Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA

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1 The Oncologist Mayo Clinic Hematology/Oncology Reviews Is There a Preferred Combination Chemotherapy Regimen for Metastastic Non-Small Cell Lung Cancer? DAVID S. ETTINGER Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA Key Words. Metastatic non-small cell lung cancer Combination chemotherapy Phase III studies LEARNING OBJECTIVES After completing this course, the reader will be able to: 1. Choose the appropriate chemotherapeutic regimen to treat a patient with metastatic non-small cell lung cancer. 2. Identify the advantages and disadvantages of the various regimens to treat stage IV non-small cell cancer. 3. Understand the toxicities associated with each of the various chemotherapeutic regimens. CME ABSTRACT Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com Since over 70% of patients with non-small cell lung cancer (NSCLC) have advanced (locally advanced or metastatic) disease, the majority of NSCLC patients might benefit from chemotherapy. During the past decade, a number of new agents (paclitaxel, docetaxel, gemcitabine, vinorelbine, irinotecan, and topotecan) have been found to be effective against lung cancer. These agents have been combined with cisplatin, carboplatin, and nonplatinum drugs to treat NSCLC. They, in general, produce median survival times of 8-10 months and 1- and 2-year survival rates of 35%-40% and 10%- 15%, respectively. Based on this review, there is not a preferred combination chemotherapy regimen to treat advanced NSCLC patients. However, there are a number of different regimens from which to choose. The Oncologist 2002;7: INTRODUCTION It is estimated that there will be 169,400 (90,200 male and 79,200 female) new cases of lung cancer diagnosed in 2002 with approximately 154,900 deaths (89,200 male and 65,700 female) [1]. Unfortunately, only 14% of all lung cancer patients (all stages) will be alive 5 or more years after their diagnosis [2]. Over 70% of lung cancer patients, when diagnosed, have advanced (locally advanced or metastatic) disease. There is an obvious need for systemic chemotherapy since the majority of non-small cell lung cancer (NSCLC) tumors are inoperable at diagnosis, and patients treated with surgery and or radiation therapy develop distant metastases. During the last 10 years, a number of new agents were found to be effective against lung cancer (Table 1). They have all been incorporated in a number of combination Correspondence: David S. Ettinger, M.D., The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Bunting Blaustein Cancer Research Building, Room G88, 1650 Orleans Street, Baltimore, Maryland , USA. Telephone: ; Fax: ; ettinda@jhmi.edu Received December 5, 2001; accepted for publication January 23, AlphaMed Press /2002/$5.00/0 The Oncologist 2002;7:

2 227 Is There a Preferred Combination Chemotherapy Regimen for Metastastic NSCLC? Table 1. Classes of new agents active in lung cancer Mode of action Antimetabolite Antitubulins-classical Antitubulins- stabilizing Topoisomerase-1 inhibitors Agent(s) Gemcitabine Vinorelbine Paclitaxel, docetaxel Irinotecan, topotecan chemotherapeutic regimens, many of which included either cisplatin or carboplatin to treat patients with NSCLC. The use of chemotherapy in the treatment of metastatic NSCLC is palliative in nature. The benefits of therapy for stage IV NSCLC are to: A) cause an objective tumor response; B) decrease symptoms; C) improve quality of life, and D) improve survival. The risks associated with chemotherapy are: A) toxicities associated with therapy; B) treatment-related deaths; C) increased costs and inconvenience of treatment, and D) increased hospitalization time. This article addresses the question: Is there a preferred combination chemotherapy regimen for metastatic NSCLC? It only includes data from phase III trials; however, not