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Chemotherapy in NSCLC: historical review
Lung Cancer 38 (2002) S19 /S22 www.elsevier.com/locate/lungcan
Chemotherapy in NSCLC: historical review Paris Kosmidis Department of Medical Oncology, Ygeia Hospital, 2an. Tsoka & Vas. Sofias Aven, 11521 Athens, Greece
Abstract The use of chemotherapy in patients with advanced NSCLC has been under investigation for several years. It has evolved from administration in the palliative care setting to integration into combined-modality curative therapy settings in patients with locoregionally-advanced disease. Following the largest meta-analysis in 1995 it was suggested that platinum-based chemotherapy was effective in treating patients with advanced disease. The absolute improvement in survival was 10% at 1 year and an increased median survival of 1.5 months. Since this analysis, platinum-based chemotherapy is considered the gold standard of treatment in this disease. # 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Chemotherapy; NSCLC; Historical review
1. Introduction Lung cancer is one of the commonest malignancies in the world [1] and remains the leading cause of cancerrelated deaths in Western countries [2,3]. The incidence is increasing especially among women in whom lung cancer is now the most common cause of cancer death in the USA [4]. In the European Union, the crude incidence is 52.5 cases per 100 000 per year and the death rate 48.7 per 100 000 per year. For men, the rates are 79.3 and 78.3 and for women 21.6 and 20.5, respectively [5]. Non-small cell lung cancer (NSCLC) accounts for almost 85% of all lung cancer cases, and roughly more than 70% of patients have locally advanced or disseminated disease at presentation and are not candidates for surgery [1]. Patients with advanced disease who receive best supportive care (BSC) survive for a few months and approximately 90% do not survive 1 year [6]. These are the patients in whom chemotherapy has a primary role to play. The use of chemotherapy in patients with advanced NSCLC has been under investigation for several decades. It has evolved from administration in the palliative care setting to integration into combined-modality curative therapy settings in patients with locoregionally Tel.: /30-1-64-58602; fax: /30-1-64-52616 E-mail address: [email protected] (P. Kosmidis).
advanced disease. Most drugs have at best moderate activity ( ]/15%) in NSCLC. Throughout the 1970s and 1980s, only six drugs were thought to have such activity: Cisplatin, Mitomycin-C, Ifosfamide, Vindesine, Vinblastine and Etoposide. The response duration with these drugs was short with an average of 2 /3 months, and median survival was 6/8 months [7]. Combination chemotherapy was investigated in an attempt to increase response rate [8]. Generally, higher response rates were reported, but it remained unclear whether a more prolonged survival was achieved. In most studies, cisplatin was the main agent in the combination because it was considered by most investigators to be the most active [8 /10]. Cisplatin was combined most commonly with vinca alkaloids, etoposide or mitomycin and ifosfamide. Following these trials and based on the ECOG study in which carboplatin had shown the longest median survival time, cisplatin had been substituted in many trials by carboplatin which was less toxic and equally effective [11]. Therefore, the term platinum-based regimens is applied to treatment programs which include cisplatin or carboplatin as one of the component drugs.
2. Randomized studies With the limited activity observed with chemotherapy in advanced disease it was questioned whether benefits
0169-5002/02/$ - see front matter # 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 9 - 5 0 0 2 ( 0 2 ) 0 0 2 6 1 - 1
P. Kosmidis / Lung Cancer 38 (2002) S19 /S22
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Table 1 NSCLC: randomized trials of BSC vs. chemotherapy prior to 1995 Author
Year
Regimen
Patients BSC/chemo
Survival (weeks) BSC/chemo
P -value
Cormier et al. Rapp et al. Ganz et al. Woods et al. Kassa et al. Quoix et al. Cellerino et al. Cartei et al.
1982 1988 1989 1990 1991 1991 1991 1993
MACC CAP/VP VP VP VP VP CEP/MEC CCM
19/20 50/43/44 26/22 91/97 43/44 10/28 57/58 50/52
9/31 17/25/33 14/19 17/27 17/22 17/27 21/34 17/37
0.0005 0.05/0.01 0.26 0.33 0.28 0.33 0.135 0.0001
Table 2 NSCLC: meta-analysis of BSC vs. chemotherapy prior to 1995 Author
Year
Studies
Results
Conclusion
Souquet et al. Grilli et al. Marino et al.
