Taxotere: Clinical Trials in Non-Small Cell Lung Cancer

Taxotere: Clinial Trials in Non-Small Cell Lung Caner DEBORAH L. ORNSTEIN, JAMES R. RIGAS Thorai Onology Program, Norris Cotton Caner Center, Setion of Hematology/Onology; Department of Mediine, Dartmouth-Hithok Medial Center, Leanon, New Hampshire, USA; Dartmouth Medial Shool, Hanover, New Hampshire, USA Key Words. Non-small ell lung aner Doetaxel Phase II trials ABSTRACT Cisplatin-ased hemotherapy regimens of the 1980s have shown a small ut signifiant impat on survival for patients with advaned non-small ell lung aner (NSCLC). New agents, inluding doetaxel, have shown enouraging single-agent ativity in this disease. This potent mirotuule stailizing agent was seleted for linial development ased on its prelinial superiority to palitaxel. Three hundred twentyeight (328) patients with advaned or reurrent NSCLC have een enrolled in seven phase II trials of 100 mg/m 2 of doetaxel administered intravenously every 21 days. Four of the trials enrolled 160 hemotherapy-naive patients, and three of the trials enrolled 168 patients who failed prior platinum-ontaining hemotherapy. The antitumor response rate for 160 hemotherapy-naive patients was 27% (95% onfidene interval: 20%-34%) with a median survival time of 9.2 months and for 168 platinum-treated patients, 17% (95% onfidene interval: 11%-23%). Alopeia, fluid retention, infusion-related reations, leukopenia, onyholysis, and rash were adverse events oserved in these trials. Dexamethasone premediation lessens the frequeny and severity of fluid retention, infusion-related reations, and rash. Doetaxel demonstrates signifiant antitumor ativity in hemotherapy-naive and platinumtreated patients with NSCLC. Trials of doetaxel in omination with aroplatin, isplatin, vinoreline, gemitaine, irinotean, and thorai radiation and as primary hemotherapy for stage III NSCLC are in progress. The Onologist 1998;3:86-93 INTRODUCTION Non-small ell lung aner (NSCLC) is the primary ause of aner-related deaths in the United States [1], and only reently has it een shown that treating patients having advaned disease with platinum-ased regimens onfers a signifiant survival advantage over supportive are [2, 3]. Over the past few years, however, there have een several advanes in the development of ytotoxi therapy for NSCLC, leading to enthusiasm for treating patients with hemotherapy in oth the initial and seond-line settings. Among these advanes has een the demonstration of higher antitumor response rates, symptom palliation, improved management of adverse events and trends toward improved survival. The semisyntheti taxane, doetaxel is one new agent whih has shown promising ativity in NSCLC The taxane family of ompounds has a ommon 10- deaetyl aatin III struture. Doetaxel (Taxotere ; Rhône-Poulen Rorer; Collegeville, PA) is a syntheti produt produed y esterifiation of the side hain at C-13 of 10-deaetyl aatin III, a nonytotoxi preursor extrated from the needles of the European yew tree (Taxus aata) (Fig. 1) [4]. This hemisyntheti taxane shares a similar Figure 1. Chemial struture of doetaxel. This agent is distinguished from other taxoids y the syntheti lipophili side hain at C-13. Correspondene: James R. Rigas, M.D., Dartmouth-Hithok Medial Center, One Medial Center Drive, Leanon, New Hampshire, 03756-0001 USA. Telephone: 603-650-6344; Fax: 603-650-8287; e-mail: james.r.rigas@dartmouth.edu Aepted for puliation Marh 3, 1998. AlphaMed Press 1083-7159/98/$5.00/0 The Onologist 1998;3:86-93

Ornstein, Rigas 87 mehanism of ation with palitaxel, whih is unique among ytotoxi agents. These agents ind to the eta-suunit of tuulin and alter mirotuule depolymerization [4-6]. Although palitaxel and doetaxel operate on aner ells via a similar asi mehanism, they differ with respet to several important features, inluding poteny, ellular pharmaokinetis, ell yle effets, metaolism, and in vitro and in vivo antitumor ativity [4-8]. In the most asi assay of tuulin polymerization, doetaxel is approximately twie as potent an inhiitor of mirotuule depolymerization as palitaxel. Palitaxel appears to inhiit ells in the transition from G 2 to M phase of the ell yle, while maximum ytotoxiity of doetaxel ours in the S phase. Both agents are metaolized in the liver y the ytohrome P-450 (CYP) oxidases with hydroxylation of palitaxel y CYP 2C8 and doetaxel y CYP 3A4 [9]. The omparative ellular pharmaokinetis of the taxanes show differenes in ellular uptake and efflux favoring inreased intraellular exposure for doetaxel. Finally, in vitro ytotoxiity studies of doetaxel showed ativity against a road spetrum of murine and human ell lines, whih was 1.3- to 12-fold higher than the antitumor ativity of palitaxel in the same panel of ell lines [10]. Similar results were otained in studies of freshly explanted human tumor ells [11]. Initial interest in studying doetaxel in lung aner patients grew out of prelinial studies demonstrating antitumor ativity against human and murine lung aner ells [12]. Phase I studies reommended 100 mg/m 2, administered i.v. over one h every three weeks. In this paper, we review the four original phase II studies that have doumented the linial effiay of single-agent doetaxel in previously untreated patients with advaned NSCLC. In addition, we review the results of reported phase II trials of doetaxel in patients who have failed first-line treatment with platinum agents. Finally, we summarize our approah to treating patients with advaned NSCLC with doetaxel in the outpatient setting. PATIENTS AND METHODS Phase II Trials: Previously Untreated Patients Four phase II studies of doetaxel administered as a single agent at a dose of 100 mg/m 2 infused over one h every three weeks have een reported [13-16]. Colletively, these studies enrolled 160 hemotherapy-naive patients with advaned NSCLC in the United States and Europe. Study Design Study design was similar for the four trials, eah onfigured as an open-lael, phase II trial enrolling patients with unresetale loally advaned or metastati NSCLC who had reeived no prior hemotherapy. In three of the studies, idimensionally measurale disease was required for entry, ut measurale or evaluale disease was permitted for entry into the Memorial Sloan-Kettering Caner Center (MSKCC) trial, whih enrolled 29 patients [13]. Treatment Plan All eligile patients were to reeive doetaxel, 100 mg/m 2 via one-hour infusion every three weeks in the outpatient lini until tumor progression, unaeptale toxiity, or death ourred. No antiemetis, growth fators, or ortiosteroid premediations were administered initially in these trials. Later protools were revised to inlude a ourse of ortiosteroid premediation to redue the inidene and severity of infusion-related reations, fluid retention, and utaneous reations. Response Assessment Antitumor responses were assessed every three weeks y physial examination and hest radiograph and every six weeks y CT san. Measurale responses were onfirmed y follow-up CT san within four to six weeks. Response to therapy was defined y the status of measurale disease efore, during, and after treatment and was graded as a omplete response (CR), partial response (PR), or no response. Major response was defined as a CR or PR. All major responses were reviewed y a referene radiologist and an external review panel, and only onfirmed responses were inluded in the effiay analysis. Statistial Analysis Statistial analysis was similar in all four studies. Intent-totreat analysis was used to analyze the results, and patients with only evaluale disease were inluded as non-responders. Overall response rates and median and overall survival were reported. Phase II Trials: Previously Platinum-Treated Patients Results are availale for three phase II trials of doetaxel at 100 mg/m 2 every three weeks in patients with advaned NSCLC who have failed treatment with a platinum-ased regimen [16-18]. The original two studies enrolled a total of 88 patients and were onduted at the MD Anderson Caner Center (MDACC) (44 patients) and at the University of Texas Health Sienes Center at San Antonio (44 patients at three sites). The third U.S. study, reported y Gandara et al. [19, 20], was a multienter trial whih enrolled 80 previously platinum-treated patients. Study Design Study design was similar for all three trials. Eah study enrolled patients with unresetale loally advaned or

88 Taxotere in NSCLC metastati NSCLC who had een previously treated with not more than two platinum-ased hemotherapy regimens. Patients were deemed platinum-resistant if their tumors responded initially to a platinum regimen ut susequently progressed. Platinum-refratory patients were defined as those whose tumors showed no response to an initial platinum-ased regimen. Measurale disease and a Zurod performane status of 0-2 were required in eah study. Treatment Plan As in the studies with hemotherapy-naive patients, all eligile patients were to reeive doetaxel, 100 mg/m 2 via one-hour infusion every three weeks in the outpatient lini until tumor progression, unaeptale toxiity, or death ourred. Antiemetis and growth fators were not used, ut ortiosteroids and/or diphenhydramine were administered. Response Assessment Antitumor responses were assessed y physial examination and radiographi studies. Response to therapy was graded as a CR, PR, or no response. Statistial Analysis Intent-to-treat analyses were reported for the MDACC and San Antonio studies. The reent study y Gandara et al. reported response rates for evaluale patients. As in previous studies, overall response rates and median and overall survival were reported. RESULTS Phase II Trials: Previously Untreated Patients Patient Charateristis The harateristis of all 160 patients enrolled in the four trials are summarized in Tale 1. The majority of patients had a good pretreatment performane status (83% Zurod 0-1) despite the preponderane of metastati disease (81% stage IV). Approximately one-third of patients were women. The predominant histologi sutype was adenoarinoma, found in 54% of patients. Antitumor Response The median numer of yles of doetaxel administered was four (range, 1-33), and the median relative dose intensity was 96%. Effiay data are summarized in Tale 2. Patients were onsidered evaluale for response if they reeived at least one yle of doetaxel. The overall response rate (CR + PR) among the 136 evaluale patients was 31% (95% onfidene interval: 24%-39%). The overall response rate for the four studies in 160 patients using intent-to-treat analysis was 27%, with a median response duration of six months (range: 2-13+ months). Survival The median overall survival for all 160 patients was 9.2 months, and the one-year and two-year survival rates were Tale 1. Charateristis of 160 previously untreated patients with advaned NSCLC treated with doetaxel, 100 mg/m 2 every three weeks Charateristi Numer Perent Patients entered MDACC a 41 26% MSKCC 29 18% CTRC 48 30% EORTC d 42 26% Performane Status 0-1 (Zurod) 133 83% Disease Stage III 30 19% IV 130 81% Gender Male 110 69% Female 50 31% Histology Adenoarinoma 87 54% Squamous arinoma 36 23% Large ell arinoma 22 14% Unlassified NSCLC 15 9% Previous therapy Surgery 62 39% Radiotherapy 55 34% Chemotherapy 0 0% Note: Median patient age was 60 years (range, 38-79) a MD Anderson Caner Center. Memorial Sloan-Kettering Caner Center. Caner Therapy and Researh Center, San Antonio, Texas; patients arued at three sites. d European Organization for Researh and Treatment of Caner-Early Clinial Trials Group; patients arued at thirteen sites. Tale 2. Response to treatment with doetaxel, 100 mg/m 2 every three weeks in 160 previously untreated patients with advaned NSCLC* Overall response rate 27% (95% CI: 21%-35%) Median response duration 6 months (range, 2-13+ months) Median time to progression 3 months (range, 0-14+ months) Median numer of yles 4 (range, 1-33) Median relative dose intensity 96% *Intent-to-treat analysis. CI = onfidene interval.

Ornstein, Rigas 89 39% and 20%, respetively (Fig. 2). The results of the four individual trials are summarized in Tale 3 and inlude an overall analysis of responses in evaluale patients ompared with patients in the intent-to-treat group. Adverse Events Overall, doetaxel was well tolerated, although the majority of patients developed grade 3 or 4 neutropenia with at least one yle of therapy. The overall inidene of ferile neutropenia was 19%. Alopeia and fluid retention were the most ommon nonhematologi toxiities. Fluid retention as a ause for disontinuation in these studies ourred in 6% of patients. In patients who reeived ortiosteroid premediation, the inidene of disontinuation of therapy due to fluid retention was 0.9%. Other toxiities resulting in disontinuation inluded asthenia (4%), aute hypersensitivity reation (4%), and peripheral sensory neuropathy (3%). Other side effets, whih were generally mild, inluded nausea, vomiting, muositis, diarrhea, and dermatitis. Phase II Trials: Previously Platinum-Treated Patients Figure 2. Survival of 160 previously untreated patients with advaned non-smallell lung aner who reeived 100 mg/m 2 of doetaxel, infused over one h, one every three weeks. Median survival time of 9.2 months. One-year survival 39%. Patient Charateristis The harateristis of patients enrolled in the U.S. trials are summarized in Tale 4. As in the trials with previously untreated patients, the majority of patients with platinumrefratory or -resistant disease had metastati disease and a good pretreatment performane status. Median age was similar in the three U.S. trials. All patients had reeived prior hemotherapy, and the majority had reeived prior surgery or radiation therapy. Adenoarinoma was the predominant histology in the MDACC and San Antonio studies (65%). The MDACC and San Antonio trials inluded slightly more patients with platinum-resistant (58%) than with platinumrefratory (42%) disease, while the multienter study enrolled more platinum-refratory (36%) than -resistant (59%) patients. Tale 3. Response to treatment with doetaxel, 100 mg/m 2 every three weeks in 141 previously untreated patients with advaned, evaluale NSCLC Responses/ Overall Median response Median length evaluale response duration of survival patients rate (%) (months) (months) MDACC a 13/39 33 3.5 12 (95% CI: 18-48) MSKCC 11/28 39 5.3 6.3 (95% CI: 21-59) CTRC 11/34 32 7.0 7.1 (95% CI: 17-51) EORTC d 8/35 23 9.0 11 (95% CI: 12-41) Total assessale 31 patients (95% CI: 24-39 Intent-to-treat 27 6.2 9.2 (85% CI: 21-35) Areviation: CI= onfidene interval. a MD Anderson Caner Center. Memorial Sloan-Kettering Caner Center. Caner Therapy and Researh Center, San Antonio, Texas; patients arued at three sites. d European Organization for Researh and Treatment of Caner-Early Clinial Trials Group; patients d arued at thirteen sites. Antitumor Response Effiay for the three U.S. studies is summarized in Tale 5. Overall response rates ranged from 16%-22% in evaluale patients. The overall response rate for the 168 platinum-treated patients was 17% (95% onfidene interval: 11%-23%). Survival Median survival ranged from 6 to 11 months. The estimated one-year survival rate for the MDACC and San Antonio trials omined was 40%, whereas the estimated one-year survival in the multienter trial was 25%. Adverse Events Doetaxel was well tolerated y patients who had reeived prior hemotherapy, and the toxiity profile was similar to that for previously untreated patients. The dose-limiting toxiity was myelosuppression, with ferile neutropenia ourring in

90 Taxotere in NSCLC 14%-16% of patients overall. Nonhematologi toxiity was likewise similar to that seen in previously untreated patients, with the exeption of peripheral neuropathy, whih ourred somewhat more frequently in patients who had reeived prior platinum hemotherapy. The population pharmaokineti analysis onduted as part of these phase II studies revealed an Tale 4. Charateristis of 168 previously treated patients with NSCLC treated with doetaxel, 100 mg/m 2 every three weeks Charateristi Numer Perent Patients entered MDACC a 44 26% CTRC 44 26% Multienter 80 48% Performane status 0-1 (Zurod) 142 85% Gender Men 96 57% Women 72 43% Platinum response Resistant 80 48% Refratory 84 50% Unknown 4 2% Note: Median patient age for MDACC + CTRC was 60 years (range, 38-79); median patient age for multienter trial was 62 years (range, 34-79). a MD Anderson Caner Center. Caner Therapy and Researh Center, San Antonio, Texas; patients arued at three sites. UC Davis, U Chiago, UC San Diego, Rush U, Vanderilt U, Thomas Jefferson U, UT Southwestern, New England Medial Center, U Pittsurgh. Tale 5. Response to treatment with doetaxel, 100 mg/m 2 every three weeks in 168 previously treated patients with advaned NSCLC a Numer Overall Median response Median length of response duration of survival patients rate (%) (months) (months) MDACC 44 21 7.5 11 (95% CI: 10-35) CTRC 44 14 6.5 6 (95% CI: 5-27) Multienter d 80 16 NR 7 (95% CI: NR) Estimated one year survival: MDACC + CTRC 50% Multienter 25% Areviation: CI = onfidene interval; NR = not reported. a Intent-to-treat analysis. MD Anderson Caner Center. Caner Therapy and Researh Center, San Antonio, Texas; patients arued at three sites. d UC Davis, U Chiago, UC San Diego, Rush U, Vanderilt U, Thomas Jefferson U, UT Southwestern, New England Medial Center, U Pittsurgh. assoiation etween the learane of doetaxel and the adverse events, partiularly ferile neutropenia reports, in these patients [21]. Doetaxel learane was dereased in patients with hepati dysfuntion as manifested y serum transaminases 1.5 and alkaline phosphatase 2.5 the institutional upper limits of normal. The presene of liver metastases in the asene of elevated transaminases and alkaline phosphatase did not result in inreased toxiity. CONCLUSIONS In phase II trials in previously untreated patients, doetaxel at a dose of 100 mg/m 2 infused over one hour every three weeks ahieves an overall response rate of 27%, with a median survival of 9.2 months and an estimated one-year survival rate of 39%. The results with doetaxel as a single agent are enouraging, as they ompare very favoraly with platinum-ontaining omination regimens [22] (Tale 6) and are superior to est supportive are in this patient population [2, 3]. The three phase II studies in platinum-resistant and -refratory patients have demonstrated that doetaxel has signifiant ativity as seond-line therapy, with overall response rates ranging from 14% to 22% in intent-to-treat analysis. A retrospetive omparison with historial ontrols onduted at MDACC [23-25] suggests that response rates for doetaxel in the seond-line setting may translate into a linially meaningful survival advantage for patients with a good pretreatment performane status. FUTURE STUDIES IN NSCLC Doetaxel ontinues to e studied in order to define its optimum role in NSCLC. Two randomized phase III trials of doetaxel in platinum-resistant/refratory patients with good performane status are presently under way. One study ompares doetaxel at doses of 75 and 100 mg/m 2 administered over one h every three weeks with est supportive are. A seond study ompares doetaxel with a ontrol arm onsisting of single-agent vinoreline or ifosfamide. In addition, a randomized phase III trial omparing doetaxel with supportive are as initial therapy for NSCLC patients with good performane status is presently under way. Eah study has overall survival as

Ornstein, Rigas 91 Tale 6. Doetaxel versus omination hemotherapy versus supportive are as first-line treatment of advaned NSCLC Numer Overall Median response Median length Treatment of response duration of survival patients rate (%) (months) (months) Doetaxel, 100 mg/m 2 160 27 9.2 39 Vindesine/isplatin 200 19 7.4 26 Vinoreline/isplatin 206 30 9.2 37 Best supportive are 362 NA 4.0 12 Areviation: NA = not appliale. the primary endpoint, with response rate and quality of life as seondary endpoints. In previously untreated patients, doetaxel is urrently eing studied in phase II trials in omination with other hemotherapy agents, inluding isplatin [26-30], aroplatin, gemitaine [31], and vinoreline [32, 33]. Preliminary results are urrently availale for isplatin and vinoreline ominations. Response rates are very enouraging, ranging from 30% to 51% for the doetaxel/isplatin omination and 23% to 55% for the doetaxel/vinoreline omination. Results of a phase I study of doetaxel and onomitant thorai radiation have een reported in patients with advaned NSCLC requiring radiation as part of their treatment regimen [34]. Esophagitis and neutropenia were the dose-limiting adverse events, and the reommendation for a phase II dose and administration shedule is 20 mg/m 2 /week. Finally, studies using doetaxel as primary hemotherapy in the neoadjuvant setting for patients with early-stage NSCLC prior to surgial resetion or thorai radiation therapy are ongoing [35]. Advaned NSCLC Failed platinum-ontaining regimen results of reently pulished randomized trials [22, 37], single-agent vinoreline for patients with advaned disease is an exellent hoie for initial therapy. Singleagent vinoreline in this setting resulted in median and one-year survival rates similar to the older platinum-ontaining regimen (vindesine and isplatin). In general, we enourage patients in a position to reeive seond-line treatment to partiipate in a linial trial whenever possile. However, in ases where patients with good performane status are otherwise not andidates to partiipate in a study, we regard doetaxel as an exellent seond-line treatment option. Our protool (Fig. 3) administers doetaxel at a dose of 75 to 100 mg/m 2 via one-hour i.v. infusion every three weeks in the outpatient lini. We administer dexamethasone, 8 mg orally twie a day for five doses, eginning the day efore hemotherapy administration. This oral premediation redues the inidene and severity of infusionrelated reations, rash, and peripheral edema. We do not use growth fators, and most patients do not require antiemetis. We ontinue therapy in patients with stale or responding disease until disease progression, unaeptale toxiity, or patient request to stop therapy ours. Our experiene with adverse reations parallels that of the major trials. For those patients with a normal iliruin and hepati dysfuntion defined as transaminases 1.5 and alkaline phosphatase 2.5 upper limit of normal, the learane of PRACTICAL USE OF DOCETAXEL IN NSCLC Our approah to treating patients with stage IIIB (T4 pleural effusion) or IV NSCLC who have a good performane status is to use a platinum-ontaining regimen (e.g., vinoreline and isplatin) as the first-line therapy, onsistent with the reently pulished Amerian Soiety of Clinial Onology guidelines [36]. In light of the Alternate seond-line management PS 0-2 AST/ALT 1.5 normal and alkaline phosphatase 2.5 normal Adequate hematologi parameters NO YES Dexamethasone, 8 mg po id days -1, 0, 1 Doetaxel, 100 mg/m 2 over 1 h on day 0 in outpatient lini Repeat every 3 weeks in stale or responding disease Peripheral edema Hypersensitivity Ferile neutorpenia Severe fatigue Peripheral neuropathy Figure 3. Treatment algorithm for NSCLC patients after failure of platinum-ased hemotherapy. Diuresis, supportive measures 25% dose redution

92 Taxotere in NSCLC doetaxel will e delayed, and these patients are at greater risk for ferile neutropenia. We do not administer doetaxel to patients in whom there is evidene of hyperiliruinemia. Studies are under way to define the safe dose and shedule of doetaxel for patients with hepati dysfuntion. We routinely administer doetaxel safely to patients with liver metastases whose liver enzymes are within these parameters. In patients who develop ferile neutropenia, we institute a 25% dose redution with susequent yles. Other adverse events for whih we dose redue are peripheral neuropathy and severe fatigue. Infusion-related reations and peripheral edema develop in a very small proportion of patients who reeive appropriate dexamethasone treatment and are readily managed with standard supportive measures in the outpatient lini. Speifially, infusion-related reations are often related to the infusion rate and may e minimized y slower initial infusion. A short ourse of diuretis, dose redution, and/or longer treatment intervals (every four to five weeks) are useful for managing peripheral edema, should it develop. Overall, we have found that doetaxel is an effetive seond-line treatment for patients with NSCLC having a good performane status after platinum-ased primary therapy. Doetaxel is easily delivered in the outpatient setting, and the majority of patients find the toxiity profile aeptale. SUMMARY The outlook for patients with advaned NSCLC has improved over the past few years with the development of more effetive hemotherapy agents. Previously, treating NSCLC patients with seond-line hemotherapy after first-line platinum therapy had failed was onsidered hopeless. Currently, however, a signifiant proportion of patients an look forward to improved survival with seond-line treatment. The phase II data for doetaxel in advaned NSCLC are very enouraging for oth hemotherapy-naive and pretreated patients. The response rates for single-agent doetaxel at 100 mg/m 2 every three weeks in previously untreated patients are omparale to response rates for platinum-ased ominations and are superior to those reported for est supportive are (Tale 6). In platinum failures, doetaxel shows signifiant antitumor ativity, whih appears to translate into linially meaningful survival. Cominations of doetaxel and newer agents show signifiant promise in initial studies. Although the optimum role for doetaxel in NSCLC remains to e eluidated, given the enouraging phase II results in platinum failures, we regard doetaxel as a reasonale hemotherapeuti option as initial and seond-line therapy for patients with a good performane status. It has demonstrated effiay with an aeptale toxiity profile and is onveniently administered in the outpatient setting. ACKNOWLEDGMENTS The authors do not have any finanial interests and have not reeived any finanial support for the preparation of this manusript. The authors have reeived grant support for linial researh from the Hithok Foundation, Amerian Caner Soiety, Janssen Pharmaeutia, Ligand Pharmaeutial, Bristol-Myers Squi, Rhône-Poulen Rorer, and Ortho Bioteh. Presented in part at the Network for Onology Communiation and Researh meeting in Boa Raton, Florida, Feruary 21, 1997. REFERENCES 1 Parker SL, Tong T, Bolden S et al. Caner statistis, 1997. CA: A Caner Journal for Cliniians 1997;47:5-27. 2 Chemotherapy in non-small ell lung aner: a meta-analysis using updated data on individual patients from 52 randomised linial trials. Non-small Cell Lung Caner Collaorative Group (Comments). Br Med J 1995;311:899-909. 3 Cullen MH, Woodroffe CM, Billingham LJ et al. Mitomyin, ifosfamide and isplatin (MIC) in non-small ell lung aner (NSCLC): 2. Results of a randomised trial in patients with extensive disease. Lung Caner 1997;18:5a. 4 Gueritte-Voegelein F, Guenard D, Lavelle F et al. Relationships etween the struture of taxol analogues and their antimitoti ativity. J Med Chem 1991;34:992-998. 5 Ringel I, Horwitz SB. Studies with RP 56976 (taxotere): a semisyntheti analogue of taxol. J Natl Caner Inst 1991;83:288-291. 6 Diaz JF, Andreu JM. Assemly of purified GDP-tuulin into mirotuules indued y taxol and taxotere: reversiility, ligand stoihiometry, and ompetition. Biohemistry 1993;32:2747-2755. 7 Von Hoff DD. The taxoids: same roots, different drugs. Semin Onol 1997;24(suppl 13):10-13. 8 Bruno R, Sanderink GJ. Pharmaokinetis and metaolism of Taxotere (doetaxel). Caner Surv 1993;17:305-313. 9 Dorr RT. Pharmaology of the taxanes. Pharmaotherapy 1997;17:96S-104S. 10 Lavelle F, Bissery MC, Comeau C et al. Prelinial evaluation of doetaxel (Taxotere). Semin Onol 1995;22(suppl 4):3-16. 11 Vogel M, Hilsenek SG, Depenrok H et al. Prelinial ativity of taxotere (RP 56976, NSC 628503) against freshly explanted lonogeni human tumour ells: omparison with taxol and onventional antineoplasti agents. Eur J Caner 1993;29A:2009-2014. 12 Riou JF, Naudin A, Lavelle F. Effets of Taxotere on murine and human tumor ell lines. Biohem Biophys Res Comm 1992;187:164-170.