every phase III study is mentioned. In my opinion, the question can be answered without including every phase II or III study evaluating various chemotherapy regimens to treat metastatic NSCLC. INITIAL ECOG AND SWOG STUDIES In 1993, both the Eastern Cooperative Oncology Group (ECOG) and the Southwest Oncology Group (SWOG) initiated phase III studies evaluating two of the new drugs against NSCLC [3, 4]. In the ECOG study, stage IIIB/IV NSCLC patients were randomized to receive either paclitaxel plus cisplatin or etoposide plus cisplatin [3]. Paclitaxel was given i.v. over 24 hours as either a 135 mg/m 2 or 250 mg/m 2 dose, while etoposide was administered at 100 mg/m 2 i.v. daily on days 1-3. Each drug was administered with cisplatin given at 75 mg/m 2 i.v. on day 1. The therapy was repeated every 21 days. G-CSF was administered with the high-dose paclitaxel regimen. Five hundred and ninety-nine patients were entered in the trial. The objective response rates for the low-dose and high-dose paclitaxel regimens and for the etoposide plus cisplatin therapy were 25.3%, 27.7%, and 12.4%, respectively. The two paclitaxel regimens combined gave a superior survival time compared with the etoposide plus cisplatin regimen. The median survival times and 1-year survival rates were 9.9 months and 38% versus 7.6 months and 31.8% (p = 0.048), respectively. There was no survival difference between the two paclitaxel regimens. Toxicities were similar in the three arms, except for a greater incidence of granulocytopenia with the low-dose paclitaxel, and greater incidences of myalgias, neurotoxicity, and possible cardiac toxicity with the high-dose paclitaxel. Based on this study, low-dose paclitaxel (135 mg/m 2 ) plus cisplatin replaced etoposide plus cisplatin as the reference regimen for future ECOG studies. In the SWOG study, 432 patients with stage IIIB/IV NSCLC were randomized to receive either the single agent cisplatin, 100 mg/m 2 i.v. every 4 weeks, or cisplatin, 100 mg/m 2 i.v. every 4 weeks, plus vinorelbine, 25 mg/m 2 i.v. weekly [4]. For the single-agent therapy versus the combination regimen, the response rates were 12% versus 26% (p = ), the overall median survival times were 6 months versus 8 months (p = ), the 1-year survival rates were 20% versus 36%, and the 2-year survival rates were 6% versus 12%. The two-drug regimen had an 81% occurrence of grade 3/4 granulocytopenia versus 5% with the single agent, cisplatin. Based on this study, vinorelbine plus cisplatin became the new standard for SWOG advanced NSCLC studies. FOLLOW-UP ECOG AND SWOG STUDIES ECOG, after doing the above study, randomized 1,207 NSCLC patients to four different combination chemotherapy regimens: paclitaxel plus cisplatin (their standard ), docetaxel plus cisplatin, gemcitabine plus cisplatin, and paclitaxel plus carboplatin (Table 2) [5]. Eighty-five percent of the patients had metastatic disease. The objective response rates varied from 15.3% to 21.3%. The median survival ranged from 7.4 months to 8.2 months with 1- and 2-year survival rates varying from 31% to 36% and 10.5% to 15.7%, respectively. The differences in the above rates among the four regimens were not statistically significant. However, the time to progression (TTP) was significant, in favor of the gemcitabine plus cisplatin regimen. In part, this improvement in TTP may be explained by the fact that patients receiving gemcitabine plus cisplatin were evaluated every 4 weeks rather than every 3 weeks, as with the other regimens in the study. The paclitaxel plus carboplatin treatment was reasonably well tolerated except for a higher rate of neuropathy, while the gemcitabine plus cisplatin regimen was associated with more renal toxicity, anemia, and thrombocytopenia. The ECOG study did not identify a superior regimen that would be recommended as the standard therapy for patients with metastatic NSCLC. However, many of the ECOG NSCLC studies that followed utilized the paclitaxel plus carboplatin regimen. SWOG conducted a phase III trial comparing a cisplatin plus vinorelbine treatment regimen with a paclitaxel plus carboplatin treatment regimen in patients with stage IIIB/IV NSCLC (Table 3) [7]. For these regimens, only 12% and 11% of patients, respectively, had stage IIIB disease. Four hundred and eight patients were eligible for the