1993 1993 1994
7 6 8
Reduced mortality at 3 and 6 months Survival benefit 6 weeks Survival benefit 2.8 months
Chemotherapy benefit Chemotherapy benefit Chemotherapy benefit
patients could derive were sufficient to offset toxicity. Therefore, a number of studies [12 /19] were initiated to compare BSC with chemotherapy (Table 1). The first study was reported by Cormier et al. in 1982 which was in favor of chemotherapy. This study was followed by others which, however, included an only insufficient number of patients to make definite conclusions. Certainly, most of the studies suggested at least a trend for improved survival. The most pivotal of these studies was by Rapp et al. from the National Cancer Institute of Canada in which the authors demonstrated that platinum-based chemotherapy proffered a survival advantage of between 12 and 14 weeks over BSC with 1 year survival rate improving from 12 to 14% with BSC to approximately 24/26% with platinum-based chemotherapy. In this study, the cost was found to be less in the chemotherapy arm.
3. Meta-analyzes of randomized studies Due to the inadequacies of these studies, metaanalyzes were suggested. Up to 1995 three metaanalyzes were done (Table 2). All three studies supported the same conclusion that chemotherapy prolongs
survival by modest but statistically significant time and, therefore, should be offered to patients [20 /22]. In 1995, the largest meta-analysis was published in the Lancet [23]. This was the most convincing meta-analysis because it included data from 52 randomized trials, which had enrolled 9387 patients. In this analysis, results of chemotherapy efficacy in advanced, locally advanced and early disease were reported.
3.1. Advanced disease: supportive care versus supportive care plus chemotherapy Data from 11 trials were available. These trials included 1190 patients. Two trials used long term alkylating agents and one used Etoposide. The remaining eight trials used cisplatin-based chemotherapy. Cisplatin was combined mainly with vinca alkaloids or etoposide. The results for trials using alkylating agents suggested a detrimental effect of chemotherapy with a hazard ratio of 1.26 (P /0.095). The cisplatin-based trials showed a chemotherapy benefit with a hazard ratio of 0.73 (P B/0.0001). The absolute improvement in survival was 10% (5 /15%) at 1 year and an increased median survival of 1.5 months (1 /2.5 months). In this analysis no evidence was found that any subgroup of
Table 3 NSCLC: advanced disease (1190 patients) Chemotherapy
Trials
Hazard ratio
P -value
Effect
Cisplatin-based Alkylating agents
8 2
0.73 1.26
0.0001 0.095
Beneficial 1-year 10% OS(m) 112 Detrimental
Supportive care vs. supportive care plus chemotherapy.
P. Kosmidis / Lung Cancer 38 (2002) S19 /S22
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Table 4 NSCLC: locally advanced (3033 patients) radiotherapy vs. radiotherapy plus chemotherapy Chemotherapy
Trials
Hazard ratio
P -value
Effect
Cisplatin-based Alkylating agents Vinca alkaloids Other
11 5 3 3
0.87 0.98 0.87 0.98
0.005 0.81 0.23 0.88
Beneficial 4%0 2 years, 2% 0 5 years Beneficial Beneficial Beneficial
Table 5 NSCLC: early disease (4357 patients) surgery vs. surgery plus chemotherapy Chemotherapy
Trials
Hazard ratio
P -value
Effect
Cisplatin-based Alkylating agents Other
8 5 3
0.87 1.15 0.89
0.08 0.005 0.30
Beneficial 3%0 2 years, 5% 0 5 years Detrimental Insufficient data
patients benefited more or less from chemotherapy (Table 3). 3.2. Locally advanced disease: radical radiotherapy versus radical radiotherapy plus chemotherapy Data were available from 22 trials which included 3033 patients. Five trials used long term alkylating agents, three used vinca alkaloids or etoposide and three combination with doxorubicin. Eleven trials used platinum-based chemotherapy. The results of all trials showed a significant overall benefit of chemotherapy. Specifically, for platinum-based chemotherapy the hazard ratio was 0.87 (P /0.005) with an absolute benefit of 4% at 2 years and 2% at 5 years (Table 4). 3.3. Early disease: surgery versus surgery plus chemotherapy
[2] [3]
[4] [5] [6] [7]
[8] [9]
[10] [11]
Data from 14 trials were available including 4357 patients. Five trials used long term alkylating agents and eight used cisplatin-based chemotherapy. The results for the group of alkylating agents showed a hazard ratio of 1.15 (P /0.005) which translates to a detrimental effect of this type of chemotherapy. The hazard ratio for cisplatin-based chemotherapy was 0.87 (P /0.08) with a suggested absolute benefit of 3% at 2 years and 5% at 5 years (Table 5). In conclusion and based on this meta-analysis, cisplatin-based chemotherapy is beneficial for patients who have locally advanced or advanced NSCLC.
