- Email: [email protected]
State-of-the-art chemotherapy for advanced non-small cell lung cancer
State-of-the-Art Chemotherapy for Advanced Non–Small Cell Lung Cancer Sakkaraiappan Ramalingam and Chandra P. Belani The treatment of advanced non–small cell lung cancer (NSCLC) has continued to evolve over recent years. We have moved from an era of therapeutic nihilism to optimism, largely because of the advent of the newer cytotoxic agents developed in the 1990s that have complemented the platinum compounds for treatment of advanced NSCLC. Doublet chemotherapy combinations have become the current standard of care for patients with advanced NSCLC who have a good performance status. For patients with poor performance status and the elderly, single-agent chemotherapy results in modest improvements in survival. Prolongation of survival and improved quality of life have also been shown with second-line chemotherapy for patients who are either refractory to or relapse following first-line chemotherapy. Noncytotoxic, molecularly targeted agents currently under various phases of development for the treatment of lung cancer will serve as the cornerstones for further innovations in the treatment of NSCLC. Semin Oncol 31 (suppl 1):68-74. © 2004 Elsevier Inc. All rights reserved.
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ON–SMALL cell lung cancer (NSCLC) accounts for about 80% of all cases of lung cancer diagnosed in the United States.1 Approximately one third of patients with NSCLC have advanced disease at the time of diagnosis.2 Such patients are not candidates for surgical resection or definitive combined-modality therapy. Palliative chemotherapy remains the mainstay of treatment for advanced NSCLC. A meta-analysis performed by the NSCLC collaborative group showed an improvement in survival with cisplatin-based combination chemotherapy for patients with advanced NSCLC (hazard ratio, 0.73).3 However,
chemotherapy with older cytotoxic drugs such as alkylating agents was detrimental, with a hazard ratio of 1.26. During the 1990s, several novel cytotoxic drugs such as the taxanes, vinorelbine, gemcitabine, and irinotecan were shown to exhibit impressive single-agent activity in patients with advanced NSCLC. This led to the evaluation of combination chemotherapy regimens consisting of a platinum compound and a newer cytotoxic agent. The combination regimens proved superior to therapy with cisplatin alone in randomized clinical trials for advanced NSCLC (Table 1).4-7 The drugs evaluated in combination with cisplatin included paclitaxel, vinorelbine, gemcitabine, and tirapazamine. Thus, doublet combinations with a platinum compound and a novel cytotoxic agent were accepted as the standard of care for patients with advanced NSCLC. DOUBLET COMBINATIONS
From the Division of Hematology-Oncology, University of Pittsburgh School of Medicine, Pittsburg, PA; and the Lung & Thoracic Cancer Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA. Dr Ramalingam has received research grant support from Aventis and honoraria from Aventis and Eli Lilly. Dr Belani has received research grant support from Aventis, Bristol-Myers Squibb, Eli Lilly, and OrthoBiotech. Address reprint requests to Chandra P. Belani, MD, University of Pittsburgh School of Medicine, UPMC Cancer Pavilion, 5150 Centre Ave #570, Pittsburgh, PA 15232. © 2004 Elsevier Inc. All rights reserved. 0093-7754/04/3101-0109$30.00/0 doi:10.1053/j.seminoncol.2003.12.017
In recent years, several randomized trials have compared various doublet combinations to determine the chemotherapy regimen that has the most favorable therapeutic index (Table 2). Belani et al8 compared the efficacy of the carboplatin-paclitaxel combination with cisplatin-etoposide for patients with advanced NSCLC. The two regimens had comparable efficacy in this randomized trial, although the quality of life was more favorable in the carboplatin-paclitaxel arm. The Eastern Cooperative Oncology Group (ECOG) 1594 trial compared three different regimens (cisplatindocetaxel, cisplatin-gemcitabine, and carboplatinpaclitaxel) against the control arm of cisplatinpaclitaxel for patients with advanced NSCLC.9 Initially, the study enrolled patients with ECOG performance status (PS) of ⱕ2. However, the study was closed to patients with ECOG PS of 2 when excessive toxicity was noted among the first 64 patients with a PS of 2. Over 1,100 patients with advanced NSCLC were accrued to this trial. While the toxicity profiles varied between the chemotherapy regimens, there were no significant differences in most of the efficacy endpoints analyzed, including overall survival, 1-year survival, response rates, and median survival.
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69
Table 1. Cisplatin Versus Cisplatin-Based Doublet Combination
Study Wozniak et al4
No. of Patients 432
Gatzemeier et al5
414
Von Pawel et al7
446
Sandler et al6
522
Regimen Cisplatin Cisplatin Cisplatin Cisplatin Cisplatin Cisplatin Cisplatin Cisplatin
Vinorelbine (high dose) Paclitaxel Tirapazamine Gemcitabine
Response Rate
Median Survival (mos)
1-Year Survival
12% 26%* 17% 26%* 14% 28%* 11% 30%*
6.0 8.0* 8.6 8.1 6.4 8.0* 7.6 9.1*
20% 36% 36% 30% 23% 34% 28% 39%
* Indicates differences that are statistically significant.
Kelly et al10 reported the results of the Southwest Oncology Group 9509 trial that compared the combination of carboplatin-paclitaxel with their prevailing standard regimen of cisplatinvinorelbine. There were no differences in efficacy parameters between the two treatment arms. The experimental arm of carboplatin-paclitaxel was associated with a lower incidence of nausea and vomiting and a higher incidence of neurotoxicity. Fewer patients in the carboplatin-paclitaxel arm discontinued treatment because of toxicity.