3 Ettinger 228 Table 2. Eastern Cooperative Oncology Group study 1594 Drugs T Cis Gem Cis Tax Cis T Carbo Entered Eligible Median survival (mo) year survival (%) year survival (%) OR (%) TTP (mo) * Toxicities renal hypersens. grade 4/5 toxicities anemia neut. fever thrombocytopenia neuropathy neut. fever *p = T Cis = paclitaxel, 135 mg/m 2 i.v. over 24 hours, day 1; cisplatin, 75 mg/m 2 i.v., day 2 every 3 weeks Gem Cis = gemcitabine, 1,000 mg/m 2, days 1, 8, and 15; cisplatin, 100 mg/m 2, day 1 every 4 weeks Tax Cis = docetaxel, 75 mg/m 2 over 1 hour, day 1; cisplatin, 75 mg/m 2 i.v., day 1 every 3 weeks T Carbo = paclitaxel, 225 mg/m 2 i.v. over 3 hours, day 1; carboplatin (AUC 6.0), day 1 every 3 weeks Abbreviations: AUC = area under the concentration time curve; OR = overall response; TTP = time to progression Table 3. Southwest Oncology Group study PC Vino/Cis n of patients Response (%) Median survival (mo) year survival (%) Grade 4 neutropenia p < 0.05 Grade 3 nausea 6 17 p < 0.01 Grade 3 neuropathy 8 3 p < 0.05 Completed study p < 0.05 Off study due to toxicity (%) p < 0.01 PC = paclitaxel, 225 mg/m 2 over 3 hours, day 1; carboplatin, AUC = 6, day 1 every 21 days. Vino/Cis = vinorelbine, 25 mg/m 2 i.v., weekly; cisplatin, 100 mg/m 2 i.v, day 1 every 28 days. GEMCITABINE/CISPLATIN VERSUS ETOPOSIDE/CISPLATIN After a gemcitabine plus cisplatin versus cisplatin alone randomized trial in stage IIIB/IV NSCLC gave a statistically significant survival advantage for the combination [7], another phase III study compared that combination with etoposide plus cisplatin (Table 4) [8]. One hundred and thirty-five NSCLC patients were entered in the study, 133 of whom were included in the intent-to-treat analysis of response. In this study, 47.8% of patients receiving gemcitabine-cisplatin had stage IIIB disease while 51.5% of the patients receiving etoposide-cisplatin had stage IIIB disease. NSCLC patients receiving gemcitabine-cisplatin had a statistically significant higher response rate (40.6% versus 21.9%; p = 0.02) and TTP (6.9 months versus 4.3 months; p = 0.01) than patients receiving etoposide-cisplatin. study, and of these, 365 were evaluable. There were similar response rates (27%) and median survival times (8 months) in the two treatment groups. The 1- and 2-year survival rates were 38% and 15%, respectively, for the paclitaxel regimen and 36% and 16%, respectively, for the vinorelbine combination. The incidences of hematologic toxicity and nausea were higher on the vinorelbine plus cisplatin therapy, while the incidence of peripheral neuropathy was higher on the paclitaxel plus carboplatin regimen. More NSCLC patients receiving vinorelbine plus cisplatin were unable to complete the therapy due to toxicity. The investigators concluded that both regimens were effective in the treatment of advanced NSCLC, however, their future standard was to be paclitaxel plus carboplatin due to the lower toxicity and better tolerability of the regimen. Table 4. Gemcitabine/cisplatin versus etoposide/cisplatin in stage IIIB and IV NSCLC Gem/Cis E/Cis n of patients Response (%) p = 0.02 Median survival (mo) p = 0.18 TTP (mo) p = Grade 3/4 toxicity (%) Neutropenia 36/28 20/56 Thrombocytopenia 39/16 8/5 Nausea and vomiting 35/4 19/7 Alopecia 13/ 51/ Gem/Cis = gemcitabine, 1,250 mg/m 2 i.v., days 1 and 8; cisplatin, 100 mg/m 2 i.v., day 1 every 21 days. E/Cis = etoposide, 100 mg/m 2 i.v., days 1-3; cisplatin, 100 mg/m 2 i.v., day 1 every 21 days.