[12]
[13]
[14]
[15]
References [16] [1] Ginsberg RT, Vokes EE, Raben A. Non-small cell lung cancer. In: De Vita V, Jr, Hellman J, Rosenberg SR, editors. Cancer:
principles and practice of oncology, 5th ed. Philadelphia, PA: Lippincott /Raven, 1997:858 /911. Landis SM, Murray T, Bolden S, et al. Cancer statistics 1998. CA Cancer J Clin 1998;48:6 /29. Lubin JM. Lung and larynx. In: Cancer rates and risks, 4th ed. National Institute of Health, National Cancer Institute, 1996:158 /61. Greenlee RT, Murray T, Bolden S, Wingo PA. Cancer statistics. CA Cancer J Clin 2000;50(1):7 /33. ESMO Guidelines in NSCLC, 2000. Mountain CF. Revisions in the international system for staging lung cancer. Chest 1997;111:1710 /7. Sorensen JB, Clerici M, Hansen HH. Review: single agent chemotherapy in advanced adenocarcinoma of the lung cancer. Chemother Pharmacol 1988;21:89. Shepherd FA. Treatment of advanced non-small cell lung cancer. Semin Oncol 1994;21(Suppl. 7):7. Vokes EE, Vijayakumar S, Bitran JD, et al. The role of systemic therapy in advanced non-small cell lung cancer. A review. Am J Med 1990;89:777. Livingston RB. Current management of unresectable non-small cell lung cancer. Semin Oncol 1994;21(Suppl. 8):4. Bonomi P, Finkelstein D, Ruckdeschel J, et al. Combination chemotherapy versus single agents followed by combination chemotherapy in stage IV non-small cell lung cancer: a study of the eastern cooperative oncology group. J Clin Oncol 1989;7:1602. Cormier Y, Bergeron D, La Forge J, et al. Benefit of polychemotherapy in advanced non-small cell bronchogenic carcinoma. Cancer 1982;50:845. Rapp E, Pater JL, Willan A, et al. Chemotherapy can prolong survival in patients with advanced non-small cell lung cancer: report of a canadian multicenter randomized trial. J Clin Oncol 1988;6:633. Ganz P, Figlin R, Haskell C, et al. Supportive care versus supportive care and combination chemotherapy in metastatic non-small cell lung cancer: does chemotherapy make the difference. Cancer 1989;63:1271. Woods R, Williams C, Levi J, et al. A randomized trial of cisplatin and vindensine versus supportive care only in advanced non-small cell lung cancer. Br J Cancer 1990;61:608. Kaasa S, Lund E, Thorud E, et al. Symptomatic treatment versus combination chemotherapy for patients with extensive non-small cell lung cancer. Cancer 1991;67:2443.
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P. Kosmidis / Lung Cancer 38 (2002) S19 /S22
[17] Quoix E, Dietemann A, Carbenneau J, et al. La chimiotherapic comportant du cisplatin est-elle utile dans le cancer bronchique non microcellulaive au stade IV. Resultans d’une etude randomisee. Bull Cancer 1991;78:341. [18] Cellerino R, Tummarello D, Gindi F, et al. A randomized trial alternating chemotherapy versus best supportive care in advanced non-small cell lung cancer. J Clin Oncol 1991;9:1453. [19] Cartei G, Cartei F, Cantone A, et al. Cisplatin /cyclophosphamide /mitomycin combination chemotherapy with supportive care versus supportive care alone for treatment of metastatic non-small cell lung cancer. J Natl Cancer Inst 1993;85:794.
[20] Souquet PJ, Chauvin F, Boissel JP, et al. Polychemotherapy in advanced non-small cell lung cancer: a meta-analysis. Lancet 1993;342:19. [21] Grilli R, Oxman AD, Julian JM. Chemotherapy for advanced non-small cell lung cancer. How much benefit is enough. J Clin Oncol 1866;11:1993. [22] Marino P, Pampallona S, Prestoni A, et al. Chemotherapy versus supportive care in advanced non-small cell lung cancer: results of a meta-analysis of the literature. Chest 1994;106:861. [23] Non-small cell lung cancer collaborative group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomized clinical trials. Br Med J 1995;311:899.