The TAX 326 study evaluated two docetaxelcontaining doublets (cisplatin-docetaxel or carboplatin-docetaxel) against cisplatin-vinorelbine as the control arm in a randomized multinational clinical trial for patients with advanced NSCLC.11 While the overall survival was superior with the cisplatin-docetaxel arm (P ⫽ .044), the carboplatin-docetaxel arm showed similar efficacy to the control arm of cisplatin-vinorelbine. The incidence of grade 3/4 nausea and vomiting and anemia were lower with both docetaxel arms. Quality-
Table 2. Comparison of Doublet Combinations in Advanced Non–Small Cell Lung Cancer
Study Belani et
al8
Schiller et al9 ECOG 1594
Rodriguez et al11 TAX 326
No. of Patients 369 1,105
1,218
Kelly et al10 SWOG 9509
408
Niho et al13
199
Regimen
Response Rate
Median Survival (mos)
1-Year Survival
Cisplatin Etoposide Carboplatin Paclitaxel Cisplatin Paclitaxel Paclitaxel Cisplatin Gemcitabine Cisplatin Docetaxel Carboplatin Paclitaxel Cisplatin Vinorelbine Vinorelbine Cisplatin Docetaxel Carboplatin Docetaxel Cisplatin Vinorelbine Vinorelbine Carboplatin Paclitaxel Cisplatin Vindesine Cisplatin Irinotecan
14% 22% 21%
7.5 6.3 7.8
37% 32% 31%
21% 17% 15% 25%
8.1 7.4 8.2 10.1
36% 31% 35% 41%
32%* 24% 28%
11.3 9.1 8.0
46% 38% 36%
25% 22% 29%
8.0 10.0 10.0
38% 41% 36%
Abbreviations: ECOG, Eastern Cooperative Oncology Group; SWOG, Southwest Oncology Group. * P ⫽ .029
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RAMALINGAM AND BELANI
Table 3. Quality-of-Life Analysis from TAX 326 Trial11 C-D vs C ⫹ V
Carbo-D vs C ⫹ V
QOL Parameter
C⫹D
C⫹V
P Value
Carbo ⫹ D
C⫹V
P Value
Change in global QOL-EuroQol Weight loss ⱖ10% (% of patients) Change in pain score (LCSS)
⫺1.0 7% 4.6
⫺5.8 15% ⫺0.32
.016 ⬍.01 .033
⫺4.3 7% 2.7
⫺5.8 15% ⫺0.32
⬍.01 ⬍.001 .335
(⫺) represents worsening of QOL. Abbreviations: C, cisplatin; D, docetaxel; V, vinorelbine; Carbo, carboplatin; LCSS, Lung Cancer Symptom Scale; QOL, quality of life.
of-life parameters were analyzed as secondary endpoints in this study. More than 900 patients returned questionnaires that evaluated several quality-of-life indicators. Clinical benefit was superior for both docetaxel arms as evidenced by improvement in pain, global quality-of-life scores, and a lower degree of weight loss compared with patients treated with cisplatin-vinorelbine (Table 3).12 This study established the efficacy of docetaxel-platinum combinations as first-line treatment for advanced NSCLC. Two randomized trials conducted in Japan evaluated the efficacy of irinotecan-platinum combinations in advanced NSCLC. Niho et al13 randomized 210 patients with advanced NSCLC to treatment with the combination of cisplatin-irinotecan versus cisplatin-vindesine. Efficacy was comparable between both arms. The irinotecan arm was associated with a lower incidence of grades 3/4 neutropenia and a higher incidence of diarrhea. In another study, patients with advanced NSCLC were randomized to one of the following three
treatment arms: cisplatin-irinotecan, cisplatinvindesine, or irinotecan alone.14 Both of the irinotecan-containing arms were associated with a lower incidence of neutropenia. There was no significant difference in median survival and 1-year survival between the three arms. Thus, clinical trials with various platinum-based doublet combinations have shown comparable efficacy of these regimens in the treatment of advanced NSCLC. In fact, a therapeutic plateau has been reached in the treatment of advanced NSCLC. Chemotherapy should be tailored to patients based on toxicity profile, frequency of administration, and cost. DOUBLET VERSUS SINGLE-AGENT CHEMOTHERAPY
Three recent clinical trials have compared the efficacy of single-agent chemotherapy with a novel cytotoxic agent against a platinum-based doublet combination for patients with advanced NSCLC (Table 4). In a trial by the Cancer and Leukemia
Table 4. Single-Agent Versus Doublet Combination Therapy in Advanced Non–Small Cell Lung Cancer
No. of Patients
Regimen
Response Rate
Median Survival (mos)
1-Year Survival
Lilenbaum et al15
561
Sederholm16
334
Georgoulias et al17
308
Masuda et al14
259
Paclitaxel Carboplatin Paclitaxel Gemcitabine Carboplatin Gemcitabine Docetaxel Cisplatin Docetaxel Irinotecan Cisplatin Irinotecan
29% 17% 30% 12% 36%* 20% 43% 21%
8.6 6.8 11.0 9.0 10.0 8.0 12.0 11.0
37% 33% 44% 32% 45% 40% 49% 44%
Study
* P ⫽ .003
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Table 5. Nonplatinum Combinations in the Treatment of Advanced Non–Small Cell Lung Cancer
Study
No. of Patients
Regimen
Response Rate
Median Survival (mos)
1-Year Survival
Van Meerbeeck et al20
480
Georgoulias et al22
441
Gridelli et al21
502
Cisplatin Paclitaxel Cisplatin Gemcitabine Paclitaxel Gemcitabine Cisplatin Docetaxel Gemcitabine Docetaxel Gemcitabine Vinorelbine Control*
31% 36% 27% 35% 33% 25% 30%
8.1 8.8 6.9 10.0 9.5 8.0 9.5
35% 32% 26% 42% 37% 31% 37%
* Control arm consisted of therapy with cisplatin-vinorelbine or cisplatin-gemcitabine.
Group B (CALGB 9730), patients were randomized to treatment with the carboplatin-paclitaxel combination or paclitaxel alone.15 Of the 561 patients enrolled on the study, 27% were over the age of 70 years and approximately 20% had ECOG PS of 2. Median survival, progression-free survival, and response rates were superior with the combination-therapy arm compared with single-agent therapy. Even for elderly patients and those with PS of 2, combination therapy was more efficacious, although the extent of benefit was smaller. The Swedish Lung Cancer Group compared the combination of carboplatin-gemcitabine to therapy with gemcitabine alone for patients with advanced NSCLC.16 The study enrolled 334 patients with ECOG PS ⱕ2. The response rate and 1- and 2-year survival rates were higher for the doublettherapy arm. In another trial, Georgoulias et al17 compared the cisplatin-docetaxel combination with docetaxel therapy alone. The preliminary results of the study suggested a more favorable response rate and survival for the combination arm. From these trials, it is evident that platinumbased doublet combination therapy will continue to be the standard of care in the treatment of patients with advanced NSCLC.
ine; arm B: cisplatin-gemcitabine-vinorelbine; arm C: sequential therapy with three cycles each of vinorelbine-gemcitabine followed by ifosfamidevinorelbine.18 There was no significant difference in response rates or survival between the three arms. The incidence of grades 3/4 neutropenia, thrombocytopenia, and febrile neutropenia were higher in the three-drug combination arm. Similar results were noted with another trial that compared a doublet regimen with a triplet combination. The doublet combination of carboplatingemcitabine was compared with a cisplatinifosfamide-mitomycin regimen in a randomized study that included 422 patients.19 While the response rates were similar between the two arms, 1-year survival and median survival were superior in the cisplatin-gemcitabine arm. The incidence of nausea, vomiting, alopecia, and constipation were higher with the three-drug combination arm. Based on these studies, it is apparent that the therapeutic index of doublet combinations is superior to triplet chemotherapy combinations. Hence, the combination of three cytotoxic agents should not be used in the routine care of patients with advanced NSCLC.