4 229 Is There a Preferred Combination Chemotherapy Regimen for Metastastic NSCLC? Unfortunately, there was no statistically significant difference in survival time between the regimens (8.7 months versus 7.2 months, p = 0.18). Nausea and vomiting as well as thrombocytopenia were more frequent with the gemcitabine regimen, while alopecia was markedly less with the combination. There were no thrombocytopenia-related complications associated with the gemcitabine-cisplatin regimen. The gemcitabine-cisplatin regimen, although not significantly improving survival times, did provide a significantly higher response rate and TTP without significantly affecting the quality of life in stage IIIB/IV NSCLC patients. HELLENIC COOPERATIVE ONCOLOGY GROUP STUDY In 1998, the Hellenic Cooperative Oncology Group initiated a phase III study comparing gemcitabine/paclitaxel with carboplatin/paclitaxel in patients with advanced NSCLC (Table 5) [9]. Eligible patients had inoperable stage IIIA, IIIB, or IV NSCLC. There was no statistically significant difference between the two regimens in the treatment of advanced NSCLC in regard to response rate, TTP, median survival, 1-year survival, or toxicity, although the response rate, survival time, and 1-year survival rate were superior for the noncisplatin-containing regimen gemcitabine plus paclitaxel. It should be noted that, although patients receiving either regimen were reported to be well matched with baseline demographics and patient characteristics, no mention was made regarding what percentage of patients had stage IIIA/IIIB disease. EORTC LUNG STUDY The European Organization for Research and Treatment of Cancer (EORTC) lung cancer group performed a randomized phase III trial of three chemotherapy regimens (paclitaxel/cisplatin, gemcitabine/cisplatin, and paclitaxel/gemcitabine) in advanced NSCLC (Table 6) [10]. Four hundred and eighty patients were entered in the trial. Only 21% of all patients had stage IIIB disease, while 79% had stage IV disease. The noncisplatin regimen paclitaxel/gemcitabine had a lower response rate, survival time, and 1- year survival rate than the two cisplatin-containing regimens in the treatment of advanced NSCLC. The regimens were reasonably well tolerated, although there was more thrombocytopenia with the gemcitabine/cisplatin treatment than with the other two regimens. ITALIAN LUNG CANCER TRIAL Six hundred and twelve patients with stage IIIB/IV NSCLC, 81% of whom had stage IV disease, were entered in a phase III randomized study comparing three platinumbased doublets (Table 7) [11]. The response rates (60%-63%) and median survival times (9.5 months to 9.9 months) were Table 5. Hellenic Oncology Group study Gemcitabine/ Carboplatin/ paclitaxel* paclitaxel** p value n of patients entered Grade 3/4 neutropenia (%) Grade 3/4 thrombocytopenia (%) Grade 3/4 anemia (%) Grade 3/4 neurotoxicity (%) Number of patients evaluated Complete + partial responses (%) Median time to tumor progression (mo) Median survival (mo) year survival (%) **Gemcitabine = 1 g/m 2, days 1 and 8, paclitaxel, 200 mg/m 2 over 3 hours, day 1 **every 21 days. **Carboplatin = AUC 6, day 1, paclitaxel, 200 mg/m 2 over 3 hours, day 1 every **21 days. Table 6. European Organization for Research and Treatment of Cancer study (08975) Pac/Cis* Gem/Cis** Pac/Gem*** n of patients Grade 3/4 neutropenia (%) Grade 3/4 thrombocytopenia (%) Toxic deaths Response rate (%) Median survival (mo) year survival (%) ***Paclitaxel = 175 mg/m 2 over 3 hours, day 1, cisplatin, 80 mg/m 2, day 1 over 21 days. ***Gemcitabine = 1,250 