Chemotherapy in NSCLC: historical review Paris Kosmidis Department of Medical Oncology, Ygeia Hospital, 2an. Tsoka & Vas. Sofias Aven, 11521 Athens, Greece
Abstract The use of chemotherapy in patients with advanced NSCLC has been under investigation for several years. It has evolved from administration in the palliative care setting to integration into combined-modality curative therapy settings in patients with locoregionally-advanced disease. Following the largest meta-analysis in 1995 it was suggested that platinum-based chemotherapy was effective in treating patients with advanced disease. The absolute improvement in survival was 10% at 1 year and an increased median survival of 1.5 months. Since this analysis, platinum-based chemotherapy is considered the gold standard of treatment in this disease. # 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Chemotherapy; NSCLC; Historical review
1. Introduction Lung cancer is one of the commonest malignancies in the world [1] and remains the leading cause of cancerrelated deaths in Western countries [2,3]. The incidence is increasing especially among women in whom lung cancer is now the most common cause of cancer death in the USA [4]. In the European Union, the crude incidence is 52.5 cases per 100 000 per year and the death rate 48.7 per 100 000 per year. For men, the rates are 79.3 and 78.3 and for women 21.6 and 20.5, respectively [5]. Non-small cell lung cancer (NSCLC) accounts for almost 85% of all lung cancer cases, and roughly more than 70% of patients have locally advanced or disseminated disease at presentation and are not candidates for surgery [1]. Patients with advanced disease who receive best supportive care (BSC) survive for a few months and approximately 90% do not survive 1 year [6]. These are the patients in whom chemotherapy has a primary role to play. The use of chemotherapy in patients with advanced NSCLC has been under investigation for several decades. It has evolved from administration in the palliative care setting to integration into combined-modality curative therapy settings in patients with locoregionally Tel.: /30-1-64-58602; fax: /30-1-64-52616 E-mail address: [email protected] (P. Kosmidis).
advanced disease. Most drugs have at best moderate activity ( ]/15%) in NSCLC. Throughout the 1970s and 1980s, only six drugs were thought to have such activity: Cisplatin, Mitomycin-C, Ifosfamide, Vindesine, Vinblastine and Etoposide. The response duration with these drugs was short with an average of 2 /3 months, and median survival was 6/8 months [7]. Combination chemotherapy was investigated in an attempt to increase response rate [8]. Generally, higher response rates were reported, but it remained unclear whether a more prolonged survival was achieved. In most studies, cisplatin was the main agent in the combination because it was considered by most investigators to be the most active [8 /10]. Cisplatin was combined most commonly with vinca alkaloids, etoposide or mitomycin and ifosfamide. Following these trials and based on the ECOG study in which carboplatin had shown the longest median survival time, cisplatin had been substituted in many trials by carboplatin which was less toxic and equally effective [11]. Therefore, the term platinum-based regimens is applied to treatment programs which include cisplatin or carboplatin as one of the component drugs.
2. Randomized studies With the limited activity observed with chemotherapy in advanced disease it was questioned whether benefits
0169-5002/02/$ - see front matter # 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 9 - 5 0 0 2 ( 0 2 ) 0 0 2 6 1 - 1
P. Kosmidis / Lung Cancer 38 (2002) S19 /S22
S20
Table 1 NSCLC: randomized trials of BSC vs. chemotherapy prior to 1995 Author
Year
Regimen
Patients BSC/chemo
Survival (weeks) BSC/chemo
P -value
Cormier et al. Rapp et al. Ganz et al. Woods et al. Kassa et al. Quoix et al. Cellerino et al. Cartei et al.
1982 1988 1989 1990 1991 1991 1991 1993
MACC CAP/VP VP VP VP VP CEP/MEC CCM
19/20 50/43/44 26/22 91/97 43/44 10/28 57/58 50/52
9/31 17/25/33 14/19 17/27 17/22 17/27 21/34 17/37
0.0005 0.05/0.01 0.26 0.33 0.28 0.33 0.135 0.0001
Table 2 NSCLC: meta-analysis of BSC vs. chemotherapy prior to 1995 Author
Year
Studies
Results
Conclusion
Souquet et al. Grilli et al. Marino et al.