DOUBLET VERSUS TRIPLET COMBINATIONS
To reduce the toxicity associated with the platinum compounds, nonplatinum doublets have been evaluated for the treatment of advanced NSCLC (Table 5). The European Organization for Research and Treatment of Cancer randomized patients with advanced NSCLC to treatment with cisplatin-paclitaxel, cisplatin-gemcitabine, or paclitaxel-gemcitabine.20 The nonplatinum arm of
Three-drug combinations have been evaluated for NSCLC therapy with the intention of improving upon the benefits seen with doublet combinations. The Spanish Lung Cancer Group randomized patients with advanced NSCLC to one of the following three arms: arm A: cisplatin-gemcitab-
NONPLATINUM COMBINATIONS
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RAMALINGAM AND BELANI
paclitaxel-gemcitabine was associated with inferior efficacy when compared with the platinum arms, though the differences were not statistically significant. The GEMVIN trial compared the nonplatinum combination of gemcitabine-vinorelbine with two different platinum combinations (cisplatin-gemcitabine and cisplatin-vinorelbine).21 This study included more than 500 patients with advanced NSCLC. There was a trend towards inferior response rate, median survival, and 1-year survival with the nonplatinum arm. Georgoulias et al22 conducted a randomized phase II study for patients with advanced NSCLC. Patients received therapy with either cisplatin-docetaxel or gemcitabine-docetaxel. The efficacy was comparable between both regimens, while the toxicity profile was more favorable with the nonplatinum arm. An unplanned subset analysis showed that patients with adenocarcinoma benefited more from the nonplatinum arm, while patients with squamous cell histology benefited more from the platinum combination. An ongoing phase III trial by the Coalition of Cancer Cooperative groups will compare the efficacy of the nonplatinum combination to the platinum combination. This study will include tumor histology as a stratification factor to evaluate the observation made in subgroup analysis of the Georgoulias trial.22 The results of this trial will help to determine if nonplatinum combinations can be used as standard first-line therapy for patients with advanced NSCLC. Based on available evidence, nonplatinum combinations should be reserved for patients with advanced NSCLC who cannot tolerate platinum-based regimens. TREATMENT OF ELDERLY PATIENTS WITH ADVANCED NON–SMALL CELL LUNG CANCER
Approximately 30% to 40% of patients diagnosed with NSCLC are over the age of 70 years.23 However, elderly patients have been largely underrepresented in clinical trials.24 Concerns about their ability to tolerate chemotherapy have discouraged oncologists in recommending standard chemotherapy regimens to elderly patients. The Elderly Lung Vinorelbine Italian Study (ELVIS) trial randomized patients ⱖ70 years of age to single-agent therapy with vinorelbine or best supportive care.25 Although the study was stopped early because of slow accrual, there was a statistically
significant survival advantage for therapy with vinorelbine. While the incidence of grade 3/4 toxicities was less than 10%, there was improvement in overall quality of life for patients treated with vinorelbine. The Multicenter Italian Lung Elderly Study (MILES) randomized elderly patients with advanced NSCLC to single-agent therapy with vinorelbine alone, gemcitabine alone, or the combination of vinorelbine-gemcitabine.26 The efficacy of the combination was not superior to singleagent therapy. However, there was a higher incidence of leukopenia, alopecia, and neuropathy with combination therapy. The efficacy of platinum compounds as single-agent therapy in elderly patients has not been evaluated in randomized trials. The CALGB 9730 study showed that elderly patients tolerate platinum-based combination therapy well and experienced greater benefit when compared with single-agent therapy.15 Retrospective subgroup analyses from randomized clinical trials have also confirmed the efficacy and tolerability of platinum-based combination regimens in elderly patients with advanced NSCLC.27,28 Thus, for elderly patients with a favorable PS, platinumbased combination chemotherapy is the preferred treatment, while single-agent therapy will be appropriate for elderly patients with poor PS. Proportionate representation of elderly patients should be encouraged in prospective randomized clinical trials to arrive at meaningful conclusions that will be applicable to routine clinical practice. TARGETED THERAPIES IN NON–SMALL CELL LUNG CANCER
Identification of molecular targets that are unique to cancer cells to develop therapies that are cancer cell-specific and nontoxic to the normal cell has been a long-held pursuit for researchers. Several molecularly targeted therapies are currently in various phases of development. Inhibition of the epidermal growth factor receptor pathway with gefitinib, a small-molecule tyrosine kinase inhibitor, was shown to result in response rates of 11% to 18% for patients with advanced NSCLC who had failed prior chemotherapy.29,30 However, two large randomized clinical trials (Iressa NSCLC Trial Assessing Combination Treatment 1 and 2 [INTACT-1, -2]) in advanced NSCLC that compared the efficacy of the combination of gefitinib with platinum-based chemotherapy failed to demonstrate a survival advantage
STATE-OF-THE-ART CHEMOTHERAPY FOR ADVANCED NSCLC
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over chemotherapy alone. Two other clinical trials that have combined chemotherapy with erlotinib, another small-molecule epidermal growth factor receptor tyrosine kinase inhibitor, have been completed.31 Another novel strategy that involved the combination of chemotherapy with ISIS 3521, an antisense inhibitor of protein kinase C, was evaluated in a phase I/II study.32 Based on the promising results noted in this trial, two randomized phase III trials are currently underway to compare combination chemotherapy (cisplatin-gemcitabine, carboplatin-paclitaxel) with or without ISIS 3521. A monoclonal antibody to vascular endothelial growth factor, bevacizumab, is also being evaluated in a randomized trial in combination with chemotherapy for advanced NSCLC by the ECOG. The treatment strategies mentioned here represent only a small sample of the several therapeutic targets that are under evaluation. In addition to determining the efficacy of such targeted approaches, the challenges for the future will lie in elucidating the appropriate methods of incorporating them into existing treatment paradigms.
3. NSCLC Collaborative Group: Chemotherapy in non– small cell lung cancer: A meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ 311:899-909, 1995 4. 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 16:2459-2465, 1998 5. Gatzemeier U, von Pawel J, Gottfried M, et al: Phase III comparative study of high-dose cisplatin versus a combination of paclitaxel and cisplatin in patients with advanced non– small-cell lung cancer. J Clin Oncol 18:3390-3399, 2000 6. 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 18:122-130, 2000 7. von Pawel J, von Roemeling R, Gatzemeier U, et al: Tirapazamine plus cisplatin versus cisplatin in advanced non– small-cell lung cancer: A report of the international CATAPULT I study group. Cisplatin and tirapazamine in subjects with advanced previously untreated non–small-cell lung tumors. J Clin Oncol 18:1351-1359, 2000 8. Belani CP, Natale RB, Lee JS, et al: Randomized phase III trial comparing cisplatin/etoposide versus carboplatin/paclitaxel in advanced and metastatic non–small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 17:455a, 1998 (abstr 1751) 9. Schiller J, Harrington D, Belani CP, et al: Comparison of four chemotherapy regimens for advanced non–small-cell lung cancer. N Engl J Med 346:92-98, 2002 10. Kelly K, Crowley J, Bunn PA, 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 19:3210-3218, 2001 11. Rodriguez J, Pawel J, Pluzanska A, et al: A multicenter, randomized phase III study of docetaxel ⫹ cisplatin (DC) and docetaxel ⫹ carboplatin (DCB) vs. vinorelbine ⫹ cisplatin (VC) in chemotherapy-naive patients with advanced and metastatic non–small cell lung cancer. Proc Am Soc Clin Oncol 202001314a (abstr 1252) 12. Gralla RJ, Rodrigues J, Von Pawel J, et al: Prospective analysis of quality of life (QOL) in a randomized multinational phase III study comparing docetaxel (D) plus either cisplatin (C) or carboplatin (Cb) with vinorelbine plus cisplatin (VC) in patients with advanced non–small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 21:300a, 2002 (abstr 1196) 13. Niho S, Nagao K, Nishiwaki Y, et al: Randomized multicenter phase III trial of irinotecan (CPT-11) and cisplatin (CDDP) versus CDDP and vindesine (VDS) in patients with advanced non–small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 18:492a, 1999 (abstr 1897) 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: A multicenter phase III study. Proc Am Soc Clin Oncol 18:459a, 1999 (abstr 1774) 15. Lilenbaum RC, Herndon J, List M, et al: Single-agent (SA) versus combination chemotherapy (CC) in advanced non–small cell lung cancer (NSCLC): A CALGB randomized trial of efficacy, quality of life (QOL), and cost-effectiveness. Proc Am Soc Clin Oncol 21:1a, 2002 (abstr 2)
CONCLUSIONS
Combination chemotherapy has led to improvements in survival and quality of life for patients with advanced NSCLC. Platinum compounds continue to be an essential component of chemotherapy regimens for the treatment of NSCLC. While the development of newer cytotoxic agents has widened treatment options, it appears that we have reached a chemotherapy efficacy plateau in the treatment of advanced NSCLC. Strategies to predict response to specific chemotherapeutic agents are being pursued to individualize therapy for patients based on molecular profiles of tumors. Novel targeted therapies are currently under evaluation and hold hope for the future. Integration of targeted agents into current chemotherapeutic regimens will represent the next major step in the treatment of advanced NSCLC. REFERENCES 1. Rivera MP, Detterbeck FC, Loomis DP: Epidemiology and classification of lung cancer, in Detterbeck FC, Rivera MP, Socinksi MA (eds): Diagnosis and Treatment of Lung Cancer. ed 1. Philadelphia, PA, Saunders, 2001, pp 25-44 2. Bulzebruck H, Bopp R, Drings P, et al: New aspects in the staging of lung cancer: Prospective validation of the International Union Against Cancer TNM classification. Cancer 70: 1102-1110, 1992
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16. Sederholm C: Gemcitabine (G) compared with gemcitabine plus carboplatin (GC) in advanced non–small cell lung cancer (NSCLC): A phase III study by the Swedish Lung Cancer Study Group (SLUSG). Proc Am Soc Clin Oncol 21:291a, 2002 (abstr 1162) 17. Georgoulias V, Ardavanis A, Agelidou M, et al: Preliminary analysis of a multicenter phase III trial comparing docetaxel (D) versus docetaxel/cisplatin (D/C) in patients with inoperable advanced and metastatic non–small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 21:291a, 2002 (abstr 1163) 18. Alberola V, Camps C, Provencia M, et al: Cisplatin/ gemcitabine (CG) vs cisplatin/gemcitabine/vinorelbine (CGV) vs sequential doublets of gemcitabine/vinorelbine (GV) followed by ifosfamide/vinorelbine (GV/IV) in advanced non–small cell lung cancer (NSCLC): Results of a Spanish Lung Cancer Group phase III trial (GEPC/98-02). Proc Am Soc Clin Oncol 20:308a, 2001 (abstr 1229) 19. Rudd RM, Gower NH, James LE, et al: Phase III randomised comparison of gemcitabine and carboplatin (GC) with mitomycin, ifosfamide and cisplatin (MIP) in advanced non– small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 21:292a, 2002 (abstr 1164) 20. Van Meerbeeck JP, Smit EF, Lianes P, et al: A EORTC randomized phase III trial of three chemotherapy regimens in advanced non–small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 20:308a, 2001 (abstr 1228) 21. Gridelli C, Shepherd FA, Perrone F, et al: Gemvin III: A phase III trial of gemcitabine plus vinorelbine (GV) compared to cisplatin plus vinorelbine or gemcitabine chemotherapy (PCT) for stage IIIB or IV non–small cell lung cancer (NSCLC): An Italo-Canadian study. Proc Am Soc Clin Oncol 21:292a, 2002 (abstr 1165) 22. Georgoulias V, Papadakis E, Alexopoulos A, et al: Platinum-based and non-platinum-based chemotherapy in advanced non–small cell lung cancer: A randomized multicenter trial. Lancet 357:1478-1484, 2001 23. Lee-Chiong TL Jr, Matthay RA: Lung cancer in the elderly patient. Clin Chest Med 14:453-478, 1993
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24. Hutchins LF, Unger JM, Crowley JJ, et al: Underrepresentation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med 341:2061-2067, 1999 25. The Elderly Lung Cancer Vinorelbine Italian Study Group: Effects of vinorelbine on quality of life and survival of elderly patients with advanced non–small cell lung cancer. J Natl Cancer Inst 91:66-72, 1999 26. Gridelli C, Perrone F, Cigolari S: The MILES (Multicenter Italian Lung Cancer in the Elderly Study) phase 3 trial: Gemcitabine ⫹ vinorelbine vs vinorelbine and vs gemcitabine in elderly advanced NSCLC patients. Proc Am Soc Clin Oncol 20:308a, 2001 (abstr 1230) 27. Langer CJ, Manola J, Bernardo P, et al: Cisplatin-based therapy for elderly patients with advanced non–small-cell lung cancer: Implications of Eastern Cooperative Oncology Group 5592, a randomized trial. J Natl Cancer Inst 94:173-181, 2002 28. Kelly K, Giarritta S, Hayes S: Should older patients (pts) receive combination chemotherapy for advanced non–small cell lung cancer (NSCLC)? An analysis of Southwest Oncology Trials 9509 and 9308. Proc Am Soc Clin Oncol 20:329a, 2001 (abstr 1313) 29. Kris MG, Natale RB, Herbst RS, et al: A phase II trial of ZD1839 (“Iressa”) in advanced non–small cell lung cancer (NSCLC) patients who had failed platinum- and docetaxelbased regimens (IDEAL 2). Proc Am Soc Clin Oncol 21:292a, 2002 (abstr 1166) 30. Fukuoka M, Yano S, Giaccone G, et al: Final results from a phase II trial of ZD1839 (Iressa) for patients with advanced non–small cell lung cancer (IDEAL1). Proc Am Soc Clin Oncol 21:298a, 2002 (abstr 1188) 31. Herbst RS, Giaccone G, Schiller J, et al: Subset analyses of INTACT results for gefitinib (ZD1839) when combined with platinum-based chemotherapy for advanced non–small cell lunger cancer. Proc Am Soc Clin Oncol 22:627, 2003 (abstr) 32. 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 20:309a, 2001 (abstr 1234)
N
ON–SMALL cell lung cancer (NSCLC) accounts for about 80% of all cases of lung cancer diagnosed in the United States.1 Approximately one third of patients with NSCLC have advanced disease at the time of diagnosis.2 Such patients are not candidates for surgical resection or definitive combined-modality therapy. Palliative chemotherapy remains the mainstay of treatment for advanced NSCLC. A meta-analysis performed by the NSCLC collaborative group showed an improvement in survival with cisplatin-based combination chemotherapy for patients with advanced NSCLC (hazard ratio, 0.73).3 However,
chemotherapy with older cytotoxic drugs such as alkylating agents was detrimental, with a hazard ratio of 1.26. During the 1990s, several novel cytotoxic drugs such as the taxanes, vinorelbine, gemcitabine, and irinotecan were shown to exhibit impressive single-agent activity in patients with advanced NSCLC. This led to the evaluation of combination chemotherapy regimens consisting of a platinum compound and a newer cytotoxic agent. The combination regimens proved superior to therapy with cisplatin alone in randomized clinical trials for advanced NSCLC (Table 1).4-7 The drugs evaluated in combination with cisplatin included paclitaxel, vinorelbine, gemcitabine, and tirapazamine. Thus, doublet combinations with a platinum compound and a novel cytotoxic agent were accepted as the standard of care for patients with advanced NSCLC. DOUBLET COMBINATIONS
From the Division of Hematology-Oncology, University of Pittsburgh School of Medicine, Pittsburg, PA; and the Lung & Thoracic Cancer Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA. Dr Ramalingam has received research grant support from Aventis and honoraria from Aventis and Eli Lilly. Dr Belani has received research grant support from Aventis, Bristol-Myers Squibb, Eli Lilly, and OrthoBiotech. Address reprint requests to Chandra P. Belani, MD, University of Pittsburgh School of Medicine, UPMC Cancer Pavilion, 5150 Centre Ave #570, Pittsburgh, PA 15232. © 2004 Elsevier Inc. All rights reserved. 0093-7754/04/3101-0109$30.00/0 doi:10.1053/j.seminoncol.2003.12.017
In recent years, several randomized trials have compared various doublet combinations to determine the chemotherapy regimen that has the most favorable therapeutic index (Table 2). Belani et al8 compared the efficacy of the carboplatin-paclitaxel combination with cisplatin-etoposide for patients with advanced NSCLC. The two regimens had comparable efficacy in this randomized trial, although the quality of life was more favorable in the carboplatin-paclitaxel arm. The Eastern Cooperative Oncology Group (ECOG) 1594 trial compared three different regimens (cisplatindocetaxel, cisplatin-gemcitabine, and carboplatinpaclitaxel) against the control arm of cisplatinpaclitaxel for patients with advanced NSCLC.9 Initially, the study enrolled patients with ECOG performance status (PS) of ⱕ2. However, the study was closed to patients with ECOG PS of 2 when excessive toxicity was noted among the first 64 patients with a PS of 2. Over 1,100 patients with advanced NSCLC were accrued to this trial. While the toxicity profiles varied between the chemotherapy regimens, there were no significant differences in most of the efficacy endpoints analyzed, including overall survival, 1-year survival, response rates, and median survival.
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Table 1. Cisplatin Versus Cisplatin-Based Doublet Combination
Study Wozniak et al4
No. of Patients 432
Gatzemeier et al5
414
Von Pawel et al7
446
Sandler et al6
522
Regimen Cisplatin Cisplatin Cisplatin Cisplatin Cisplatin Cisplatin Cisplatin Cisplatin
Vinorelbine (high dose) Paclitaxel Tirapazamine Gemcitabine
Response Rate
Median Survival (mos)
1-Year Survival
12% 26%* 17% 26%* 14% 28%* 11% 30%*
6.0 8.0* 8.6 8.1 6.4 8.0* 7.6 9.1*
20% 36% 36% 30% 23% 34% 28% 39%
* Indicates differences that are statistically significant.
Kelly et al10 reported the results of the Southwest Oncology Group 9509 trial that compared the combination of carboplatin-paclitaxel with their prevailing standard regimen of cisplatinvinorelbine. There were no differences in efficacy parameters between the two treatment arms. The experimental arm of carboplatin-paclitaxel was associated with a lower incidence of nausea and vomiting and a higher incidence of neurotoxicity. Fewer patients in the carboplatin-paclitaxel arm discontinued treatment because of toxicity.
The TAX 326 study evaluated two docetaxelcontaining doublets (cisplatin-docetaxel or carboplatin-docetaxel) against cisplatin-vinorelbine as the control arm in a randomized multinational clinical trial for patients with advanced NSCLC.11 While the overall survival was superior with the cisplatin-docetaxel arm (P ⫽ .044), the carboplatin-docetaxel arm showed similar efficacy to the control arm of cisplatin-vinorelbine. The incidence of grade 3/4 nausea and vomiting and anemia were lower with both docetaxel arms. Quality-
Table 2. Comparison of Doublet Combinations in Advanced Non–Small Cell Lung Cancer
Study Belani et
al8
Schiller et al9 ECOG 1594
Rodriguez et al11 TAX 326
No. of Patients 369 1,105
1,218
Kelly et al10 SWOG 9509
408
Niho et al13
199
Regimen
Response Rate
Median Survival (mos)
1-Year Survival
Cisplatin Etoposide Carboplatin Paclitaxel Cisplatin Paclitaxel Paclitaxel Cisplatin Gemcitabine Cisplatin Docetaxel Carboplatin Paclitaxel Cisplatin Vinorelbine Vinorelbine Cisplatin Docetaxel Carboplatin Docetaxel Cisplatin Vinorelbine Vinorelbine Carboplatin Paclitaxel Cisplatin Vindesine Cisplatin Irinotecan
14% 22% 21%
7.5 6.3 7.8
37% 32% 31%
21% 17% 15% 25%
8.1 7.4 8.2 10.1
36% 31% 35% 41%
32%* 24% 28%
11.3 9.1 8.0
46% 38% 36%
25% 22% 29%
8.0 10.0 10.0
38% 41% 36%
Abbreviations: ECOG, Eastern Cooperative Oncology Group; SWOG, Southwest Oncology Group. * P ⫽ .029
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Table 3. Quality-of-Life Analysis from TAX 326 Trial11 C-D vs C ⫹ V
Carbo-D vs C ⫹ V
QOL Parameter
C⫹D
C⫹V
P Value
Carbo ⫹ D
C⫹V
P Value
Change in global QOL-EuroQol Weight loss ⱖ10% (% of patients) Change in pain score (LCSS)
⫺1.0 7% 4.6
⫺5.8 15% ⫺0.32
.016 ⬍.01 .033
⫺4.3 7% 2.7
⫺5.8 15% ⫺0.32
⬍.01 ⬍.001 .335
(⫺) represents worsening of QOL. Abbreviations: C, cisplatin; D, docetaxel; V, vinorelbine; Carbo, carboplatin; LCSS, Lung Cancer Symptom Scale; QOL, quality of life.