mg/m 2, days 1 and 8, cisplatin, 80 mg/m 2, day 1 over 21 days. ***Paclitaxel = 175 mg/m 2 over 3 hours, day 1, gemcitabine, 1,250 mg/m 2, days 1 ***and 8 over 21 days. similar among the three regimens. There were greater incidences of grade 3/4 neutropenia and alopecia with the paclitaxel/carboplatin than with either of the two cisplatincontaining regimens. However, there was more peripheral neuropathy associated with the noncisplatin-containing regimen paclitaxel/carboplatin. DOCETAXEL STUDY TAX 326 The Tax 326 phase III study compared two docetaxelcontaining regimens with a regimen of vinorelbine and cisplatin in NSCLC patients with stage IIIB/IV disease (Table 8) [12]. The percentage of patients with stage IIIB disease ranged from 31% to 34%. The three regimens were similar in toxicity except there were higher incidences of anemia and vomiting associated with the vinorelbine/cisplatin regimen. The response rate was not reported. The median survival, 1- year survival, and 2-year survival rates were higher for the

5 Ettinger 230 Table 7. Italian lung cancer trial Cis/Gem* Pac/Carbo** Cis/Vino*** Grade 3/4 neutropenia (%) Grade 3/4 thrombocytopenia (%) 16 3 <1 Grade 3/4 anemia (%) Alopecia (%) Peripheral neuropathy ( grade 2) (%) Nausea and vomiting (%) Response rate (%) Median survival (mo) ***Cisplatin = 75 mg/m 2, day 2, gemcitabine, 1,250 mg/m 2, days 1 and 8 every ***3 weeks. ***Paclitaxel = 225 mg/m 2 over 3 hours, carboplatin, AUC = 6 every 3 weeks. ***Cisplatin = 100 mg/m 2, day 1, vinorelbine 25 mg/m 2, weekly every 4 weeks. Table 8. Docetaxel study Tax 326 DC* D Carbo** VC*** n of patients Stage IV (%) Grade 3/4 anemia (%) Grade 3/4 neutropenia (%) Grade 3/4 vomiting (%) p < 0.01 Grade 3/4 neurosensory Response rate NR NR NR Median survival (mo) year survival (%) year survival (%) ***DC = docetaxel, 75 mg/m 2 over 1 hour, cisplatin, 75 mg/m 2 every 21 days. ***D Carbo = docetaxel, 75 mg/m 2 over 1 hour, carboplatin, AUC = 6 every ***21 days. ***VC = vinorelbine, 25 mg/m 2, weekly, cisplatin, 100 mg/m 2 every 28 days. docetaxel/cisplatin combination, however, these were not statistically significant. Table 9. National Coalition of Cooperative Groups study Gemcitabine 1,000 mg/m 2, days 1 and 8 Carboplatin AUC = 5.5, day 1 every 21 days Gemcitabine 1,000 mg/m 2, days 1 and 8 Paclitaxel 200 mg/m 2 over 3 hours, day 1 every 21 days Paclitaxel 225 mg/m 2 over 3 hours, day 1 Carboplatin AUC = 6, day 1 every 21 days Table 10. Cancer and Leukemia Group B study Paclitaxel 200 mg/m 2 over 3 hours, day 1 every 21 days Paclitaxel 200 mg/m 2 over 3 hours, day 1 every 21 days Carboplatin AUC = 6, day 1 Table 11. CPT-11 Lung Cancer Study Group trial CPT-11/Cis VDS/Cis Grade 3/4 neutropenia (%) Grade 3/4 diarrhea (%) 13 1 Response rate (%) Median survival (weeks) For stage IV patients only Median survival (mo) year survival (%) year survival (%) 9 10 CPT-11/Cis = irinotecan, 60 mg/m 2 i.v., days 1, 8, and 15; cisplatin, 80 mg/m 2 i.v., day 1 every 4 weeks. VDS/Cis = vindesine 3 mg/m 2 i.v., days 1, 8, and 15; cisplatin 80 mg/m 2 i.v., day 1 every 4 weeks. (Table 10). The results of the study will be presented at the American Society of Clinical Oncology meeting in May of NATIONAL COALITION OF COOPERATIVE GROUPS STUDY The National Coalition of Cooperative Groups is conducting a phase III study in stage IIIB/IV NSCLC patients that compares gemcitabine/carboplatin treatment with gemcitabine/paclitaxel and with paclitaxel/carboplatin treatments (Table 9). The plan is to enter 300 patients in each arm. The end points include