1993 1993 1994
7 6 8
Reduced mortality at 3 and 6 months Survival benefit 6 weeks Survival benefit 2.8 months
Chemotherapy benefit Chemotherapy benefit Chemotherapy benefit
patients could derive were sufficient to offset toxicity. Therefore, a number of studies [12 /19] were initiated to compare BSC with chemotherapy (Table 1). The first study was reported by Cormier et al. in 1982 which was in favor of chemotherapy. This study was followed by others which, however, included an only insufficient number of patients to make definite conclusions. Certainly, most of the studies suggested at least a trend for improved survival. The most pivotal of these studies was by Rapp et al. from the National Cancer Institute of Canada in which the authors demonstrated that platinum-based chemotherapy proffered a survival advantage of between 12 and 14 weeks over BSC with 1 year survival rate improving from 12 to 14% with BSC to approximately 24/26% with platinum-based chemotherapy. In this study, the cost was found to be less in the chemotherapy arm.
3. Meta-analyzes of randomized studies Due to the inadequacies of these studies, metaanalyzes were suggested. Up to 1995 three metaanalyzes were done (Table 2). All three studies supported the same conclusion that chemotherapy prolongs
survival by modest but statistically significant time and, therefore, should be offered to patients [20 /22]. In 1995, the largest meta-analysis was published in the Lancet [23]. This was the most convincing meta-analysis because it included data from 52 randomized trials, which had enrolled 9387 patients. In this analysis, results of chemotherapy efficacy in advanced, locally advanced and early disease were reported.
3.1. Advanced disease: supportive care versus supportive care plus chemotherapy Data from 11 trials were available. These trials included 1190 patients. Two trials used long term alkylating agents and one used Etoposide. The remaining eight trials used cisplatin-based chemotherapy. Cisplatin was combined mainly with vinca alkaloids or etoposide. The results for trials using alkylating agents suggested a detrimental effect of chemotherapy with a hazard ratio of 1.26 (P /0.095). The cisplatin-based trials showed a chemotherapy benefit with a hazard ratio of 0.73 (P B/0.0001). The absolute improvement in survival was 10% (5 /15%) at 1 year and an increased median survival of 1.5 months (1 /2.5 months). In this analysis no evidence was found that any subgroup of
Table 3 NSCLC: advanced disease (1190 patients) Chemotherapy
Trials
Hazard ratio
P -value
Effect
Cisplatin-based Alkylating agents
8 2
0.73 1.26
0.0001 0.095
Beneficial 1-year 10% OS(m) 112 Detrimental
Supportive care vs. supportive care plus chemotherapy.
P. Kosmidis / Lung Cancer 38 (2002) S19 /S22
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Table 4 NSCLC: locally advanced (3033 patients) radiotherapy vs. radiotherapy plus chemotherapy Chemotherapy
Trials
Hazard ratio
P -value
Effect
Cisplatin-based Alkylating agents Vinca alkaloids Other
11 5 3 3
0.87 0.98 0.87 0.98
0.005 0.81 0.23 0.88
Beneficial 4%0 2 years, 2% 0 5 years Beneficial Beneficial Beneficial
Table 5 NSCLC: early disease (4357 patients) surgery vs. surgery plus chemotherapy Chemotherapy
Trials
Hazard ratio
P -value
Effect
Cisplatin-based Alkylating agents Other
8 5 3
0.87 1.15 0.89
0.08 0.005 0.30
Beneficial 3%0 2 years, 5% 0 5 years Detrimental Insufficient data
patients benefited more or less from chemotherapy (Table 3). 3.2. Locally advanced disease: radical radiotherapy versus radical radiotherapy plus chemotherapy Data were available from 22 trials which included 3033 patients. Five trials used long term alkylating agents, three used vinca alkaloids or etoposide and three combination with doxorubicin. Eleven trials used platinum-based chemotherapy. The results of all trials showed a significant overall benefit of chemotherapy. Specifically, for platinum-based chemotherapy the hazard ratio was 0.87 (P /0.005) with an absolute benefit of 4% at 2 years and 2% at 5 years (Table 4). 3.3. Early disease: surgery versus surgery plus chemotherapy
[2] [3]
[4] [5] [6] [7]
[8] [9]
[10] [11]
Data from 14 trials were available including 4357 patients. Five trials used long term alkylating agents and eight used cisplatin-based chemotherapy. The results for the group of alkylating agents showed a hazard ratio of 1.15 (P /0.005) which translates to a detrimental effect of this type of chemotherapy. The hazard ratio for cisplatin-based chemotherapy was 0.87 (P /0.08) with a suggested absolute benefit of 3% at 2 years and 5% at 5 years (Table 5). In conclusion and based on this meta-analysis, cisplatin-based chemotherapy is beneficial for patients who have locally advanced or advanced NSCLC.
