- Email: [email protected]
Chemotherapy for advanced non-small cell lung cancer (NSCLC)
Lung Cancer 38 (2002) S47 /S50 www.elsevier.com/locate/lungcan
Chemotherapy for advanced non-small cell lung cancer (NSCLC) Christian Manegold Department of Internal Medicine/Medical Oncology, Thoraxklinik-Heidelberg gGmbH, Amalienstraße 5, 69129 Heidelberg, Germany
1. Introduction Chemotherapy’s role in the treatment of NSCLC has increased greatly over the last years. One of the main reasons for chemotherapy’s increased acceptance has been the development of new substances with unique mechanisms of action and high single-agent activity, combined with favourable toxicity. Cytotoxic drugs are currently used as single agents or in combination for first- and second-line therapy to achieve palliation in locally advanced and metastatic disease.
2. Platin-based combination chemotherapy According to the ASCO-Guidelines the following factors should be taken into consideration, when a decision about chemotherapy needs to be made for advanced NSCLC [1]: / Chemotherapy is appropriate for selected patients and prolongs survival in patients with good performance status. / Chemotherapy should be platinum-based, initiated while the patient has good performance status and should not exceed eight treatment cycles. The current recommendations stem from randomized studies which compared chemotherapy to best supportive care (BSC). These studies revealed a moderate but statistically significant survival advantage for the patients receiving chemotherapy. These positive results have recently been confirmed for the combination Mitomycin C/Ifosfamide/Cisplatin [2]. The clinical avail-
ability of new agents such as Docetaxel and Paclitaxel, Vinorelbine, Gemcitabine and the topoisemase-I-inhibitors increase the chemotherapeutic options for platinum-based chemotherapy considerably. Randomized trials comparing regimens with new combinations to older, platinum-containing regimens [7 /11] or to singleagent therapy with Cisplatin [3 /6]underline the greater possibilities which the new agents can offer. The difficulty of choosing the most appropriate chemotherapy became especially clear when oncologists were confronted with the results of the ECOG 1594study comparing Cisplatin/24-h Paclitaxel to Cisplatin/ Docetaxel, Cisplatin/Gemcitabine or Carboplatin/3-h Paclitaxel [12]. Not only did ECOG 1594 show no survival differences among the treatment arms; this trial also documented disappointingly low response rates for platinum-containing regimens in advanced non-small cell lung cancer. At this point it is, therefore, impossible to state conclusively what role the various platinum-containing regimens will play in the future. However, ECOG 1594 also made clear that Gemcitabine/Cisplatin is one of the effective combinations. Furthermore, there are a number of reasons why a clinician, would tend to choose this combination for advanced NSCLC patients in good clinical condition. Not only are according to ECOG 1594 the response rate, median survival, time to progression and 1-year survival rate as good or significantly better than the other combinations, above all it is the practicability and tolerability of the 3-week schedule that makes Gemcitabine/Cisplatin appear to be one of the most reasonable standard-platinum-based chemotherapies [13].
3. Platinum-free combination chemotherapy Tel.: /49-6221-396-283; fax: /49-6221-396-436 E-mail address: [email protected] (C. Manegold).
Given the results from ECOG 1594, one of the pertinent questions would now seem to be whether,
0169-5002/02/$ - see front matter # 2002 Published by Elsevier Science Ireland Ltd. PII: S 0 1 6 9 - 5 0 0 2 ( 0 2 ) 0 0 2 6 8 - 4
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C. Manegold / Lung Cancer 38 (2002) S47 /S50
and in what form, a Cisplatin-free combination therapy with new agents such as Docetaxel/Gemcitabine, Paclitaxel/Gemcitabine, or Vinorelbine/Gemcitabine should replace the platinum-based regimens currently recommended. There is hope that EORTC 08975, a recently completed three-arm randomized study which enrolled about 500 patients, will answer this question. EORTC 08975 compared two popular Cisplatin-based regimens (Cisplatin/Paclitaxel; Cisplatin/Gemcitabine) to the Cisplatin-free combination Gemcitabine/Paclitaxel in patients having stage IIIB or IV NSCLC and having a performance status of 0/2. A strong indication that platinum-free combinations in terms of survival and toxicity are not inferior to platinum-based regimens comes from two randomized Greek two-arm trials which included about 300 patients each [14,15].
4. Single agent chemotherapy Already it has become clear that performance status 2 patients do not benefit from platinum-containing regimens [16 /19]. Results from 1991 have recently been confirmed, which showed that PS-2 patients gained a significantly lower median survival time and a lower 1year survival rate. For these patients and for elderly patients, singleagent therapy using the new drugs may be the more attractive chemotherapeutic option for palliation because of their high efficacy and lower toxicity. For Gemcitabine this promising single-agent activity, combined with favourable toxicity, has been confirmed in two randomized phase II studies showing a response rate of about 20% and a median survival of about 8 months [20,21]. Promising results for single-agent therapy in patients with advanced NSCLC were also obtained in our recently completed phase II study, in which patients were randomized to either first-line single-agent Gemcitabine or single-agent Docetaxel. Then, in case of tumor progression during or after completion of first-line therapy, patients received second-line therapy with the corresponding alternative agent [22]. In patients receiving Gemcitabine first-line, the median overall survival was 8 months and the 1-year survival rate 31%. Single-agent therapy is also superior to BSC. This superiority has been documented for Vinorelbine, Paclitaxel, Docetaxel and Gemcitabine [23 /26]. Results indicate a significantly longer overall survival and a statistically significant improvement of clinical symptoms [23,25]. Results have also demonstated Gemcitabine’s clinical benefit [26], whereas 79% of the patients receiving only BSC required palliative radiotherapy, only 49% needed radiotherapy in the Gemcitabinearm. The mediane time to radiotherapy was 29 weeks
for Gemcitabine/BSC and about 4 weeks for BSC alone. Patients on Gemcitabine/BSC reported better quality of life and reduced disease related symptoms compared with those on BSC only. The response rate for Gemcitabine was 19%.
5. Chemotherapy for the elderly patient Certainly the availability of new agents has increased the chemotherapeutic options in general, but the options have increased even more for elderly Patients having advanced NSCLC. Vinorelbine was the first new agent tested in randomized trials in the elderly population. The ELVIS-trial found a statistically significant survival advantage for patients receiving Vinorelbine and clearly established the potential benefit of single-agent therapy for elderly patients [23]. A retrospective review focusing on patients over 65 enrolled in four phase II trials has recently been completed using single-agent Gemcitabine [27]. The results showed Gemcitabine proved to be both active and well tolerated in elderly patients. No differences could be seen in response rates, response duration, median survival and 1-year survival rates between the elderly and the younger patients. The question of whether or not the addition of Gemcitabine to Vinorelbine improves treatment outcome in the elderly has also recently been addressed in a randomized study [28]. Interim analysis data from 120 patients showed that the combination is superior to single-agent Vinorelbine, with a statistically significant longer median survival time and a significantly higher 1-year survival rate. The combination was also associated with a clear delay in symptom and quality of life deterioration.
6. Second line chemotherapy As chemotherapy gains wider acceptance for advanced and early stage NSCLC, the need for effective second-line chemotherapy is also growing. Over the last years there have been several trials which strongly indicate that some of these new drugs are not only effective in first-line use, but also show considerable activity when used for second-line therapy [29,30]. On the basis of two randomised phase III studies, Docetaxel has recently become the first cytotoxic agent to be registered for second-line therapy in NSCLC [31,32]. Both of these studies demonstrated that 75 mg/m2 Docetaxel given every 3 weeks significantly prolonged survival and that it offered clinically meaningful benefits to patients having acceptable performance status, when compared to BSC or to single-agent Vinorelbine or Ifosfamide. Promising results for second-line singleagent Gemcitabine have also been reported from a large
C. Manegold / Lung Cancer 38 (2002) S47 /S50
phase II trial, in which about 19% of the patients achieved a partial response and the median duration of response was about 7 months [33]. The high efficacy combined with favourable toxicity as reported here would suggest that Gemcitabine could be another option as a second-line treatment for patients showing either a previous response to or stable disease after platinum-based first-line therapy.
[15]
[16]
[17]
References [1] American Society of Clinical Oncology: clinical practice guidelines for the treatment of unresectable non-small cell lung cancer, J Clin Oncol 1997;15: 2996 /3018. [2] Cullen MH, Billingham LJ, Woodroffe CM, et al. Mitomycin, Ifosfamide, and Cisplatin in unresectable non-small cell lung cancer. Effects on survival and quality of life. J Clin Oncol 1999;17:3188 /94. [3] Wozniak AJ, Crowley JJ, Balcerzak SP, et al. Randomized trial comparing Cisplatin with Cisplatin plus Vinorelbine in the treatment of advanced non-small cell lung cancer. A Southwest Oncology Group study. J Clin Oncol 1998;16:2459 /65. [4] Sandler AB, Nemunaitis J, Denham C, et al. Phase III trial of Gemcitabine plus Cisplatin versus Cisplatin alone in patients with locally advanced or metastatic non-small cell lung cancer. J Clin Oncol 2000;18:122 /30. [5] Gatzemeier U, von Pawel J, Gottfried M, et al. Phase III comparative study of high-dose Cisplatin versus a combination of Paclitaxel and Cisplatin in patients with advanced non-small cell lung cancer. J Clin Oncol 2000;18:3390 /9. [6] Von Pawel J, von Roemeling R, Gatzemeier U, et al. Tirapazamine plus Cisplatin versus Cisplatin in advanced non-small cell lung cancer: a report of the international CATAPULT l studygroup. J Clin Oncol 2000;18:1351 /9. [7] Le Chevalier T, Brisgand D, Douillard JY, et al. Randomized study of Vinorelbine and Cisplatin versus Vindesine and Cisplatin versus Vinorelbine alone in non-small cell lung cancer: results of an European multicentertrial including 612 patientsm. J Clin Oncol 1994;12:360 /7. [8] Bonomi P, Kim K, Chang A, et al. Phase III trial comparing Etoposide/Cisplatin versus Taxol with Cisplatin-G-CSF versus Taxol/Cisplatin in advanced non-small cell lung cancer. Proc ASCO 1996;15:382A(abstr. 1145). [9] Crino L, Scagliotti GV, Ricci S, et al. Gemcitabine/Cisplatin versus Mitomycin, Ifosfamide, and Cisplatin in advanced nonsmall cell lung cancer: a randomized phase III study of the Italian lung cancer project. J Clin Oncol 1999;17:3522 /30. [10] Belani CP, Natale RB, Lee JS, et al. Randomized phase III trial comparing Cisplatin/Etoposide versus Carboplatin/Paclitaxel in advanced and metastatic non-small cell lung cancer. Proc ASCO 1998;17:455a(abstr. 1751). [11] Cardenal F, Lopez-Cabrerizo MP, Anton A, et al. Randomized phase III study of Gemcitabine/Cisplatin versus Etoposide/ Cisplatin in the treatment of locally advanced or metastatic non-small cell lung cancer. J Clin Oncol 1999;17(1):12 /8. [12] Schiller JH, Harrington D, Sandler A, et al. A randomized phase III trial of four chemotherapy regiments in advanced non-small cell lung cancer. Proc ASCO 2000;19:1a(abstr. 2). [13] Manegold C, Zatloukal P, Krejcy K, Blatter J, et al. Gemcitabine in non-small cell lung cancer (NSCLC). Investigational New Drugs 2000;18(1):29 /42. [14] Georgoulias V, Papadakis E, Alexopoulos A, et al. Docetaxel plus Cisplatin versus Docetaxel plus Gemcitabine chemotherapy in
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
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advanced non-small cell lung cancer: a preliminary analyses of a multicenter randomized phase II trial. Proc ASCO 1999;18:461a(abst. 1778). Kosmides PA, Bacoyiannis C, Mylonakis N, et al. A randomised phase III trial of Paclitaxel plus Carboplatin versus Paclitaxel plus Gemcitabine in advanced non-small cell lung cancer. A preliminary analyses. Proc ASCO 2000;19:488a(abstr. 1908). Albain KS, Crowley JJ, LeBlanc M, Livingston RB. Survival determinants in extensive stage non-small cell lung cancer: The Southwest Oncology Group experience. J Clin Oncol 1991;9:1618 /26. Jiroutek M, Johnson D, Blum R, et al. Prognostic factus in advanced non-small cell lung cancer: analysis of Eastern Cooperative Oncology Group (ECOG) trials from 1981 /1992. Proc ASCO 1998;17:461a(abstr. 1774). Johnson DH, Zhu J, Schiller J, et al. E 1594 */A randomized phase III trial in metatstatic non-small cell lung cancer-outcome of PS-ll-patients: an Eastern Cooperative Oncology Group (ECOG) trial. Proc ASCO 1999;18:461a(abstr. 1779). Sorea JC, Douillard JY, Pujol JL, et al. Prognostic analyses of survival in the European randomized trial comparing Navelbine versus Navelbine/Cisplatin versus Vindesine/Cisplatin. Proc ASCO 1999;18(491a)(abstr. 1893). Perng RP, Chen YM, Ming-Liu J, et al. Gemcitabine versus the combination of Cisplatin and Etoposide m patients with inoperable non-small cell lung cancer in a phase II randomized study. J Clin Oncol 1997;15:2097 /101. Manegold C, Bergman B, Chemaissani A, et al. Single-agent Gemcitabine versus Cisplatin /Etoposide: early results of a randomised phase II study in locally advanced or metastatic non-small cell lung cancer. Ann Oncol 1997;8:525 /9. Manegold C, Pilz L, Koschel G, et al. Gemcitabine followed by 2nd line Docetaxel is feasible in advanced NSCLC: results from a randomised Phase II study. Proc ASCO 2000;19:549a(abstr. 2166). The elderly lung cancer Vinorelbine Italian Study Group, Gridelli C. Effects of Vinorelbine on quality of life and survival in elderly patients with advanced non-small cell lung cancer. J NCI 1999;91(1):66 /72. Thatcher N, Ranson M, Andersen H, et al. Phase III study of Paclitaxel versus best supportive care in inoperable non-small cell lung cancer. Ann Oncol 1998;9(Suppl. 4):1(abstr. 4.0). 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. Lung Cancer 2000;27:145 /58. Andersen H, Hopwood P, Stephens RJ, et al. Phase III study of Gemcitabine plus best supportive care (BSC) versus BSC in an inoperable non-small cell lung cancer a randomized trial with quality of life as the primary outcome. Br J Cancer 2000;83:447 / 53. Shepherd FA, Abratt RP, Andersen H, et al. Gemcetabine in the treatment of elderly patients with advanced non-small cell lung cancer. Sem Oncol 1997;24(Suppl. 7):50 /5. Frasci G, Lorusso V, Panza N, et al. Gemticabine plus Vinorelbine versus Vinorelbine alone in elderly patients with advanced non-small cell lung cancer. J Clin Oncol 2000;18:2529 /36. Garcia-Giron C, Rodriguez JC, de las Heras Garcia B, et al. Second-line chemotherapy in non-small cell lung cancer. Rev Oncologia 1999;1(Suppl. 2):75 /83. Manegold C, Drings P. Second-line Chemotherapie mit Docetaxel (Taxotere) beim nichtkleinzelligen Bronchialkarzinom(NSCLC). Onkologe 2000;6:1098 /106. Shepherd FA, Dancey J, Ramlau R, et al. Prospective randomized trial of Docetaxel versus best supportive care in patients with non-
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small cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 2000;18:2095 /103. [32] The TAX 320 Non-Small Cell Lung Cancer Study Group, Fossella FV, DeVore R, Kerr RN, et al. Randomized phase II trial of Docetaxel versus Vinorelbine of Ifosfamide in patients with advanced non-small cell lung cancer previously treated with
platinum-containing chemotherapy regimens. J Clin Oncol 2000;18:2354 /62. [33] Crino L, Mosconi AM, Scagliotti G, et al. Gemcitabine as secondline treatment for advanced non-small cell lung cancer: a phase II trial. J Clin Oncol 1999;17:2081 /5.
Chemotherapy for advanced non-small cell lung cancer (NSCLC) Christian Manegold Department of Internal Medicine/Medical Oncology, Thoraxklinik-Heidelberg gGmbH, Amalienstraße 5, 69129 Heidelberg, Germany
1. Introduction Chemotherapy’s role in the treatment of NSCLC has increased greatly over the last years. One of the main reasons for chemotherapy’s increased acceptance has been the development of new substances with unique mechanisms of action and high single-agent activity, combined with favourable toxicity. Cytotoxic drugs are currently used as single agents or in combination for first- and second-line therapy to achieve palliation in locally advanced and metastatic disease.
2. Platin-based combination chemotherapy According to the ASCO-Guidelines the following factors should be taken into consideration, when a decision about chemotherapy needs to be made for advanced NSCLC [1]: / Chemotherapy is appropriate for selected patients and prolongs survival in patients with good performance status. / Chemotherapy should be platinum-based, initiated while the patient has good performance status and should not exceed eight treatment cycles. The current recommendations stem from randomized studies which compared chemotherapy to best supportive care (BSC). These studies revealed a moderate but statistically significant survival advantage for the patients receiving chemotherapy. These positive results have recently been confirmed for the combination Mitomycin C/Ifosfamide/Cisplatin [2]. The clinical avail-
ability of new agents such as Docetaxel and Paclitaxel, Vinorelbine, Gemcitabine and the topoisemase-I-inhibitors increase the chemotherapeutic options for platinum-based chemotherapy considerably. Randomized trials comparing regimens with new combinations to older, platinum-containing regimens [7 /11] or to singleagent therapy with Cisplatin [3 /6]underline the greater possibilities which the new agents can offer. The difficulty of choosing the most appropriate chemotherapy became especially clear when oncologists were confronted with the results of the ECOG 1594study comparing Cisplatin/24-h Paclitaxel to Cisplatin/ Docetaxel, Cisplatin/Gemcitabine or Carboplatin/3-h Paclitaxel [12]. Not only did ECOG 1594 show no survival differences among the treatment arms; this trial also documented disappointingly low response rates for platinum-containing regimens in advanced non-small cell lung cancer. At this point it is, therefore, impossible to state conclusively what role the various platinum-containing regimens will play in the future. However, ECOG 1594 also made clear that Gemcitabine/Cisplatin is one of the effective combinations. Furthermore, there are a number of reasons why a clinician, would tend to choose this combination for advanced NSCLC patients in good clinical condition. Not only are according to ECOG 1594 the response rate, median survival, time to progression and 1-year survival rate as good or significantly better than the other combinations, above all it is the practicability and tolerability of the 3-week schedule that makes Gemcitabine/Cisplatin appear to be one of the most reasonable standard-platinum-based chemotherapies [13].
3. Platinum-free combination chemotherapy Tel.: /49-6221-396-283; fax: /49-6221-396-436 E-mail address: [email protected] (C. Manegold).
Given the results from ECOG 1594, one of the pertinent questions would now seem to be whether,
0169-5002/02/$ - see front matter # 2002 Published by Elsevier Science Ireland Ltd. PII: S 0 1 6 9 - 5 0 0 2 ( 0 2 ) 0 0 2 6 8 - 4
S48
C. Manegold / Lung Cancer 38 (2002) S47 /S50
and in what form, a Cisplatin-free combination therapy with new agents such as Docetaxel/Gemcitabine, Paclitaxel/Gemcitabine, or Vinorelbine/Gemcitabine should replace the platinum-based regimens currently recommended. There is hope that EORTC 08975, a recently completed three-arm randomized study which enrolled about 500 patients, will answer this question. EORTC 08975 compared two popular Cisplatin-based regimens (Cisplatin/Paclitaxel; Cisplatin/Gemcitabine) to the Cisplatin-free combination Gemcitabine/Paclitaxel in patients having stage IIIB or IV NSCLC and having a performance status of 0/2. A strong indication that platinum-free combinations in terms of survival and toxicity are not inferior to platinum-based regimens comes from two randomized Greek two-arm trials which included about 300 patients each [14,15].
4. Single agent chemotherapy Already it has become clear that performance status 2 patients do not benefit from platinum-containing regimens [16 /19]. Results from 1991 have recently been confirmed, which showed that PS-2 patients gained a significantly lower median survival time and a lower 1year survival rate. For these patients and for elderly patients, singleagent therapy using the new drugs may be the more attractive chemotherapeutic option for palliation because of their high efficacy and lower toxicity. For Gemcitabine this promising single-agent activity, combined with favourable toxicity, has been confirmed in two randomized phase II studies showing a response rate of about 20% and a median survival of about 8 months [20,21]. Promising results for single-agent therapy in patients with advanced NSCLC were also obtained in our recently completed phase II study, in which patients were randomized to either first-line single-agent Gemcitabine or single-agent Docetaxel. Then, in case of tumor progression during or after completion of first-line therapy, patients received second-line therapy with the corresponding alternative agent [22]. In patients receiving Gemcitabine first-line, the median overall survival was 8 months and the 1-year survival rate 31%. Single-agent therapy is also superior to BSC. This superiority has been documented for Vinorelbine, Paclitaxel, Docetaxel and Gemcitabine [23 /26]. Results indicate a significantly longer overall survival and a statistically significant improvement of clinical symptoms [23,25]. Results have also demonstated Gemcitabine’s clinical benefit [26], whereas 79% of the patients receiving only BSC required palliative radiotherapy, only 49% needed radiotherapy in the Gemcitabinearm. The mediane time to radiotherapy was 29 weeks
for Gemcitabine/BSC and about 4 weeks for BSC alone. Patients on Gemcitabine/BSC reported better quality of life and reduced disease related symptoms compared with those on BSC only. The response rate for Gemcitabine was 19%.
5. Chemotherapy for the elderly patient Certainly the availability of new agents has increased the chemotherapeutic options in general, but the options have increased even more for elderly Patients having advanced NSCLC. Vinorelbine was the first new agent tested in randomized trials in the elderly population. The ELVIS-trial found a statistically significant survival advantage for patients receiving Vinorelbine and clearly established the potential benefit of single-agent therapy for elderly patients [23]. A retrospective review focusing on patients over 65 enrolled in four phase II trials has recently been completed using single-agent Gemcitabine [27]. The results showed Gemcitabine proved to be both active and well tolerated in elderly patients. No differences could be seen in response rates, response duration, median survival and 1-year survival rates between the elderly and the younger patients. The question of whether or not the addition of Gemcitabine to Vinorelbine improves treatment outcome in the elderly has also recently been addressed in a randomized study [28]. Interim analysis data from 120 patients showed that the combination is superior to single-agent Vinorelbine, with a statistically significant longer median survival time and a significantly higher 1-year survival rate. The combination was also associated with a clear delay in symptom and quality of life deterioration.
6. Second line chemotherapy As chemotherapy gains wider acceptance for advanced and early stage NSCLC, the need for effective second-line chemotherapy is also growing. Over the last years there have been several trials which strongly indicate that some of these new drugs are not only effective in first-line use, but also show considerable activity when used for second-line therapy [29,30]. On the basis of two randomised phase III studies, Docetaxel has recently become the first cytotoxic agent to be registered for second-line therapy in NSCLC [31,32]. Both of these studies demonstrated that 75 mg/m2 Docetaxel given every 3 weeks significantly prolonged survival and that it offered clinically meaningful benefits to patients having acceptable performance status, when compared to BSC or to single-agent Vinorelbine or Ifosfamide. Promising results for second-line singleagent Gemcitabine have also been reported from a large
C. Manegold / Lung Cancer 38 (2002) S47 /S50
phase II trial, in which about 19% of the patients achieved a partial response and the median duration of response was about 7 months [33]. The high efficacy combined with favourable toxicity as reported here would suggest that Gemcitabine could be another option as a second-line treatment for patients showing either a previous response to or stable disease after platinum-based first-line therapy.
[15]
[16]
[17]
References [1] American Society of Clinical Oncology: clinical practice guidelines for the treatment of unresectable non-small cell lung cancer, J Clin Oncol 1997;15: 2996 /3018. [2] Cullen MH, Billingham LJ, Woodroffe CM, et al. Mitomycin, Ifosfamide, and Cisplatin in unresectable non-small cell lung cancer. Effects on survival and quality of life. J Clin Oncol 1999;17:3188 /94. [3] Wozniak AJ, Crowley JJ, Balcerzak SP, et al. Randomized trial comparing Cisplatin with Cisplatin plus Vinorelbine in the treatment of advanced non-small cell lung cancer. A Southwest Oncology Group study. J Clin Oncol 1998;16:2459 /65. [4] Sandler AB, Nemunaitis J, Denham C, et al. Phase III trial of Gemcitabine plus Cisplatin versus Cisplatin alone in patients with locally advanced or metastatic non-small cell lung cancer. J Clin Oncol 2000;18:122 /30. [5] Gatzemeier U, von Pawel J, Gottfried M, et al. Phase III comparative study of high-dose Cisplatin versus a combination of Paclitaxel and Cisplatin in patients with advanced non-small cell lung cancer. J Clin Oncol 2000;18:3390 /9. [6] Von Pawel J, von Roemeling R, Gatzemeier U, et al. Tirapazamine plus Cisplatin versus Cisplatin in advanced non-small cell lung cancer: a report of the international CATAPULT l studygroup. J Clin Oncol 2000;18:1351 /9. [7] Le Chevalier T, Brisgand D, Douillard JY, et al. Randomized study of Vinorelbine and Cisplatin versus Vindesine and Cisplatin versus Vinorelbine alone in non-small cell lung cancer: results of an European multicentertrial including 612 patientsm. J Clin Oncol 1994;12:360 /7. [8] Bonomi P, Kim K, Chang A, et al. Phase III trial comparing Etoposide/Cisplatin versus Taxol with Cisplatin-G-CSF versus Taxol/Cisplatin in advanced non-small cell lung cancer. Proc ASCO 1996;15:382A(abstr. 1145). [9] Crino L, Scagliotti GV, Ricci S, et al. Gemcitabine/Cisplatin versus Mitomycin, Ifosfamide, and Cisplatin in advanced nonsmall cell lung cancer: a randomized phase III study of the Italian lung cancer project. J Clin Oncol 1999;17:3522 /30. [10] Belani CP, Natale RB, Lee JS, et al. Randomized phase III trial comparing Cisplatin/Etoposide versus Carboplatin/Paclitaxel in advanced and metastatic non-small cell lung cancer. Proc ASCO 1998;17:455a(abstr. 1751). [11] Cardenal F, Lopez-Cabrerizo MP, Anton A, et al. Randomized phase III study of Gemcitabine/Cisplatin versus Etoposide/ Cisplatin in the treatment of locally advanced or metastatic non-small cell lung cancer. J Clin Oncol 1999;17(1):12 /8. [12] Schiller JH, Harrington D, Sandler A, et al. A randomized phase III trial of four chemotherapy regiments in advanced non-small cell lung cancer. Proc ASCO 2000;19:1a(abstr. 2). [13] Manegold C, Zatloukal P, Krejcy K, Blatter J, et al. Gemcitabine in non-small cell lung cancer (NSCLC). Investigational New Drugs 2000;18(1):29 /42. [14] Georgoulias V, Papadakis E, Alexopoulos A, et al. Docetaxel plus Cisplatin versus Docetaxel plus Gemcitabine chemotherapy in
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
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advanced non-small cell lung cancer: a preliminary analyses of a multicenter randomized phase II trial. Proc ASCO 1999;18:461a(abst. 1778). Kosmides PA, Bacoyiannis C, Mylonakis N, et al. A randomised phase III trial of Paclitaxel plus Carboplatin versus Paclitaxel plus Gemcitabine in advanced non-small cell lung cancer. A preliminary analyses. Proc ASCO 2000;19:488a(abstr. 1908). Albain KS, Crowley JJ, LeBlanc M, Livingston RB. Survival determinants in extensive stage non-small cell lung cancer: The Southwest Oncology Group experience. J Clin Oncol 1991;9:1618 /26. Jiroutek M, Johnson D, Blum R, et al. Prognostic factus in advanced non-small cell lung cancer: analysis of Eastern Cooperative Oncology Group (ECOG) trials from 1981 /1992. Proc ASCO 1998;17:461a(abstr. 1774). Johnson DH, Zhu J, Schiller J, et al. E 1594 */A randomized phase III trial in metatstatic non-small cell lung cancer-outcome of PS-ll-patients: an Eastern Cooperative Oncology Group (ECOG) trial. Proc ASCO 1999;18:461a(abstr. 1779). Sorea JC, Douillard JY, Pujol JL, et al. Prognostic analyses of survival in the European randomized trial comparing Navelbine versus Navelbine/Cisplatin versus Vindesine/Cisplatin. Proc ASCO 1999;18(491a)(abstr. 1893). Perng RP, Chen YM, Ming-Liu J, et al. Gemcitabine versus the combination of Cisplatin and Etoposide m patients with inoperable non-small cell lung cancer in a phase II randomized study. J Clin Oncol 1997;15:2097 /101. Manegold C, Bergman B, Chemaissani A, et al. Single-agent Gemcitabine versus Cisplatin /Etoposide: early results of a randomised phase II study in locally advanced or metastatic non-small cell lung cancer. Ann Oncol 1997;8:525 /9. Manegold C, Pilz L, Koschel G, et al. Gemcitabine followed by 2nd line Docetaxel is feasible in advanced NSCLC: results from a randomised Phase II study. Proc ASCO 2000;19:549a(abstr. 2166). The elderly lung cancer Vinorelbine Italian Study Group, Gridelli C. Effects of Vinorelbine on quality of life and survival in elderly patients with advanced non-small cell lung cancer. J NCI 1999;91(1):66 /72. Thatcher N, Ranson M, Andersen H, et al. Phase III study of Paclitaxel versus best supportive care in inoperable non-small cell lung cancer. Ann Oncol 1998;9(Suppl. 4):1(abstr. 4.0). 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. Lung Cancer 2000;27:145 /58. Andersen H, Hopwood P, Stephens RJ, et al. Phase III study of Gemcitabine plus best supportive care (BSC) versus BSC in an inoperable non-small cell lung cancer a randomized trial with quality of life as the primary outcome. Br J Cancer 2000;83:447 / 53. Shepherd FA, Abratt RP, Andersen H, et al. Gemcetabine in the treatment of elderly patients with advanced non-small cell lung cancer. Sem Oncol 1997;24(Suppl. 7):50 /5. Frasci G, Lorusso V, Panza N, et al. Gemticabine plus Vinorelbine versus Vinorelbine alone in elderly patients with advanced non-small cell lung cancer. J Clin Oncol 2000;18:2529 /36. Garcia-Giron C, Rodriguez JC, de las Heras Garcia B, et al. Second-line chemotherapy in non-small cell lung cancer. Rev Oncologia 1999;1(Suppl. 2):75 /83. Manegold C, Drings P. Second-line Chemotherapie mit Docetaxel (Taxotere) beim nichtkleinzelligen Bronchialkarzinom(NSCLC). Onkologe 2000;6:1098 /106. Shepherd FA, Dancey J, Ramlau R, et al. Prospective randomized trial of Docetaxel versus best supportive care in patients with non-
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