survival, quality-of-life measurements, and toxicity. CALGB STUDY The Cancer and Leukemia Group B (CALGB) has completed a phase III randomized study comparing single-agent paclitaxel therapy with a paclitaxel plus carboplatin regimen CPT-11 LUNG CANCER STUDY GROUP TRIAL In Japan, a randomized multicenter phase III trial was done comparing irinotecan/cisplatin treatment with vindesine/cisplatin treatment (Table 11) [13]. Two hundred and ten advanced NSCLC patients were entered into the trial. Forty-one percent of patients had stage IIIB disease. For the irinotecan/cisplatin regimen, the response rate was 29%, median survival was 45.4 weeks, and toxicities (grade 3 or higher) included neutropenia (63%) and diarrhea 13%; for the vindesine/cisplatin regimen, the response rate was 22%, median survival was 49.6 weeks, and toxicities (grade 3 or higher) included neutropenia (83%) and diarrhea (1%). The new regimen of irinotecan/cisplatin appears as active as the standard regimen of vindesine/cisplatin.

6 231 Is There a Preferred Combination Chemotherapy Regimen for Metastastic NSCLC? Table 12. Second CPT-11 Lung Cancer Study Group trial CPT-11/Cis VDS/Cis CPT-11 Grade 4 neutropenia (%) Grade 3 diarrhea (%) Response rate (%) Median survival (weeks) year survival (%) For stage IV patients only Median survival (mo) year survival (%) year survival (%) CPT-11/Cis = irinotecan, 60 mg/m 2 i.v., days 1, 8, and 15; cisplatin, 80 mg/m 2 i.v., day 1 every 4 weeks. VDS/Cis = vindesine 3 mg/m 2 i.v., days 1, 8, and 15; cisplatin, 80 mg/m 2 i.v., day 1 every 4 weeks. CPT-11 = irinotecan, 100 mg/m 2 i.v., days 1, 8, and 15 every 4 weeks. Another phase III study compared irinotecan/cisplatin with vindesine/cisplatin and with irinotecan alone in stage IIIB/IV NSCLC patients (Table 12) [14]. Three hundred and ninety-eight patients were entered into the trial, 37% of whom had stage IIIB disease. For the above three arms, response rates were 43%, 31%, and 21%, respectively; median survival times were 50.3 weeks, 47.4 weeks, and 46.1 weeks, respectively; 1-year survival rates were 47.5%, 37.9%, and 40.7%, respectively; grade 4 neutropenia occurred in 36.2%, 53.2%, and 7.9% of patients, respectively, and grade 3 diarrhea was observed in 12.6%, 4.0%, and 15.0% of patients, respectively. Although the response rate was highest for the irinotecan/cisplatin combination, the survival times for all three regimens were similar. In the above two studies, when only data from patients with stage IV NSCLC were analyzed, the combination of irinotecan/cisplatin resulted in a median survival rate greater than or equal to that of vindesine/cisplatin in both studies [15]. In the irinotecan/cisplatin versus vindesine study the median survival times were 10.3 months and 10.4 months, respectively, and the 1- and 2-year survival rates were 36% versus 41% and 9% versus 10%, respectively. In the three-arm study comparing irinotecan/cisplatin with vindesine/cisplatin and with irinotecan alone, the median survival times were 11.5 months, 8.4 months, and 9.7 months, respectively. Both irinotecan arms had a statistically significant better survival time than did the vindesine/cisplatin arm. For the three regimens, the 1- and 2-year survival rates were 48%, 26%, and 37%, respectively, and 18%, 11%, and 21%, respectively. MOLECULAR AND BIOLOGIC TARGETED THERAPIES A number of small molecules have been developed to inhibit specific targets. They include angiogenesis inhibitors, epidermal growth factor receptor inhibitors, matrix metalloproteinase inhibitors, and HER 2/neu inhibitors. Phase I/II studies