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New drug and multimodality combinations in the treatment of advanced non-small cell lung cancer
Seminars in Oncology
Vol 28, No 3, Suppl 9
New
Drug
and Multimodality Combinations Advanced Non-Small Cell Lung Masaaki
Kawahara,
Mark
G. Kris,
I
N THE 1980s and 1990s platinum-based chemotherapy was shown to improve survival in patients with metastatic non-small cell lung cancer (NSCLC), those with locally advanced disease treated by radiotherapy, and, as preoperative chemotherapy for stage III resectable disease.‘-3 Over the last decade a range of new agents has become available for the treatment of patients with NSCLC. These include antimetabolites such as gemcitabine and multi-targeted antifolate, antitubulin (vinorelbine), tubulin-stabilizing taxanes (docetaxel and paclitaxel), and topoisomerase- 1 inhibitors such as irinotecan. Taxanes have contributed substantially to the progress that has been made. Docetaxel, in particular, is the first drug shown to be beneficial in the second-line setting (ie, in patients with NSCLC refractory or resistant to platinum therapy). The focus of a symposium held in Tokyo as part of the Ninth World Conference on Lung Cancer was the role of docetaxel in the evolution of more effective therapy and as a potential foundation for new combination treatments in advanced disease and in the induction setting. DOCETAXEL
AND SURVIVAL: SECOND LINE
FIRST
AND
Used first line in NSCLC, single-agent docetaxel produces a pooled response rate of approximately 31% with median survivals exceeding 9 months and 39% overall one-year survival.4xs These results are similar to those reported previously with combination regimens. Used secondline, the response rate to single agent docetaxel in phase II trials is approximately 2O%.6 In the first-line setting, a randomized phase III trial has shown that single-agent docetaxel leads to significantly improved survival relative to best supportive care.7 At 1 year, 25% of docetaxelSeminars
in Oncology,
Vol 28, No
3, Suppl
9 tune),
200 I : pp I-4
Mark
Green,
June 2001
in the Treatment Cancer
and Hideo
of
Kunitoh
treated patients were alive, compared with 16% in the control arm. In the year 2000, the Journal of Clinical Oncology published two papers reporting phase III studies of docetaxel in the second-line setting.s,9 At the Tokyo meeting, Thomas Lynch reviewed these two studies. In the trial versus best supportive care, docetaxel 75 mg/m2 produced survival advantages compared with the control patients who received supportive care only.s Importantly, treatment also brought clinical benefit: patients treated with docetaxel required less opioid analgesia and palliative radiotherapy, lost less weight, and suffered less fatigue. In the second phase III study, docetaxel at two doses was compared with a standard regimen of vinorelbine or ifosfamide.9 The response rate and time to progression with docetaxel were significantly higher than with either of the comparator agents. One-year survival in the patients treated with docetaxel 75 mg/m2 was 32%. One-year survival in patients receiving vinorelbine or ifosfamide was 19%. These data confirm that the survival benefit was achieved without compromising quality of life.
From the National Kinki Central Hospital, Japan; the Thomcic Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; the Department of Medicine, Hematology/Oncology Division, Medical University of South Carolina, Charleston; and the National Cancer Center Hospital, Japan. Drs Kru and Green serve as consultants to and have received research grant support and honoraria fromAuentis Pharmaceuticals Inc. Address reprmt requests to Mark G. Kris, MD, Memorial Sloan Kettering Cancer Center-, 1275 York Awe, New York, NY 10021. Copyright 0 2001 by W.B. Saunders Company 0093-7754/Oi/Z803-0901$35.00/O doi:10.1053/sonc.2001.24600
2
KAWAHAM
COMBINATION REGIMENS WITH WITHOUT PLATINUM
AND
Docetaxel also has been extensively studied in combination regimens, particularly with cisplatin, carboplatin, gemcitabine, and vinorelbine. These combinations have shown substantial activity.ia+iz Dr Chandra Belani presented preliminary analysis of the TAX 326 study comparing docetaxel plus cisplatin with docetaxel plus carboplatin and vinorelbine plus cisplatin.13 The full toxicity and efficacy analysis from this study should be available for the American Society of Clinical Oncology meeting in 2001. Together with the results of the Eastern Cooperative Oncology Group comparison11 between paclitaxel/cisplatin, docetaxel/cisplatin, gemcitabine/cisplatin, and paclitaxel/carboplatin, the TAX 326 results should provide considerable guidance for choosing among platinum-containing combinations in advanced disease. The meeting heard a full review by Dr James Rigas covering the rapidly evolving field of nonplatinum combination chemotherapy. A randomized trial has already shown that the combination of docetaxel and gemcitabine is equivalent to that of docetaxel and cisplatin in efficacy while being superior in tolerability. 14 A controlled trial also has shown that the combination of docetaxel with irinotecan achieves response rates and l-year survival similar to that seen with docetaxel/cisplatin.15 Toxicity, in this instance, had a different profile than seen with cisplatin or carboplatinbased regimens. The increased range of therapeutic options opens up the possibility of customizing therapy to the individual patient. Chemotherapy choices can or will be made based on comorbidities and characteristics of the disease shown in biological markers. Those attending were reminded that expanding choice concerns not only the single or multiple agents selected for chemotherapy but also their scheduling. Dr John Hainsworth presented data supporting the use of weekly docetaxel and achieving toxicity benefits that are not bought at the expense of antitumor efficacy.16p17 The reduction in myelosuppression, which switches from being the most prominent every 3 week docetaxel-related toxicity to being the least prominent with weekly docetaxel, is particularly dramatic. This
ET AL
opens up the possibility of combinations with other potentially myelosuppressive agents. It also renders eligible for therapy patients who are elderly, who are of poor performance status, or simply those who wish to receive chemotherapy but want treatment to have the smallest possible impact on their daily (and frequently their working) lives. The data presented showing the efficacy of a wide range of combinations in advanced disease sets the stage for their introduction at earlier stages in the treatment of NSCLC. These novel combinations are ripe for testing pre- and postoperatively in patients with resectable tumors and concurrently with radiation therapy. The new doublets also appear well suited for use in combination with the next generation of agents such as those targeted at vascular epithelial growth factor, bcl-2, or epidermal growth factor receptor. MULTIMODALITY
AND THERAPY
NEOADJUVANT
The integration of docetaxel into multimodality therapy for stage III NSCLC was discussed by Dr David Gandara. He focused on the Southwest Oncology Group 9504 trial, which shows that concurrent chemoradiotherapy with cisplatin plus etoposide followed by three cycles of consolidation with full-dose docetaxel results in a l-year survival rate of 76% and a 2-year survival rate of 53%.1s Dr Karin Mattson presented data showing that it is feasible to use docetaxel as induction therapy and that such use of the drug does not compromise later radical radiotherapy.19 Phase II trials of docetaxel plus platinum in the induction setting have produced response rates of up to 82% and complete resection rates of up to 79%.20-22 The area of induction therapy provoked lively discussion. Several important questions remain unanswered. In stage IIIA disease, should induction therapy be chemotherapy or chemoradiotherapy? Is surgery still indicated in all such patients? Stage IIIA N2 patients with a positive initial scan which normalizes following induction therapy may have a very good prognosis. If it is assumed that the good outcome in these patients results from the eradication of micrometastases by systemic therapy, the need f or surgery is called into question. Even among patients who have had induction chemoradiotherapy, the proportion who achieve a
NEW
CHEMOTHERAPIES
FOR LUNG
3
CANCER
pathologic complete response is small, the local failure rate remains substantial, and the cure rate is no more than 20% to 25%. For patients of good performance status, surgery remains a viable modality. Indeed, its importance may grow as a means of monitoring biological endpoints. These questions will become of increasing interest with the introduction of agents such as the angiogenesis and tyrosine kinase inhibitors that have novel mechanisms of action. In Japan, many patients with stage IIIA N2 disease undergo surgery without preoperative chemotherapy. Survival data are provocative. However, there is a need to be clear about how these patients are staged. Worldwide, the results following surgery alone in N2 patients are not good, and there is a clear case for induction treatment. Data from the Eastern Cooperative Oncology Group adjuvant trial suggest that these patients cannot be successfully managed by leaving chemotherapy until after surgery has been performed. Data from the Southwest Oncology Group study of stage IIIA N2 and IIIB patients show that use of chemotherapy and radiotherapy together can achieve a pathologic complete or near-complete response in a higher proportion