[12]
[13]
[14]
[15]
References [16] [1] Ginsberg RT, Vokes EE, Raben A. Non-small cell lung cancer. In: De Vita V, Jr, Hellman J, Rosenberg SR, editors. Cancer:
principles and practice of oncology, 5th ed. Philadelphia, PA: Lippincott /Raven, 1997:858 /911. Landis SM, Murray T, Bolden S, et al. Cancer statistics 1998. CA Cancer J Clin 1998;48:6 /29. Lubin JM. Lung and larynx. In: Cancer rates and risks, 4th ed. National Institute of Health, National Cancer Institute, 1996:158 /61. Greenlee RT, Murray T, Bolden S, Wingo PA. Cancer statistics. CA Cancer J Clin 2000;50(1):7 /33. ESMO Guidelines in NSCLC, 2000. Mountain CF. Revisions in the international system for staging lung cancer. Chest 1997;111:1710 /7. Sorensen JB, Clerici M, Hansen HH. Review: single agent chemotherapy in advanced adenocarcinoma of the lung cancer. Chemother Pharmacol 1988;21:89. Shepherd FA. Treatment of advanced non-small cell lung cancer. Semin Oncol 1994;21(Suppl. 7):7. Vokes EE, Vijayakumar S, Bitran JD, et al. The role of systemic therapy in advanced non-small cell lung cancer. A review. Am J Med 1990;89:777. Livingston RB. Current management of unresectable non-small cell lung cancer. Semin Oncol 1994;21(Suppl. 8):4. Bonomi P, Finkelstein D, Ruckdeschel J, et al. Combination chemotherapy versus single agents followed by combination chemotherapy in stage IV non-small cell lung cancer: a study of the eastern cooperative oncology group. J Clin Oncol 1989;7:1602. Cormier Y, Bergeron D, La Forge J, et al. Benefit of polychemotherapy in advanced non-small cell bronchogenic carcinoma. Cancer 1982;50:845. Rapp E, Pater JL, Willan A, et al. Chemotherapy can prolong survival in patients with advanced non-small cell lung cancer: report of a canadian multicenter randomized trial. J Clin Oncol 1988;6:633. Ganz P, Figlin R, Haskell C, et al. Supportive care versus supportive care and combination chemotherapy in metastatic non-small cell lung cancer: does chemotherapy make the difference. Cancer 1989;63:1271. Woods R, Williams C, Levi J, et al. A randomized trial of cisplatin and vindensine versus supportive care only in advanced non-small cell lung cancer. Br J Cancer 1990;61:608. Kaasa S, Lund E, Thorud E, et al. Symptomatic treatment versus combination chemotherapy for patients with extensive non-small cell lung cancer. Cancer 1991;67:2443.
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P. Kosmidis / Lung Cancer 38 (2002) S19 /S22
[17] Quoix E, Dietemann A, Carbenneau J, et al. La chimiotherapic comportant du cisplatin est-elle utile dans le cancer bronchique non microcellulaive au stade IV. Resultans d’une etude randomisee. Bull Cancer 1991;78:341. [18] Cellerino R, Tummarello D, Gindi F, et al. A randomized trial alternating chemotherapy versus best supportive care in advanced non-small cell lung cancer. J Clin Oncol 1991;9:1453. [19] Cartei G, Cartei F, Cantone A, et al. Cisplatin /cyclophosphamide /mitomycin combination chemotherapy with supportive care versus supportive care alone for treatment of metastatic non-small cell lung cancer. J Natl Cancer Inst 1993;85:794.
[20] Souquet PJ, Chauvin F, Boissel JP, et al. Polychemotherapy in advanced non-small cell lung cancer: a meta-analysis. Lancet 1993;342:19. [21] Grilli R, Oxman AD, Julian JM. Chemotherapy for advanced non-small cell lung cancer. How much benefit is enough. J Clin Oncol 1866;11:1993. [22] Marino P, Pampallona S, Prestoni A, et al. Chemotherapy versus supportive care in advanced non-small cell lung cancer: results of a meta-analysis of the literature. Chest 1994;106:861. [23] Non-small cell lung cancer collaborative group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomized clinical trials. Br Med J 1995;311:899.