combining some of these agents (anti-vascular endothelial growth factor, OSI 774, ISIS 3521, Iressa, etc.) with chemotherapy to treat advanced NSCLC appear promising [16-19]. There is experimental evidence that cyclooxygenase-2 (COX-2) is overexpressed in the majority of NSCLC tumors, especially adenocarcinomas [20]. Because of this, studies are ongoing evaluating a selective COX-2 inhibitor, celecoxib, with chemotherapy in patients with NSCLC. A phase I/II trial of Iressa (ZD 1839), a tyrosine kinase inhibitor of epidermal growth factor receptor, to treat advanced NSCLC produced a 10% response rate [19]. There have been two randomized trials using either paclitaxel/carboplatin or gemcitabine/cisplatin compared with the same drugs with two different doses of Iressa as firstline therapy for advanced NSCLC (Fig. 1). These studies have closed and the data are being analyzed. Randomize *Gemcitabine/cisplatin or *Paclitaxel/carboplatin Chemotherapy* mg Iressa 6 cycles Chemotherapy* mg Iressa 6 cycles Chemotherapy* + placebo 6 cycles Primary end point: survival Continue Iressa or placebo until disease progression Figure 1. Iressa trials. First-line NSCLC.

7 Ettinger 232 DISCUSSION Is there a treatment of choice for patients with metastatic NSCLC? Or is there a choice of treatments for the cancer? In my opinion, there is a choice of treatments for NSCLC patients. No one regimen appears superior to another. This review included only phase III studies evaluating chemotherapy to treat patients with stage IIIB/IV NSCLC. The studies are from the U.S., Europe, and Japan. It is difficult to compare the data from the various studies for a variety of reasons, including different patient characteristics, patient selection criteria, etc. For example, those studies having greater than 30% of NSCLC patients with stage IIIB disease usually have higher response rates and better survival times than those studies having less than 20% of patients having stage IIIB NSCLC. There is still the question whether a noncisplatin-containing regimen is as good as or better than a cisplatin-containing regimen. The EORTC study showed that a paclitaxel/gemcitabine regimen had a lower median survival time and 1-year survival rate compared with a paclitaxel/cisplatin or gemcitabine/cisplatin regimen. However, there are not enough data to make the determination as to the effectiveness of noncisplatin-containing regimens REFERENCES 1 Jemal A, Thomas A, Murray T et al. Cancer statistics, CA Cancer J Clin 2002;52: Ginsberg KJ, Vokes EE, Rosenzweig K. Non small cell lung cancer. In: DeVita V, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology, Sixth Edition. Philadelphia: Lippincott Williams and Wilkins 2001: Bonomi P, Kim K, 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 Cooperative Oncology Group trial. J Clin Oncol 2000;18: 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: Schiller JH, Harrington D, Belani CP et al. Comparison of four chemotherapy regimens for advanced non-small cell lung cancer. N Engl J Med 2002;346: Kelly K, Crowley J, Bunn PA et al. A randomized phase III trial of paclitaxel + carboplatin (PC) versus vinorelbine + cisplatin (VC) in NSCLC: a Southwest Oncology Group (SWOG) study. Proc Am Soc Clin Oncol 1999;18:461a. 7 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: versus cisplatin-containing regimens to treat advanced NSCLC. There are a number of combination chemotherapeutic regimens that can be used to treat advanced NSCLC. Most of these combinations are cisplatin based. The choice of the effective regimen to treat patients