of-life parameters were analyzed as secondary endpoints in this study. More than 900 patients returned questionnaires that evaluated several quality-of-life indicators. Clinical benefit was superior for both docetaxel arms as evidenced by improvement in pain, global quality-of-life scores, and a lower degree of weight loss compared with patients treated with cisplatin-vinorelbine (Table 3).12 This study established the efficacy of docetaxel-platinum combinations as first-line treatment for advanced NSCLC. Two randomized trials conducted in Japan evaluated the efficacy of irinotecan-platinum combinations in advanced NSCLC. Niho et al13 randomized 210 patients with advanced NSCLC to treatment with the combination of cisplatin-irinotecan versus cisplatin-vindesine. Efficacy was comparable between both arms. The irinotecan arm was associated with a lower incidence of grades 3/4 neutropenia and a higher incidence of diarrhea. In another study, patients with advanced NSCLC were randomized to one of the following three
treatment arms: cisplatin-irinotecan, cisplatinvindesine, or irinotecan alone.14 Both of the irinotecan-containing arms were associated with a lower incidence of neutropenia. There was no significant difference in median survival and 1-year survival between the three arms. Thus, clinical trials with various platinum-based doublet combinations have shown comparable efficacy of these regimens in the treatment of advanced NSCLC. In fact, a therapeutic plateau has been reached in the treatment of advanced NSCLC. Chemotherapy should be tailored to patients based on toxicity profile, frequency of administration, and cost. DOUBLET VERSUS SINGLE-AGENT CHEMOTHERAPY
Three recent clinical trials have compared the efficacy of single-agent chemotherapy with a novel cytotoxic agent against a platinum-based doublet combination for patients with advanced NSCLC (Table 4). In a trial by the Cancer and Leukemia
Table 4. Single-Agent Versus Doublet Combination Therapy in Advanced Non–Small Cell Lung Cancer
No. of Patients
Regimen
Response Rate
Median Survival (mos)
1-Year Survival
Lilenbaum et al15
561
Sederholm16
334
Georgoulias et al17
308
Masuda et al14
259
Paclitaxel Carboplatin Paclitaxel Gemcitabine Carboplatin Gemcitabine Docetaxel Cisplatin Docetaxel Irinotecan Cisplatin Irinotecan
29% 17% 30% 12% 36%* 20% 43% 21%
8.6 6.8 11.0 9.0 10.0 8.0 12.0 11.0
37% 33% 44% 32% 45% 40% 49% 44%
Study
* P ⫽ .003
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Table 5. Nonplatinum Combinations in the Treatment of Advanced Non–Small Cell Lung Cancer
Study
No. of Patients
Regimen
Response Rate
Median Survival (mos)
1-Year Survival
Van Meerbeeck et al20
480
Georgoulias et al22
441
Gridelli et al21
502
Cisplatin Paclitaxel Cisplatin Gemcitabine Paclitaxel Gemcitabine Cisplatin Docetaxel Gemcitabine Docetaxel Gemcitabine Vinorelbine Control*
31% 36% 27% 35% 33% 25% 30%
8.1 8.8 6.9 10.0 9.5 8.0 9.5
35% 32% 26% 42% 37% 31% 37%
* Control arm consisted of therapy with cisplatin-vinorelbine or cisplatin-gemcitabine.
Group B (CALGB 9730), patients were randomized to treatment with the carboplatin-paclitaxel combination or paclitaxel alone.15 Of the 561 patients enrolled on the study, 27% were over the age of 70 years and approximately 20% had ECOG PS of 2. Median survival, progression-free survival, and response rates were superior with the combination-therapy arm compared with single-agent therapy. Even for elderly patients and those with PS of 2, combination therapy was more efficacious, although the extent of benefit was smaller. The Swedish Lung Cancer Group compared the combination of carboplatin-gemcitabine to therapy with gemcitabine alone for patients with advanced NSCLC.16 The study enrolled 334 patients with ECOG PS ⱕ2. The response rate and 1- and 2-year survival rates were higher for the doublettherapy arm. In another trial, Georgoulias et al17 compared the cisplatin-docetaxel combination with docetaxel therapy alone. The preliminary results of the study suggested a more favorable response rate and survival for the combination arm. From these trials, it is evident that platinumbased doublet combination therapy will continue to be the standard of care in the treatment of patients with advanced NSCLC.
ine; arm B: cisplatin-gemcitabine-vinorelbine; arm C: sequential therapy with three cycles each of vinorelbine-gemcitabine followed by ifosfamidevinorelbine.18 There was no significant difference in response rates or survival between the three arms. The incidence of grades 3/4 neutropenia, thrombocytopenia, and febrile neutropenia were higher in the three-drug combination arm. Similar results were noted with another trial that compared a doublet regimen with a triplet combination. The doublet combination of carboplatingemcitabine was compared with a cisplatinifosfamide-mitomycin regimen in a randomized study that included 422 patients.19 While the response rates were similar between the two arms, 1-year survival and median survival were superior in the cisplatin-gemcitabine arm. The incidence of nausea, vomiting, alopecia, and constipation were higher with the three-drug combination arm. Based on these studies, it is apparent that the therapeutic index of doublet combinations is superior to triplet chemotherapy combinations. Hence, the combination of three cytotoxic agents should not be used in the routine care of patients with advanced NSCLC.