Ornstein, Rigas 93 13 Franis P, Rigas JR, Kris MG et al. Phase II trial of doetaxel in patients with stage III and IV non-small-ell lung aner. J Clin Onol 1994;12:1232-1237. 14 Fossella FV, Lee JS, Murphy WK et al. Phase II study of doetaxel for reurrent or metastati non-small ell lung aner. J Clin Onol 1994;12:1238-1244. 15 Cerny T, Kaplan S, Pavlidis N et al. Doetaxel (Taxotere) is ative in non small ell lung aner: a phase II trial of the EORTC Early Clinial Trials Group (ECTG). Br J Caner 1994;70:384-387. 16 Burris H, Ekhardt J, Fields S et al. Phase II trial of taxotere in patients with non-small ell lung aner. Pro Am So Clin Onol 1993;12:335a. 17 Fossella FV, Lee JS, Shin DM et al. Phase II study of doetaxel for advaned or metastati platinum-refatory non-small ell lung aner. J Clin Onol 1995;13:645-651. 18 Rigas JR. Doetaxel in stage III and IV non-small ell lung aner. Eur J Caner 1995;31A(suppl 4):S18-S20. 19 Gandara DR, Vokes E, Green M et al. Doetaxel (Taxotere) in platinum-treated non-small ell lung aner (NSCLC): onfirmation of prolonged survival in a multienter trial. Pro Am So Clin Onol 1997;16:454a. 20 Gandara DR, Vokes E, Green M et al. Multienter trial of doetaxel (Taxotere) in platinum-treated non-small ell lung aner (NSCLC): onfirmation of prolonged survival. Lung Caner 1997;18:21a. 21 Bruno R, Hille D, Riva A et al. Population pharmaokinetis/pharmaodynamis of doetaxel in phase II studies in patients with aner. J Clin Onol 1998;16:187-196. 22 Le Chevalier T, Brisgand D, Douillard JY et al. Randomized study of vinoreline and isplatin versus vindesine and isplatin versus vinoreline alone in advaned non-small-ell lung aner: results of a European multienter trial inluding 612 patients. J Clin Onol 1994;12:360-367. 23 Fossella FV, Lee JS, Shin DM et al. Taxotere (Doetaxel: DTXL), an ative agent for platinum-refratory non-small ell lung aner (NSCLC): preliminary report of a phase II study. Pro Am So Clin Onol 1994;13:336a. 24 Fossella FV, Lee JS, Berille J et al. Summary of phase II data of doetaxel (Taxotere), an ative agent in the first- and seondline treatment of advaned non-small ell lung aner. Semin Onol 1995;22(suppl 4):22-29. 25 Fossella FV, Lee JS, Hong WK. Management strategies for reurrent non-small ell lung aner. Semin Onol 1997;24:455-462. 26 Cole JT, Gralla RJ, Marques CB et al. Phase I-II study of isplatin and doetaxel (Taxotere) in non-small ell lung aner. Pro Am So Clin Onol 1995;14:357a. 27 Le Chevalier T, Belli L, Monnier A et al. Phase II study of doetaxel (Taxotere) and isplatin in advaned non small ell lung aner: an interim analysis. Pro Am So Clin Onol 1995;14:350a. 28 Mattson K, Saarinen A, Jekunen A. Comination treatment with doetaxel (Taxotere) and platinum ompounds for non-small ell lung aner. Semin Onol 1997;24(suppl 14):5-8. 29 Millward MJ, Zalerg J, Bishop JF et al. Phase I trial of doetaxel and isplatin in previously untreated patients with advaned non-small ell lung aner J Clin Onol 1997;15:750-758. 30 Pronk LC, Shellens JHM, Planting AST et al. Phase I and pharmaologi study of doetaxel and isplatin in patients with advaned solid tumors. J Clin Onol 1997;15:1071-1079. 31 Georgoulias V, Kourousis C, Androulakis N et al. Doetaxel (Taxotere) and gemitaine in the treatment of non-small ell lung aner: preliminary results. Semin Onol 1997;24(suppl 14):22-25. 32 Georgoulias V, Kourousis C, Androulakis N et al. Doetaxel (Taxotere) and vinoreline in the treatment of non-small ell lung aner. Semin Onol 1997;24(suppl 14):9-14. 33 Miller VA. Doetaxel (Taxotere) and vinoreline in the treatment of advaned non-small ell lung aner: preliminary results of a phase I/II trial. Semin Onol 1997;24(suppl 14):15-17. 34 Mauer AM, Master GA, Haraf DJ et al. Phase I study of doetaxel with onomitant thorai radiation therapy. J Clin Onol 1998;16:159-164. 35 Harper P. The role of doetaxel (Taxotere) as a single agent or in omination efore loal treatment of non-small ell lung aner. Semin Onol 1997;24(suppl 14):30-32. 36 Clinial pratie guidelines for the treatment of unresetale non-small-ell lung aner. Adopted on May 16, 1997 y the Amerian Soiety of Clinial Onology. J Clin Onol 1997;15:2996-3018. 37 Crawford J, O Rourke M, Shiller JH et al. Randomized trial of vinoreline ompared with fluorourail plus leuovorin in patients with stage IV non-small-ell lung aner. J Clin Onol 1996;14:2774-2784.