with NSCLC should be based on: Familiarity with the regimen Toxicity of the therapy Convenience of its administration Cost of the treatment Advanced NSCLC patients should be entered in clinical trials in order to improve the therapies. There is hope that, in the future, advances will be made in the treatment of patients with advanced NSCLC with the development of novel agents and with these agents used in combination with chemotherapeutic regimens. ACKNOWLEDGMENTS Presented in part at the Mayo Clinic s 11th Annual Hematology/Oncology Reviews, State-of-the-Art Treatment of Hematology/Oncology Treatments, Amelia Island, Florida, August 16-19, 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: Kosmidis PA, Bacoyiannis C, Mylonakis N et al. A randomized phase III trial of paclitaxel plus carboplatin versus paclitaxel plus gemcitabine in advanced non-small cell lung cancer (NSCLC). Preliminary analysis. Proc Am Soc Clin Oncol 2000;19:488a. 10 Van Meerbeeck JP, Smit E, Lianes P et al. A EORTC randomized phase III trial of three chemotherapy regimen advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 2001;20:308a. 11 Scagliotti GV, Dmarinis F, Rinaldi M et al. Phase III randomized trial comparing three platinum-based doublets in advanced non-small cell lung cancer. Proc Am Soc Clin Oncol 2001;20:308a. 12 Rodriquez J, Parvel J, Pluzanska A et al. A multicenter randomized phase III study of docetaxel + carboplatin (DCB) vs. vinorelbine + cisplatin (VC) in chemotherapy-naïve patients with advanced and metastatic non-small cell lung cancer. Proc Am Soc Clin Oncol 2001;20:314a. 13 Niho S, Nagao K, Nishiwaki Y et al. Randomized multicenter phase III trial of irinotecan (CPT-11) and cisplatin (DDP) versus CDDP and vindesine (VDS) in patients with advanced

8 233 Is There a Preferred Combination Chemotherapy Regimen for Metastastic NSCLC? non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 1999;18:492a. 14 Masuda N, Fukuoka M, Negoro S et al. Randomized trial comparing cisplatin (CDDP) and irinotecan (CPT-11) versus CDDP and vindesine (VDS) versus CPT-11 alone in advanced non-small cell lung cancer (NSCLC), a multicenter phase III study. Proc Am Soc Clin Oncol 1999;18:459a. 15 Fukuoka M, Nagao K, Ohashi Y et al. Impact of irinotecan (CPT-11) and cisplatin (CDDP) on survival in previously untreated metastatic non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 2000;19:495a. 16 Devore RT, Fehrenbacker I, Herbst RS et al. A randomized phase II trial comparing rhumab VEGF (recombinant humanized monoclonal antibody to vascular endothelial cell growth factor) plus carboplatin/paclitaxel (CP) to CP alone in patients with stage IIIB/IV NSCLC. Proc Am Soc Clin Oncol 2000;19:485a. 17 Yuen A, Halsey J, Fisher G et al. Phase I/II trial of ISIS 3521 an antisense inhibitor of PKC-Alpha with carboplatin and paclitaxel in non-small cell lung cancer. Proc Am Soc Clin Oncol 2001;20:309a. 18 Perez-Soler R, Chachoua A, Huberman M et al. A phase II trial of the EGFR tyrosine kinase inhibitor OSI-774 following platinum-based chemotherapy in patients with EGFR expressing NSCLC. Proc Am Soc Clin Oncol 2001;20:310a. 19 Ferry D, Hammond L, Ranson M et al. Intermittent oral ZD1839 (Iressa), a novel EGFR tyrosine kinase inhibitor, shows evidence of good tolerability and activity: final results from a phase I study. Proc Am Soc Clin Oncol 2000;19:3a. 20 Hida T, Kozaki K, Muramatsu H et al. Cyclooxygenase-2 inhibitor induces apoptosis and enhances cytotoxicity of various anticancer agents in non-small cell lung cancer cell lines. Clin Cancer Res 2000;6: