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Chemotherapy of advanced non-small cell lung cancer: any standard treatment?
Lung Cancer 37 (2002) 15 /16 www.elsevier.com/locate/lungcan
Editorial Chemotherapy of advanced non-small cell lung cancer: any standard treatment? At the time of initial diagnosis, almost 50% of patients with non-small-cell lung cancer (NSCLC) have clinically detectable metastases outside the thorax and another 10 /15% have locally advanced unresectable tumours. In addition, more than 50% of patients who undergo surgery recur with either localised, unresectable tumours or extrathoracic dissemination. This means that more than three quarters of all patients with NSCLC are potential candidates for chemotherapy at some time during the course of their disease. For those patients with a good performance status (PS), the role of chemotherapy is no longer controversial in North America and Western Europe. Several randomised trials and meta-analyses have supported the use of chemotherapy as standard treatment for patients with advanced NSCLC and a good PS [1,2]. Meta-analyses confirmed the benefit of cisplatinbased chemotherapy over best supportive care; chemotherapy confers a benefit in median survival of 10 weeks and in some trials an improvement in quality of life (QoL) and symptoms control could also be obtained [3]. The cost of chemotherapy administration in patients with advanced NSCLC compares with that of other accepted medical interventions, and may actually be less than that of best supportive care [4]. The chemotherapy regimens of the 1980s and early 1990s combined the drugs listed in Table 1. As single agents, these drugs typically produced response, defined as significant tumour shrinkage, in at least 15% of patients. Several newer agents with better single-agent activity have resulted in longer median survival times. New regimens combining these agents with cisplatin or carboplatin were developed and investigated in phase II trials. The new combination regimens have a tendency to offer better side-effect profiles, higher response rates, and better survival [5]. Randomised phase III trials have compared several of these new regimens with the previous standard regimens. The newer regimens seem to provide higher response rates and sometimes longer survival than single-agent cisplatin or the previous cisplatin-based combinations [6 /12]. To date, no particular chemotherapy regimen has been identified as superior in terms of efficacy. One recent large trial evaluating four new generation regimens showed a substantial equivalence in terms of
response rate and survival with an average gain in median survival of about 2 months in comparison to historical controls (8 months vs. 6 months) [13]. This is the same advantage that a review of 22 years of phase III trials in NSCLC in North America could ascertain in five trials comparing two different regimens, results defined ‘sobering’ by the authors [14]. Two recent presentations at ASCO 2001 confirmed the equivalence of various regimens [15,16]. This could justify the feeling that chemotherapy in NSCLC has reached a plateau, that it is time to move on from chemotherapy and that new approaches are required [17]. But in the meantime we need to use the available tools at their best in terms of use of financial resources, protection of patients QoL and optimisation of symptom control. In this direction the paper of Grigorescu [18] analyses the role of a relatively new regimen, the carboplatin / gemcitabine combination versus the ‘standard’ cisplatin /vinblastine regimen. This is one of the first randomized trials in advanced NSCLC coming from the Balkan states. The study has some limitations, as the authors clearly state, regarding methodology, sample size and statistical power but it is noteworthy that in that particularly difficult context for historical, economic and social reasons the authors could perform a study with 198 patients in less than 3 years of accrual. As a Past President of European Society of Medical Oncology (ESMO) I would like to think that the efforts of our society were well directed in supporting educational courses, in favouring participation in meetings and congresses and in organising co-operative groups in Central and East Europe through a specific Task Force. The main result of the study is the advantage in terms of median survival (7.9 m vs. 11.6 m) and survival at 1 year (13 vs. 36%) in favour of the experimental arm. This advantage is rather large and according to the authors could be explained with some sort of patient selection. In any case this paper raises again the question of the comparison of new generation regimens with those of the second generation, a question that is still open because some trials showed some advantage of the new regimen in terms of RR [9,10] or toxicity [12] and QoL [10,11] but in most of the studies survival was equivalent.
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 0 3 2 - 6
16
Editorial
Table 1 Drugs used in non-small-cell lung cancer (NSCLC) Old agents
New agents
Cisplatin Carboplatin Etoposide Vinblastine Vindesine
Docetaxel Paclitaxel Irinotecan Vinorelbine Gemcitabine
[6]
[7]
[8]
One exception is the Tax 326 study recently presented at the ECCO 11 showing consistent advantage in survival and QoL for the cisplatin /docetaxel arm in comparison to cisplatin /vinorelbine but the results of this study should be published in extenso before being considered definitive [19]. The results of a recently completed British large randomized trial, comparing the same experimental regimen of Grigorescu (carboplatin /gemcitabine) versus the standard MIC (mitomycin, ifosfamide, cisplatin) are also eagerly awaited since they will add substantial evidence to the choice of the best chemotherapy regimen. For the time being, most of the researchers in the field of chemotherapy of NSCLC are convinced that there is no regimen clearly superior to the others [17]. The choice of a drug or a combination should be made on the basis of the ease of administration, toxicity profile, the presence or absence of coexisting medical conditions and financial costs. All patients should be informed of the potential benefits, limitations and adverse effects before starting chemotherapy and all patients should be encouraged to participate in clinical trials including trials of new agents so that real progress can be made against NSCLC. Grigorescu’s paper is a good sign of such a trend in situations where this was not the rule in the past when the practical difficulties could have been an almost insurmountable obstacle.
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17] [18]
References [1] Non-Small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using update data on individual patients from 52 randomised clinical trials. Br Med J 1995;311:899 /09. [2] 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. [3] Anderson H, Hopwood P, Stephens RJ, et al. Gemcitabine plus best supportive care (BSC) vs BSC in inoperable non-small cell lung cancer */a randomized trial with quality of life as the primary outcome. Br J Cancer 2002;83(4):447 /53. [4] Pamela J, Goodwin J, Shepherd FA. Economic issues in lung cancer: a review. J Clin Oncol 1998;16:3900 /12. [5] Bunn PA, Kelly K. New chemotherapy agents prolong survival and improve quality of life in non-small cell lung cancer: a review
[19]
of the literature and future directions. Clin Cancer Res 1998;5:1087 /100. Le Chevalier T, Brisgard D, Douillard JK, et al. Randomized study of vinorelbine and cisplatin versus vindesine and cisplatin versus vinorelbine alone in advanced non-small cell lung cancer: results of a European multi-center trial including 612 patients. J Clin Oncol 1994;12:360 /7. 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. Sandler AB, Neumunaitis 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 /130, 20. Crino` L, Scagliotti G, Ricci S, et al. Gemcitabine and cisplatin versus mitomycin, ifosfamide and cisplatin in advanced non-small cell lung cancer: a randomised phase III study of the Italian Lung Cancer Project. J Clin Oncol 1999;17(11):3522 /30. Bonomi P, Kyung M, Fairclough D, et al. Comparison of survival and quality of life in advanced non-small cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin: results of an eastern co-operative oncology group trial. J Clin Oncol 2000;18(3):623 /31. Giaccone G, Splinter T, Debruyne C, et al. Randomized study of paclitaxel /cisplatin versus cisplatin /teniposide in patients with advanced non-small cell lung cancer. J Clin Oncol 1998;16(6):2133 /41. Kelly K, Crowley J, Bunn AP, et al. Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non-small-cell lung cancer: A Southwest Oncology Group Trial. J Clin Oncol 2001;19(13):3210 /8. Schiller JH, Harrington D, Sandler A, et al. A comparison of four chemotherapy regimens for advanced non-small cell lung cancer. N Engl J Med 2002;345:92 /8. Breathnach OS, Freidlin B, Conley B, et al. Twenty-two years of phase III trials for patients with advanced non-small cell lung cancer: sobering results. J Clin Oncol 2001;19:1734 /42. Van Meerbeek JP, Smith EF, Lianes P, et al. A EORTC randomised phase III trial of three chemotherapy regimens in advanced non-small cell lung cancer. Proc Am Soc Clin Oncol 2001;20(Abstr 1228):308a. Scagliotti GV, De Marinis F, Rinaldi D, et al. Phase III randomised trail comparing three platinum-based doublets in non-small cell lung cancer. Proc Am Soc Clin Oncol 2001;20(Abstr. 1227):308a. Carney DN. Lung cancer */time to move on from chemotherapy. Editorial. N Engl J Med 2002;346:126 /7. Grigorescu AC, Draghici IN, Nitipir C et al. Gemcitabine (GEM) and carboplatin (CBDCA) versus cisplatin (CDDP) and vinblastine (VLB) in advanced non-small-cell lung cancer (NSCLC) stages III and IV: a phase III randomised trial. Lung Cancer 2002;37(1):9 /14. Fossella F. Docetaxel/Cisplatin (DC) and Docetaxel/Carboplatin (DCb) vs Vinorelbin/Cisplatin (VC) in chemotherapynaive patients with advanced and metastatic non-smal cell lung cancer (NSCLC): results of a multicenter, randomized phase III study. Eur J Cancer 2001;37(Suppl 6);Abstract Book, ECCO 11, abstract 562, S154.
Maurizio Tonato Division of Medical Oncology, Policlinico Hospital, Perugia, Italy
Editorial Chemotherapy of advanced non-small cell lung cancer: any standard treatment? At the time of initial diagnosis, almost 50% of patients with non-small-cell lung cancer (NSCLC) have clinically detectable metastases outside the thorax and another 10 /15% have locally advanced unresectable tumours. In addition, more than 50% of patients who undergo surgery recur with either localised, unresectable tumours or extrathoracic dissemination. This means that more than three quarters of all patients with NSCLC are potential candidates for chemotherapy at some time during the course of their disease. For those patients with a good performance status (PS), the role of chemotherapy is no longer controversial in North America and Western Europe. Several randomised trials and meta-analyses have supported the use of chemotherapy as standard treatment for patients with advanced NSCLC and a good PS [1,2]. Meta-analyses confirmed the benefit of cisplatinbased chemotherapy over best supportive care; chemotherapy confers a benefit in median survival of 10 weeks and in some trials an improvement in quality of life (QoL) and symptoms control could also be obtained [3]. The cost of chemotherapy administration in patients with advanced NSCLC compares with that of other accepted medical interventions, and may actually be less than that of best supportive care [4]. The chemotherapy regimens of the 1980s and early 1990s combined the drugs listed in Table 1. As single agents, these drugs typically produced response, defined as significant tumour shrinkage, in at least 15% of patients. Several newer agents with better single-agent activity have resulted in longer median survival times. New regimens combining these agents with cisplatin or carboplatin were developed and investigated in phase II trials. The new combination regimens have a tendency to offer better side-effect profiles, higher response rates, and better survival [5]. Randomised phase III trials have compared several of these new regimens with the previous standard regimens. The newer regimens seem to provide higher response rates and sometimes longer survival than single-agent cisplatin or the previous cisplatin-based combinations [6 /12]. To date, no particular chemotherapy regimen has been identified as superior in terms of efficacy. One recent large trial evaluating four new generation regimens showed a substantial equivalence in terms of
response rate and survival with an average gain in median survival of about 2 months in comparison to historical controls (8 months vs. 6 months) [13]. This is the same advantage that a review of 22 years of phase III trials in NSCLC in North America could ascertain in five trials comparing two different regimens, results defined ‘sobering’ by the authors [14]. Two recent presentations at ASCO 2001 confirmed the equivalence of various regimens [15,16]. This could justify the feeling that chemotherapy in NSCLC has reached a plateau, that it is time to move on from chemotherapy and that new approaches are required [17]. But in the meantime we need to use the available tools at their best in terms of use of financial resources, protection of patients QoL and optimisation of symptom control. In this direction the paper of Grigorescu [18] analyses the role of a relatively new regimen, the carboplatin / gemcitabine combination versus the ‘standard’ cisplatin /vinblastine regimen. This is one of the first randomized trials in advanced NSCLC coming from the Balkan states. The study has some limitations, as the authors clearly state, regarding methodology, sample size and statistical power but it is noteworthy that in that particularly difficult context for historical, economic and social reasons the authors could perform a study with 198 patients in less than 3 years of accrual. As a Past President of European Society of Medical Oncology (ESMO) I would like to think that the efforts of our society were well directed in supporting educational courses, in favouring participation in meetings and congresses and in organising co-operative groups in Central and East Europe through a specific Task Force. The main result of the study is the advantage in terms of median survival (7.9 m vs. 11.6 m) and survival at 1 year (13 vs. 36%) in favour of the experimental arm. This advantage is rather large and according to the authors could be explained with some sort of patient selection. In any case this paper raises again the question of the comparison of new generation regimens with those of the second generation, a question that is still open because some trials showed some advantage of the new regimen in terms of RR [9,10] or toxicity [12] and QoL [10,11] but in most of the studies survival was equivalent.
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 0 3 2 - 6
16
Editorial
Table 1 Drugs used in non-small-cell lung cancer (NSCLC) Old agents
New agents
Cisplatin Carboplatin Etoposide Vinblastine Vindesine
Docetaxel Paclitaxel Irinotecan Vinorelbine Gemcitabine
[6]
[7]
[8]
One exception is the Tax 326 study recently presented at the ECCO 11 showing consistent advantage in survival and QoL for the cisplatin /docetaxel arm in comparison to cisplatin /vinorelbine but the results of this study should be published in extenso before being considered definitive [19]. The results of a recently completed British large randomized trial, comparing the same experimental regimen of Grigorescu (carboplatin /gemcitabine) versus the standard MIC (mitomycin, ifosfamide, cisplatin) are also eagerly awaited since they will add substantial evidence to the choice of the best chemotherapy regimen. For the time being, most of the researchers in the field of chemotherapy of NSCLC are convinced that there is no regimen clearly superior to the others [17]. The choice of a drug or a combination should be made on the basis of the ease of administration, toxicity profile, the presence or absence of coexisting medical conditions and financial costs. All patients should be informed of the potential benefits, limitations and adverse effects before starting chemotherapy and all patients should be encouraged to participate in clinical trials including trials of new agents so that real progress can be made against NSCLC. Grigorescu’s paper is a good sign of such a trend in situations where this was not the rule in the past when the practical difficulties could have been an almost insurmountable obstacle.
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17] [18]
References [1] Non-Small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using update data on individual patients from 52 randomised clinical trials. Br Med J 1995;311:899 /09. [2] 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. [3] Anderson H, Hopwood P, Stephens RJ, et al. Gemcitabine plus best supportive care (BSC) vs BSC in inoperable non-small cell lung cancer */a randomized trial with quality of life as the primary outcome. Br J Cancer 2002;83(4):447 /53. [4] Pamela J, Goodwin J, Shepherd FA. Economic issues in lung cancer: a review. J Clin Oncol 1998;16:3900 /12. [5] Bunn PA, Kelly K. New chemotherapy agents prolong survival and improve quality of life in non-small cell lung cancer: a review
[19]
of the literature and future directions. Clin Cancer Res 1998;5:1087 /100. Le Chevalier T, Brisgard D, Douillard JK, et al. Randomized study of vinorelbine and cisplatin versus vindesine and cisplatin versus vinorelbine alone in advanced non-small cell lung cancer: results of a European multi-center trial including 612 patients. J Clin Oncol 1994;12:360 /7. 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. Sandler AB, Neumunaitis 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 /130, 20. Crino` L, Scagliotti G, Ricci S, et al. Gemcitabine and cisplatin versus mitomycin, ifosfamide and cisplatin in advanced non-small cell lung cancer: a randomised phase III study of the Italian Lung Cancer Project. J Clin Oncol 1999;17(11):3522 /30. Bonomi P, Kyung M, Fairclough D, et al. Comparison of survival and quality of life in advanced non-small cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin: results of an eastern co-operative oncology group trial. J Clin Oncol 2000;18(3):623 /31. Giaccone G, Splinter T, Debruyne C, et al. Randomized study of paclitaxel /cisplatin versus cisplatin /teniposide in patients with advanced non-small cell lung cancer. J Clin Oncol 1998;16(6):2133 /41. Kelly K, Crowley J, Bunn AP, et al. Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non-small-cell lung cancer: A Southwest Oncology Group Trial. J Clin Oncol 2001;19(13):3210 /8. Schiller JH, Harrington D, Sandler A, et al. A comparison of four chemotherapy regimens for advanced non-small cell lung cancer. N Engl J Med 2002;345:92 /8. Breathnach OS, Freidlin B, Conley B, et al. Twenty-two years of phase III trials for patients with advanced non-small cell lung cancer: sobering results. J Clin Oncol 2001;19:1734 /42. Van Meerbeek JP, Smith EF, Lianes P, et al. A EORTC randomised phase III trial of three chemotherapy regimens in advanced non-small cell lung cancer. Proc Am Soc Clin Oncol 2001;20(Abstr 1228):308a. Scagliotti GV, De Marinis F, Rinaldi D, et al. Phase III randomised trail comparing three platinum-based doublets in non-small cell lung cancer. Proc Am Soc Clin Oncol 2001;20(Abstr. 1227):308a. Carney DN. Lung cancer */time to move on from chemotherapy. Editorial. N Engl J Med 2002;346:126 /7. Grigorescu AC, Draghici IN, Nitipir C et al. Gemcitabine (GEM) and carboplatin (CBDCA) versus cisplatin (CDDP) and vinblastine (VLB) in advanced non-small-cell lung cancer (NSCLC) stages III and IV: a phase III randomised trial. Lung Cancer 2002;37(1):9 /14. Fossella F. Docetaxel/Cisplatin (DC) and Docetaxel/Carboplatin (DCb) vs Vinorelbin/Cisplatin (VC) in chemotherapynaive patients with advanced and metastatic non-smal cell lung cancer (NSCLC): results of a multicenter, randomized phase III study. Eur J Cancer 2001;37(Suppl 6);Abstract Book, ECCO 11, abstract 562, S154.
Maurizio Tonato Division of Medical Oncology, Policlinico Hospital, Perugia, Italy