NSCLC patients were J. P., Burke, M. T., Fiore, J. J., Cibas, I. R., and Heelan, R. T. Trial of the combination of mitomycin, vindesine and cisplatin in patients with given paclitaxel (doses of 150-225 mg/rn2 by infusion over 3 h advanced non-small cell lung cancer. Cancer Treat. Rep., 70: 1091- on day 1 ) followed by etoposide ( 100-120 mg/rn2 on days 2-4). 1096, 1986. Although the design of this study does not allow definitive 5. Ruckdeschel. J. C.. Finkelstein, D. M., Mason, B. A., and Creech, conclusions to be drawn regarding the efficacy of this sequence, R. M. Chemotherapy for metastatic non-small cell bronchogenic carci- it is noteworthy that only 2 patients (8%) achieved PR, whereas noma: EST 2575, a randomized comparison of four cisplatin-containing 15 patients (63%) had SD (35). These results closely resemble regimens. J. Clin. Oncol., 3: 72-79, 1985. those obtained in part A of our study. The response rate of 6. Klastersky. J., Sculier, J. P., Ravez, P., Libert, P., Michel, J.. Vander- moten, G., Rocmans, P., Bonduelle, Y., Maraisse, M., Michiels, T., 37.5% obtained in the part B of our study is promising. Al- Thiriaux, J.. 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Although the optimal dose of paclitaxel in Chemotherapy can prolong survival in patients with advanced non-small NSCLC is yet to be defined, the results of published studies cell lung cancer: report of a Canadian multi-center randomized trial. suggest that a dose-response relationship may exist (36). Sur- J. Clin. Oncol., 6: 633-641, 1988. vival was not improved in part B of our study (P 0.29), 8. Pazdur, R., Kudelka, A. P., Kavanagh, J. J., Cohen, P. R., and Raber, despite a higher response rate. A possible explanation for the M. N. The taxoids: paclitaxel (Taxol) and docetaxel (taxotere). Cancer lack of survival benefit is that the sample size was too small to Treat. Rev., 19: 351-386, 1993. be able to detect a survival difference. Etoposide followed by 9. Hanauske, A. R., Degen, D., Hilsenbeck, S. G., Bissery, M. C., and von Hoff, D. D. 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E Felip, B Massuti, C Camps, et al.

Clin Cancer Res 1998;4:2723-2728.

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