DOUBLET VERSUS TRIPLET COMBINATIONS
To reduce the toxicity associated with the platinum compounds, nonplatinum doublets have been evaluated for the treatment of advanced NSCLC (Table 5). The European Organization for Research and Treatment of Cancer randomized patients with advanced NSCLC to treatment with cisplatin-paclitaxel, cisplatin-gemcitabine, or paclitaxel-gemcitabine.20 The nonplatinum arm of
Three-drug combinations have been evaluated for NSCLC therapy with the intention of improving upon the benefits seen with doublet combinations. The Spanish Lung Cancer Group randomized patients with advanced NSCLC to one of the following three arms: arm A: cisplatin-gemcitab-
NONPLATINUM COMBINATIONS
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paclitaxel-gemcitabine was associated with inferior efficacy when compared with the platinum arms, though the differences were not statistically significant. The GEMVIN trial compared the nonplatinum combination of gemcitabine-vinorelbine with two different platinum combinations (cisplatin-gemcitabine and cisplatin-vinorelbine).21 This study included more than 500 patients with advanced NSCLC. There was a trend towards inferior response rate, median survival, and 1-year survival with the nonplatinum arm. Georgoulias et al22 conducted a randomized phase II study for patients with advanced NSCLC. Patients received therapy with either cisplatin-docetaxel or gemcitabine-docetaxel. The efficacy was comparable between both regimens, while the toxicity profile was more favorable with the nonplatinum arm. An unplanned subset analysis showed that patients with adenocarcinoma benefited more from the nonplatinum arm, while patients with squamous cell histology benefited more from the platinum combination. An ongoing phase III trial by the Coalition of Cancer Cooperative groups will compare the efficacy of the nonplatinum combination to the platinum combination. This study will include tumor histology as a stratification factor to evaluate the observation made in subgroup analysis of the Georgoulias trial.22 The results of this trial will help to determine if nonplatinum combinations can be used as standard first-line therapy for patients with advanced NSCLC. Based on available evidence, nonplatinum combinations should be reserved for patients with advanced NSCLC who cannot tolerate platinum-based regimens. TREATMENT OF ELDERLY PATIENTS WITH ADVANCED NON–SMALL CELL LUNG CANCER
Approximately 30% to 40% of patients diagnosed with NSCLC are over the age of 70 years.23 However, elderly patients have been largely underrepresented in clinical trials.24 Concerns about their ability to tolerate chemotherapy have discouraged oncologists in recommending standard chemotherapy regimens to elderly patients. The Elderly Lung Vinorelbine Italian Study (ELVIS) trial randomized patients ⱖ70 years of age to single-agent therapy with vinorelbine or best supportive care.25 Although the study was stopped early because of slow accrual, there was a statistically
significant survival advantage for therapy with vinorelbine. While the incidence of grade 3/4 toxicities was less than 10%, there was improvement in overall quality of life for patients treated with vinorelbine. The Multicenter Italian Lung Elderly Study (MILES) randomized elderly patients with advanced NSCLC to single-agent therapy with vinorelbine alone, gemcitabine alone, or the combination of vinorelbine-gemcitabine.26 The efficacy of the combination was not superior to singleagent therapy. However, there was a higher incidence of leukopenia, alopecia, and neuropathy with combination therapy. The efficacy of platinum compounds as single-agent therapy in elderly patients has not been evaluated in randomized trials. The CALGB 9730 study showed that elderly patients tolerate platinum-based combination therapy well and experienced greater benefit when compared with single-agent therapy.15 Retrospective subgroup analyses from randomized clinical trials have also confirmed the efficacy and tolerability of platinum-based combination regimens in elderly patients with advanced NSCLC.27,28 Thus, for elderly patients with a favorable PS, platinumbased combination chemotherapy is the preferred treatment, while single-agent therapy will be appropriate for elderly patients with poor PS. Proportionate representation of elderly patients should be encouraged in prospective randomized clinical trials to arrive at meaningful conclusions that will be applicable to routine clinical practice. TARGETED THERAPIES IN NON–SMALL CELL LUNG CANCER
Identification of molecular targets that are unique to cancer cells to develop therapies that are cancer cell-specific and nontoxic to the normal cell has been a long-held pursuit for researchers. Several molecularly targeted therapies are currently in various phases of development. Inhibition of the epidermal growth factor receptor pathway with gefitinib, a small-molecule tyrosine kinase inhibitor, was shown to result in response rates of 11% to 18% for patients with advanced NSCLC who had failed prior chemotherapy.29,30 However, two large randomized clinical trials (Iressa NSCLC Trial Assessing Combination Treatment 1 and 2 [INTACT-1, -2]) in advanced NSCLC that compared the efficacy of the combination of gefitinib with platinum-based chemotherapy failed to demonstrate a survival advantage
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over chemotherapy alone. Two other clinical trials that have combined chemotherapy with erlotinib, another small-molecule epidermal growth factor receptor tyrosine kinase inhibitor, have been completed.31 Another novel strategy that involved the combination of chemotherapy with ISIS 3521, an antisense inhibitor of protein kinase C, was evaluated in a phase I/II study.32 Based on the promising results noted in this trial, two randomized phase III trials are currently underway to compare combination chemotherapy (cisplatin-gemcitabine, carboplatin-paclitaxel) with or without ISIS 3521. A monoclonal antibody to vascular endothelial growth factor, bevacizumab, is also being evaluated in a randomized trial in combination with chemotherapy for advanced NSCLC by the ECOG. The treatment strategies mentioned here represent only a small sample of the several therapeutic targets that are under evaluation. In addition to determining the efficacy of such targeted approaches, the challenges for the future will lie in elucidating the appropriate methods of incorporating them into existing treatment paradigms.
3. NSCLC Collaborative Group: Chemotherapy in non– small cell lung cancer: A meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ 311:899-909, 1995 4. 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 16:2459-2465, 1998 5. Gatzemeier U, von Pawel J, Gottfried M, et al: Phase III comparative study of high-dose cisplatin versus a combination of paclitaxel and cisplatin in patients with advanced non– small-cell lung cancer. J Clin Oncol 18:3390-3399, 2000 6. 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 18:122-130, 2000 7. von Pawel J, von Roemeling R, Gatzemeier U, et al: Tirapazamine plus cisplatin versus cisplatin in advanced non– small-cell lung cancer: A report of the international CATAPULT I study group. Cisplatin and tirapazamine in subjects with advanced previously untreated non–small-cell lung tumors. J Clin Oncol 18:1351-1359, 2000 8. Belani CP, Natale RB, Lee JS, et al: Randomized phase III trial comparing cisplatin/etoposide versus carboplatin/paclitaxel in advanced and metastatic non–small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 17:455a, 1998 (abstr 1751) 9. Schiller J, Harrington D, Belani CP, et al: Comparison of four chemotherapy regimens for advanced non–small-cell lung cancer. N Engl J Med 346:92-98, 2002 10. Kelly K, Crowley J, Bunn PA, 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 19:3210-3218, 2001 11. Rodriguez J, Pawel J, Pluzanska A, et al: A multicenter, randomized phase III study of docetaxel ⫹ cisplatin (DC) and docetaxel ⫹ carboplatin (DCB) vs. vinorelbine ⫹ cisplatin (VC) in chemotherapy-naive patients with advanced and metastatic non–small cell lung cancer. Proc Am Soc Clin Oncol 202001314a (abstr 1252) 12. Gralla RJ, Rodrigues J, Von Pawel J, et al: Prospective analysis of quality of life (QOL) in a randomized multinational phase III study comparing docetaxel (D) plus either cisplatin (C) or carboplatin (Cb) with vinorelbine plus cisplatin (VC) in patients with advanced non–small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 21:300a, 2002 (abstr 1196) 13. Niho S, Nagao K, Nishiwaki Y, et al: Randomized multicenter phase III trial of irinotecan (CPT-11) and cisplatin (CDDP) versus CDDP and vindesine (VDS) in patients with advanced non–small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 18:492a, 1999 (abstr 1897) 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: A multicenter phase III study. Proc Am Soc Clin Oncol 18:459a, 1999 (abstr 1774) 15. Lilenbaum RC, Herndon J, List M, et al: Single-agent (SA) versus combination chemotherapy (CC) in advanced non–small cell lung cancer (NSCLC): A CALGB randomized trial of efficacy, quality of life (QOL), and cost-effectiveness. Proc Am Soc Clin Oncol 21:1a, 2002 (abstr 2)
CONCLUSIONS
Combination chemotherapy has led to improvements in survival and quality of life for patients with advanced NSCLC. Platinum compounds continue to be an essential component of chemotherapy regimens for the treatment of NSCLC. While the development of newer cytotoxic agents has widened treatment options, it appears that we have reached a chemotherapy efficacy plateau in the treatment of advanced NSCLC. Strategies to predict response to specific chemotherapeutic agents are being pursued to individualize therapy for patients based on molecular profiles of tumors. Novel targeted therapies are currently under evaluation and hold hope for the future. Integration of targeted agents into current chemotherapeutic regimens will represent the next major step in the treatment of advanced NSCLC. REFERENCES 1. Rivera MP, Detterbeck FC, Loomis DP: Epidemiology and classification of lung cancer, in Detterbeck FC, Rivera MP, Socinksi MA (eds): Diagnosis and Treatment of Lung Cancer. ed 1. Philadelphia, PA, Saunders, 2001, pp 25-44 2. Bulzebruck H, Bopp R, Drings P, et al: New aspects in the staging of lung cancer: Prospective validation of the International Union Against Cancer TNM classification. Cancer 70: 1102-1110, 1992
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16. Sederholm C: Gemcitabine (G) compared with gemcitabine plus carboplatin (GC) in advanced non–small cell lung cancer (NSCLC): A phase III study by the Swedish Lung Cancer Study Group (SLUSG). Proc Am Soc Clin Oncol 21:291a, 2002 (abstr 1162) 17. Georgoulias V, Ardavanis A, Agelidou M, et al: Preliminary analysis of a multicenter phase III trial comparing docetaxel (D) versus docetaxel/cisplatin (D/C) in patients with inoperable advanced and metastatic non–small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 21:291a, 2002 (abstr 1163) 18. Alberola V, Camps C, Provencia M, et al: Cisplatin/ gemcitabine (CG) vs cisplatin/gemcitabine/vinorelbine (CGV) vs sequential doublets of gemcitabine/vinorelbine (GV) followed by ifosfamide/vinorelbine (GV/IV) in advanced non–small cell lung cancer (NSCLC): Results of a Spanish Lung Cancer Group phase III trial (GEPC/98-02). Proc Am Soc Clin Oncol 20:308a, 2001 (abstr 1229) 19. Rudd RM, Gower NH, James LE, et al: Phase III randomised comparison of gemcitabine and carboplatin (GC) with mitomycin, ifosfamide and cisplatin (MIP) in advanced non– small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 21:292a, 2002 (abstr 1164) 20. Van Meerbeeck JP, Smit EF, Lianes P, et al: A EORTC randomized phase III trial of three chemotherapy regimens in advanced non–small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 20:308a, 2001 (abstr 1228) 21. Gridelli C, Shepherd FA, Perrone F, et al: Gemvin III: A phase III trial of gemcitabine plus vinorelbine (GV) compared to cisplatin plus vinorelbine or gemcitabine chemotherapy (PCT) for stage IIIB or IV non–small cell lung cancer (NSCLC): An Italo-Canadian study. Proc Am Soc Clin Oncol 21:292a, 2002 (abstr 1165) 22. Georgoulias V, Papadakis E, Alexopoulos A, et al: Platinum-based and non-platinum-based chemotherapy in advanced non–small cell lung cancer: A randomized multicenter trial. Lancet 357:1478-1484, 2001 23. Lee-Chiong TL Jr, Matthay RA: Lung cancer in the elderly patient. Clin Chest Med 14:453-478, 1993
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24. Hutchins LF, Unger JM, Crowley JJ, et al: Underrepresentation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med 341:2061-2067, 1999 25. The Elderly Lung Cancer Vinorelbine Italian Study Group: Effects of vinorelbine on quality of life and survival of elderly patients with advanced non–small cell lung cancer. J Natl Cancer Inst 91:66-72, 1999 26. Gridelli C, Perrone F, Cigolari S: The MILES (Multicenter Italian Lung Cancer in the Elderly Study) phase 3 trial: Gemcitabine ⫹ vinorelbine vs vinorelbine and vs gemcitabine in elderly advanced NSCLC patients. Proc Am Soc Clin Oncol 20:308a, 2001 (abstr 1230) 27. Langer CJ, Manola J, Bernardo P, et al: Cisplatin-based therapy for elderly patients with advanced non–small-cell lung cancer: Implications of Eastern Cooperative Oncology Group 5592, a randomized trial. J Natl Cancer Inst 94:173-181, 2002 28. Kelly K, Giarritta S, Hayes S: Should older patients (pts) receive combination chemotherapy for advanced non–small cell lung cancer (NSCLC)? An analysis of Southwest Oncology Trials 9509 and 9308. Proc Am Soc Clin Oncol 20:329a, 2001 (abstr 1313) 29. Kris MG, Natale RB, Herbst RS, et al: A phase II trial of ZD1839 (“Iressa”) in advanced non–small cell lung cancer (NSCLC) patients who had failed platinum- and docetaxelbased regimens (IDEAL 2). Proc Am Soc Clin Oncol 21:292a, 2002 (abstr 1166) 30. Fukuoka M, Yano S, Giaccone G, et al: Final results from a phase II trial of ZD1839 (Iressa) for patients with advanced non–small cell lung cancer (IDEAL1). Proc Am Soc Clin Oncol 21:298a, 2002 (abstr 1188) 31. Herbst RS, Giaccone G, Schiller J, et al: Subset analyses of INTACT results for gefitinib (ZD1839) when combined with platinum-based chemotherapy for advanced non–small cell lunger cancer. Proc Am Soc Clin Oncol 22:627, 2003 (abstr) 32. 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 20:309a, 2001 (abstr 1234)