of patients. These data led them to the on-going trial of chemoradiotherapy with or without surgery in locally advanced NSCLC. Intriguing questions are posed by the French study suggesting that stage IB and II patients achieve a greater benefit from induction therapy than stage III patients. If this is so, there is a case for treating every candidate for surgery with induction therapy followed by mediastinoscopy, deciding only at that point whether to go ahead and perform surgery. This issue is now being addressed in part by the US trial in which patients are randomized to three cycles of carboplatin plus paclitaxel induction followed by surgery or to surgery alone. It is important to note that the majority of induction chemotherapy studies use immediate surgery as the control arm. An exception is the Spanish trial of Rose11 et al in which induction chemotherapy followed by surgery is being compared both with surgery alone and with surgery plus postoperative therapy. The results of this study will establish whether it is chemotherapy per se that confers benefit or chemotherapy specifically in the induction setting. There was much discussion on the resolution of
positron emission tomography, such as the difficulties in interpretation of the scans following chemoradiotherapy and the possibility that a “negative” scan may be found even with substantial residual disease in mediastinal nodes. Overall, the meeting heard a wealth of data confirming advances in efficacy among treatments for NSCLC and suggestions for a range of approaches that may bring further progress. The search for a more effective and better tolerated treatment of lung cancer will need to continue until the cigarette smoking that causes this disease is eradicated. REFERENCES 1. Non-Small Cell Lung Cancer Collaborative Group: Chemotherapy in NSCLC: A meta-analysis using updated data on individual patients from 52 randomized clinical trials. BMJ 311:899-909, 1995 2. Rose11 R, Gomez-Codina J, Camps C, et al: A randomized trial comparing pre-operative chemotherapy plus surgery with surgery alone in patients with non-small cell lung cancer. N Engl J Med 330:153-158, 1994 3. Sugabaker DJ, Herndon J, Kohman LJ, et al: Results of Cancer and Leukemia Group B protocol 8935. A multi-institutional phase II trimodality trial for stage IIIA (N2) non-small cell lung cancer. J Thorac Cardiovasc Surg 109:473-485, 1995 4. Kris MG: What does chemotherapy have to offer patients with advanced-stage non-small cell lung cancer? Semin Oncol 25:1-4, 1998 (suppl 8) 5. Rigas JR: Do newer chemotherapeutic agents improve survival in non-small cell lung cancer? Semin Oncol 25:5-9, 1998 (suppl 8) 6. Belani CP: Single agents in the second-line treatment of non-small cell lung cancer. Semin Oncol 25:10-14, 1998 (SUPP~ 8)
7. Roszkowski K, Pluzanska A, Krzakowski M, et al: A multicenter, randomized, phase III study of docetaxel plus best supportive care in chemotherapy-naive patients with metastatic or non-resectable non-small cell lung cancer (NSCLC). Lung Cancer 27:145-157, 2000 8. Shepherd F, Dancey J, Ramlau R, et al: A prospective randomized trial of docetaxel (Taxotere) versus best supportive care in patients with non-small cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 18: 20952103, 2000 9. Fossella F, Devore R, Kerr R, et al: Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small cell lung cancer previously treated with a platinum containing agent. J Clin Oncol 18:2354-2363, 2000 10. Belani Cl’: Docetaxel (Taxotere) in combination with platinum-based regimens in non-small cell lung cancer: Results and future developments. Semin Oncol 26:15-18, 1999 (suppl 10) 11. Schiller JH, Harrington D, Sandler A, et al: A randomized phase III trial of four chemotherapeutic regimens in ad-
4
vanced non-small cell lung cancer (NSCLC). Proc Am Sot Clin Oncol 19:la, 2000 (abstr) 12. Belani C: Use of docetaxel and carboplatin for patients wxh non-small cell lung cancer. Oncology 11:3 l-33, 1997 (SUPPl 7) 13. Belani Cl’, Rodriguez J, van Pawel J, et al: A multicenter, randomized phase III study of docetaxel + cisplatin (DC) vs docetaxel + carboplatin (DCb) vs vinorelbine + cisplatin (VC) in chemotherapy-naive patients (Pts) with advanced and metastatic non-small cell lung cancer (NSCLC). Lung Cancer, 29:60, 2000 (suppl 1) (abstr 195) 14. Georgoulias C, Papdakis E, Alexopoulos A, et al: Docetaxel plus cisplatin versus docetaxel plus gemcitabine chemotherapy in advanced non-small cell lung cancer: A preliminaly analysis of a multicenter randomized phase II trial. Eur J Cancer 35:249, 1999 (suppl 4) (abstr) 15. Takeda K, Yamamoto N, Negoro S, et al: Randomized phase II study of docetaxel (DOC) plus cisplatin (CDDP) versus DOC plus irinotecan in advanced non-small-cell lung cancer (NSCLC): A West Japan Thoracic Oncology Group (WJTOG) study. Proc Am Sot Clin Oncol 19:1944, 2000 (abstr) 16. Hainsworth JD, Burris HA, Erland JB, et al: Phase I trial of docetaxel administered by weekly infusion in patients with advanced refractory cancer. J Clin Oncol 16:2164-2168, 1998 17. Hainsworth JD, Burris HA, Morrissey LH, et al: Weekly
KAWAHARA
ET AL
docetaxel as first-line therapy for elderly patients with advanced non-small cell lung cancer (NSCLC). Lung Cancer 29:63, 2000 (suppl 1) (abstr 203) 18. Gandara DR, Lovato LC, Albain KS, et al: Pathological stage IIIb non-small cell lung cancer (NSCLC): Prolonged survival with consolidation of docetaxel following concurrent chemoradiotherapy (SWOG 9504) . Lung Cancer 29:92, 2000 (suppl 1) (abstr 302) 19. Mattson K, Ten Velde G, Krofta K, et al: Early results of an international phase III study evaluating Taxotere as neoadjuvant therapy for radically-treatable stage III NSCLC. Lung Cancer 29:90, 2000 (suppl 1) (abstr 295) 20. Betticher DC, Hsu Schmitz SF, Gauthier Y, et al: Neoadjuvant chemotherapy with docetaxel (DOC, Taxotere) and cisplatin (CIS) in patients (pts) with non-small cell lung cancer (NSCLC), stage IIIA, N2 is highly active with few toxicities. Proc Am Sot Clin Oncol 18:473a, 1999 (abstr 1824) 21. Griesinger F, Baum RP, Paul J, et al: Correlation of metabolic and morphometric tumor response after induction chemotherapy with docetaxel (D) and carboplatin (C) in stage III NSCLC. Proc Am Sot Clin Oncol 19:2160, 2000 (abstr) 22. Katakami N, Okazaki M, Nishimura T, et al: Phase II trial of induction carboplatin (CAR) and docetaxel (DOC) with concurrent radiation (RT) in early-stage non-small cell lung cancer (NSCLC). Proc Am Sot Clin Oncol 19:2060, 2000 (abstr)
Vol 28, No 3, Suppl 9
New
Drug
and Multimodality Combinations Advanced Non-Small Cell Lung Masaaki
Kawahara,
Mark
G. Kris,
I
N THE 1980s and 1990s platinum-based chemotherapy was shown to improve survival in patients with metastatic non-small cell lung cancer (NSCLC), those with locally advanced disease treated by radiotherapy, and, as preoperative chemotherapy for stage III resectable disease.‘-3 Over the last decade a range of new agents has become available for the treatment of patients with NSCLC. These include antimetabolites such as gemcitabine and multi-targeted antifolate, antitubulin (vinorelbine), tubulin-stabilizing taxanes (docetaxel and paclitaxel), and topoisomerase- 1 inhibitors such as irinotecan. Taxanes have contributed substantially to the progress that has been made. Docetaxel, in particular, is the first drug shown to be beneficial in the second-line setting (ie, in patients with NSCLC refractory or resistant to platinum therapy). The focus of a symposium held in Tokyo as part of the Ninth World Conference on Lung Cancer was the role of docetaxel in the evolution of more effective therapy and as a potential foundation for new combination treatments in advanced disease and in the induction setting. DOCETAXEL
AND SURVIVAL: SECOND LINE
FIRST
AND
Used first line in NSCLC, single-agent docetaxel produces a pooled response rate of approximately 31% with median survivals exceeding 9 months and 39% overall one-year survival.4xs These results are similar to those reported previously with combination regimens. Used secondline, the response rate to single agent docetaxel in phase II trials is approximately 2O%.6 In the first-line setting, a randomized phase III trial has shown that single-agent docetaxel leads to significantly improved survival relative to best supportive care.7 At 1 year, 25% of docetaxelSeminars
in Oncology,
Vol 28, No
3, Suppl
9 tune),
200 I : pp I-4
Mark
Green,
June 2001
in the Treatment Cancer
and Hideo
of
Kunitoh
treated patients were alive, compared with 16% in the control arm. In the year 2000, the Journal of Clinical Oncology published two papers reporting phase III studies of docetaxel in the second-line setting.s,9 At the Tokyo meeting, Thomas Lynch reviewed these two studies. In the trial versus best supportive care, docetaxel 75 mg/m2 produced survival advantages compared with the control patients who received supportive care only.s Importantly, treatment also brought clinical benefit: patients treated with docetaxel required less opioid analgesia and palliative radiotherapy, lost less weight, and suffered less fatigue. In the second phase III study, docetaxel at two doses was compared with a standard regimen of vinorelbine or ifosfamide.9 The response rate and time to progression with docetaxel were significantly higher than with either of the comparator agents. One-year survival in the patients treated with docetaxel 75 mg/m2 was 32%. One-year survival in patients receiving vinorelbine or ifosfamide was 19%. These data confirm that the survival benefit was achieved without compromising quality of life.
From the National Kinki Central Hospital, Japan; the Thomcic Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; the Department of Medicine, Hematology/Oncology Division, Medical University of South Carolina, Charleston; and the National Cancer Center Hospital, Japan. Drs Kru and Green serve as consultants to and have received research grant support and honoraria fromAuentis Pharmaceuticals Inc. Address reprmt requests to Mark G. Kris, MD, Memorial Sloan Kettering Cancer Center-, 1275 York Awe, New York, NY 10021. Copyright 0 2001 by W.B. Saunders Company 0093-7754/Oi/Z803-0901$35.00/O doi:10.1053/sonc.2001.24600
2
KAWAHAM
COMBINATION REGIMENS WITH WITHOUT PLATINUM
AND
Docetaxel also has been extensively studied in combination regimens, particularly with cisplatin, carboplatin, gemcitabine, and vinorelbine. These combinations have shown substantial activity.ia+iz Dr Chandra Belani presented preliminary analysis of the TAX 326 study comparing docetaxel plus cisplatin with docetaxel plus carboplatin and vinorelbine plus cisplatin.13 The full toxicity and efficacy analysis from this study should be available for the American Society of Clinical Oncology meeting in 2001. Together with the results of the Eastern Cooperative Oncology Group comparison11 between paclitaxel/cisplatin, docetaxel/cisplatin, gemcitabine/cisplatin, and paclitaxel/carboplatin, the TAX 326 results should provide considerable guidance for choosing among platinum-containing combinations in advanced disease. The meeting heard a full review by Dr James Rigas covering the rapidly evolving field of nonplatinum combination chemotherapy. A randomized trial has already shown that the combination of docetaxel and gemcitabine is equivalent to that of docetaxel and cisplatin in efficacy while being superior in tolerability. 14 A controlled trial also has shown that the combination of docetaxel with irinotecan achieves response rates and l-year survival similar to that seen with docetaxel/cisplatin.15 Toxicity, in this instance, had a different profile than seen with cisplatin or carboplatinbased regimens. The increased range of therapeutic options opens up the possibility of customizing therapy to the individual patient. Chemotherapy choices can or will be made based on comorbidities and characteristics of the disease shown in biological markers. Those attending were reminded that expanding choice concerns not only the single or multiple agents selected for chemotherapy but also their scheduling. Dr John Hainsworth presented data supporting the use of weekly docetaxel and achieving toxicity benefits that are not bought at the expense of antitumor efficacy.16p17 The reduction in myelosuppression, which switches from being the most prominent every 3 week docetaxel-related toxicity to being the least prominent with weekly docetaxel, is particularly dramatic. This
ET AL
opens up the possibility of combinations with other potentially myelosuppressive agents. It also renders eligible for therapy patients who are elderly, who are of poor performance status, or simply those who wish to receive chemotherapy but want treatment to have the smallest possible impact on their daily (and frequently their working) lives. The data presented showing the efficacy of a wide range of combinations in advanced disease sets the stage for their introduction at earlier stages in the treatment of NSCLC. These novel combinations are ripe for testing pre- and postoperatively in patients with resectable tumors and concurrently with radiation therapy. The new doublets also appear well suited for use in combination with the next generation of agents such as those targeted at vascular epithelial growth factor, bcl-2, or epidermal growth factor receptor. MULTIMODALITY
AND THERAPY
NEOADJUVANT
The integration of docetaxel into multimodality therapy for stage III NSCLC was discussed by Dr David Gandara. He focused on the Southwest Oncology Group 9504 trial, which shows that concurrent chemoradiotherapy with cisplatin plus etoposide followed by three cycles of consolidation with full-dose docetaxel results in a l-year survival rate of 76% and a 2-year survival rate of 53%.1s Dr Karin Mattson presented data showing that it is feasible to use docetaxel as induction therapy and that such use of the drug does not compromise later radical radiotherapy.19 Phase II trials of docetaxel plus platinum in the induction setting have produced response rates of up to 82% and complete resection rates of up to 79%.20-22 The area of induction therapy provoked lively discussion. Several important questions remain unanswered. In stage IIIA disease, should induction therapy be chemotherapy or chemoradiotherapy? Is surgery still indicated in all such patients? Stage IIIA N2 patients with a positive initial scan which normalizes following induction therapy may have a very good prognosis. If it is assumed that the good outcome in these patients results from the eradication of micrometastases by systemic therapy, the need f or surgery is called into question. Even among patients who have had induction chemoradiotherapy, the proportion who achieve a
NEW
CHEMOTHERAPIES
FOR LUNG
3
CANCER
pathologic complete response is small, the local failure rate remains substantial, and the cure rate is no more than 20% to 25%. For patients of good performance status, surgery remains a viable modality. Indeed, its importance may grow as a means of monitoring biological endpoints. These questions will become of increasing interest with the introduction of agents such as the angiogenesis and tyrosine kinase inhibitors that have novel mechanisms of action. In Japan, many patients with stage IIIA N2 disease undergo surgery without preoperative chemotherapy. Survival data are provocative. However, there is a need to be clear about how these patients are staged. Worldwide, the results following surgery alone in N2 patients are not good, and there is a clear case for induction treatment. Data from the Eastern Cooperative Oncology Group adjuvant trial suggest that these patients cannot be successfully managed by leaving chemotherapy until after surgery has been performed. Data from the Southwest Oncology Group study of stage IIIA N2 and IIIB patients show that use of chemotherapy and radiotherapy together can achieve a pathologic complete or near-complete response in a higher proportion of patients. These data led them to the on-going trial of chemoradiotherapy with or without surgery in locally advanced NSCLC. Intriguing questions are posed by the French study suggesting that stage IB and II patients achieve a greater benefit from induction therapy than stage III patients. If this is so, there is a case for treating every candidate for surgery with induction therapy followed by mediastinoscopy, deciding only at that point whether to go ahead and perform surgery. This issue is now being addressed in part by the US trial in which patients are randomized to three cycles of carboplatin plus paclitaxel induction followed by surgery or to surgery alone. It is important to note that the majority of induction chemotherapy studies use immediate surgery as the control arm. An exception is the Spanish trial of Rose11 et al in which induction chemotherapy followed by surgery is being compared both with surgery alone and with surgery plus postoperative therapy. The results of this study will establish whether it is chemotherapy per se that confers benefit or chemotherapy specifically in the induction setting. There was much discussion on the resolution of
positron emission tomography, such as the difficulties in interpretation of the scans following chemoradiotherapy and the possibility that a “negative” scan may be found even with substantial residual disease in mediastinal nodes. Overall, the meeting heard a wealth of data confirming advances in efficacy among treatments for NSCLC and suggestions for a range of approaches that may bring further progress. The search for a more effective and better tolerated treatment of lung cancer will need to continue until the cigarette smoking that causes this disease is eradicated. REFERENCES 1. Non-Small Cell Lung Cancer Collaborative Group: Chemotherapy in NSCLC: A meta-analysis using updated data on individual patients from 52 randomized clinical trials. BMJ 311:899-909, 1995 2. Rose11 R, Gomez-Codina J, Camps C, et al: A randomized trial comparing pre-operative chemotherapy plus surgery with surgery alone in patients with non-small cell lung cancer. N Engl J Med 330:153-158, 1994 3. Sugabaker DJ, Herndon J, Kohman LJ, et al: Results of Cancer and Leukemia Group B protocol 8935. A multi-institutional phase II trimodality trial for stage IIIA (N2) non-small cell lung cancer. J Thorac Cardiovasc Surg 109:473-485, 1995 4. Kris MG: What does chemotherapy have to offer patients with advanced-stage non-small cell lung cancer? Semin Oncol 25:1-4, 1998 (suppl 8) 5. Rigas JR: Do newer chemotherapeutic agents improve survival in non-small cell lung cancer? Semin Oncol 25:5-9, 1998 (suppl 8) 6. Belani CP: Single agents in the second-line treatment of non-small cell lung cancer. Semin Oncol 25:10-14, 1998 (SUPP~ 8)
7. Roszkowski K, Pluzanska A, Krzakowski M, et al: A multicenter, randomized, phase III study of docetaxel plus best supportive care in chemotherapy-naive patients with metastatic or non-resectable non-small cell lung cancer (NSCLC). Lung Cancer 27:145-157, 2000 8. Shepherd F, Dancey J, Ramlau R, et al: A prospective randomized trial of docetaxel (Taxotere) versus best supportive care in patients with non-small cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 18: 20952103, 2000 9. Fossella F, Devore R, Kerr R, et al: Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small cell lung cancer previously treated with a platinum containing agent. J Clin Oncol 18:2354-2363, 2000 10. Belani Cl’: Docetaxel (Taxotere) in combination with platinum-based regimens in non-small cell lung cancer: Results and future developments. Semin Oncol 26:15-18, 1999 (suppl 10) 11. Schiller JH, Harrington D, Sandler A, et al: A randomized phase III trial of four chemotherapeutic regimens in ad-
4
vanced non-small cell lung cancer (NSCLC). Proc Am Sot Clin Oncol 19:la, 2000 (abstr) 12. Belani C: Use of docetaxel and carboplatin for patients wxh non-small cell lung cancer. Oncology 11:3 l-33, 1997 (SUPPl 7) 13. Belani Cl’, Rodriguez J, van Pawel J, et al: A multicenter, randomized phase III study of docetaxel + cisplatin (DC) vs docetaxel + carboplatin (DCb) vs vinorelbine + cisplatin (VC) in chemotherapy-naive patients (Pts) with advanced and metastatic non-small cell lung cancer (NSCLC). Lung Cancer, 29:60, 2000 (suppl 1) (abstr 195) 14. Georgoulias C, Papdakis E, Alexopoulos A, et al: Docetaxel plus cisplatin versus docetaxel plus gemcitabine chemotherapy in advanced non-small cell lung cancer: A preliminaly analysis of a multicenter randomized phase II trial. Eur J Cancer 35:249, 1999 (suppl 4) (abstr) 15. Takeda K, Yamamoto N, Negoro S, et al: Randomized phase II study of docetaxel (DOC) plus cisplatin (CDDP) versus DOC plus irinotecan in advanced non-small-cell lung cancer (NSCLC): A West Japan Thoracic Oncology Group (WJTOG) study. Proc Am Sot Clin Oncol 19:1944, 2000 (abstr) 16. Hainsworth JD, Burris HA, Erland JB, et al: Phase I trial of docetaxel administered by weekly infusion in patients with advanced refractory cancer. J Clin Oncol 16:2164-2168, 1998 17. Hainsworth JD, Burris HA, Morrissey LH, et al: Weekly
KAWAHARA
ET AL
docetaxel as first-line therapy for elderly patients with advanced non-small cell lung cancer (NSCLC). Lung Cancer 29:63, 2000 (suppl 1) (abstr 203) 18. Gandara DR, Lovato LC, Albain KS, et al: Pathological stage IIIb non-small cell lung cancer (NSCLC): Prolonged survival with consolidation of docetaxel following concurrent chemoradiotherapy (SWOG 9504) . Lung Cancer 29:92, 2000 (suppl 1) (abstr 302) 19. Mattson K, Ten Velde G, Krofta K, et al: Early results of an international phase III study evaluating Taxotere as neoadjuvant therapy for radically-treatable stage III NSCLC. Lung Cancer 29:90, 2000 (suppl 1) (abstr 295) 20. Betticher DC, Hsu Schmitz SF, Gauthier Y, et al: Neoadjuvant chemotherapy with docetaxel (DOC, Taxotere) and cisplatin (CIS) in patients (pts) with non-small cell lung cancer (NSCLC), stage IIIA, N2 is highly active with few toxicities. Proc Am Sot Clin Oncol 18:473a, 1999 (abstr 1824) 21. Griesinger F, Baum RP, Paul J, et al: Correlation of metabolic and morphometric tumor response after induction chemotherapy with docetaxel (D) and carboplatin (C) in stage III NSCLC. Proc Am Sot Clin Oncol 19:2160, 2000 (abstr) 22. Katakami N, Okazaki M, Nishimura T, et al: Phase II trial of induction carboplatin (CAR) and docetaxel (DOC) with concurrent radiation (RT) in early-stage non-small cell lung cancer (NSCLC). Proc Am Sot Clin Oncol 19:2060, 2000 (abstr)