Current Clinical Trials

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Stage IV non-small cell lung cancer (NSCLC) is defined by the following clinical stage grouping:

• Any T, any N, M1

Palliative chemotherapy with a cisplatin-based or carboplatin-based regimen has been associated with objective and subjective responses for patients with metastatic NSCLC. Randomized trials have shown that cisplatin-based chemotherapy produces modest benefits in short-term survival compared with supportive care alone in patients with inoperable stage IIIB or IV disease. Although toxic effects may vary, outcomes are similar with most platinum-containing regimens. A prospective randomized trial comparing five older cisplatin-containing regimens showed no significant difference in response, duration of response, or survival among the different cisplatin-based regimens.[1][Level of evidence: 1iiA] Patients with good performance status (PS) and a limited number of sites of distant metastases have superior response and survival when given chemotherapy and compared with other patients.[2] A prospective randomized comparison of vinorelbine plus cisplatin versus vindesine plus cisplatin versus single-agent vinorelbine has reported an improved response rate of 30% and a median survival time of 40 weeks with the vinorelbine plus cisplatin regimen when compared with the other two regimens.[3][Level of evidence: 1iiA]

Reports of taxane and platinum combinations have shown relatively high response rates, significant 1-year survival, and palliation of lung cancer symptoms.[4] In a multicenter phase III study, the combination of cisplatin and paclitaxel showed a higher response rate than the older combination of cisplatin and etoposide.[5][Level of evidence: 1iiDii] Results from clinical trials indicate that platinum-doublet combinations are superior to both platinum and other single agents.[6]

Cisplatin-containing combination chemotherapy regimens provide clinical benefit when compared with supportive care alone; however, treatment may be contraindicated in some older patients because of the age-related reduction in the functional reserve of many organs and/or comorbid conditions. Often patients in this subgroup are not offered cytotoxic treatment because of concerns about tolerability. Several studies, including the ECOG-5592 trial, have demonstrated similar response rates, survival, and quality-of-life outcomes for patients 70 years or older as compared with patients younger than 70 years despite a greater frequency of leukopenia, weight loss, and neuropsychiatric toxic effects among the older population.[7,8] In a randomized trial of patients older than 70 years with NSCLC, single-agent vinorelbine resulted in superior survival when compared with supportive care alone (median survival of 28 weeks vs. 21 weeks).[9][Level of evidence: 1iiA] A multicenter Italian group conducted a randomized study of 698 older patients that compared both single-agent vinorelbine and single-agent gemcitabine with the combination of vinorelbine and gemcitabine.[10] Compared with each single drug, the combination treatment did not improve survival.[10][Level of evidence: 1iiA]. The hazard ratio of death for patients receiving the combination treatment was 1.17 (95% confidence interval [CI], 0.95–1.44) compared with single-agent vinorelbine and 1.06 (95% CI, 0.86–1.29) compared with single-agent gemcitabine. Studies to date suggest that fit elderly patients can receive the same benefit from platinum combination chemotherapy as younger patients with acceptable toxic effects.[11] In patients with contraindications to platinum compounds, no evidence indicates that nonplatinum combinations are superior to single-agent vinorelbine or single-agent gemcitabine. The use of single agent versus combination chemotherapy should be based on PS and comorbid conditions rather than age.[12]

A prospective randomized study compared four commonly used platinum-based chemotherapy regimens for patients with stage IIIB or stage IV NSCLC: cisplatin plus paclitaxel, gemcitabine plus cisplatin, cisplatin plus docetaxel, and carboplatin plus paclitaxel.[13] No regimen was found to have a significantly better response rate or survival time.[13][Level of evidence: 1iiA] The response rate for all 1,158 of the eligible patients was 19%, and the median survival time was 7.9 months (95% CI, 7.3–8.5 months). Patients with a PS of two had significantly worse toxic effects and survival compared with patients who had a PS of zero to one.[13] Another prospective randomized study compared the combination of carboplatin plus paclitaxel with vinorelbine plus cisplatin. This study also found no significant difference in efficacy between the two standard regimens.[14][Level of evidence: 1iiDii] A prospective randomized trial (E-4599) compared chemotherapy with carboplatin and paclitaxel with or without bevacizumab in patients with nonsquamous NSCLC. Patients with squamous cell histology were excluded because previous studies demonstrated significant bleeding complications in that group. A second planned interim analysis has been reported in abstract form.[15] Of the 842 patients entered, the response rates (10% vs. 27%, P < .001), progression-free survival (4.5 months vs. 6.4 months, P < .001), and median survival (10.2 months vs. 12.5 months, P = .075) were superior in the bevacizumab arm. The five deaths that occurred were on the bevacizumab arm and were the result of hemoptysis.

The results support further evaluation of chemotherapeutic approaches for both metastatic and locally advanced NSCLC; however, the efficacy of current platinum-based chemotherapy combinations is such that no specific regimen can be regarded as standard therapy. Appropriate patients are candidates for clinical trials that evaluate the role of platinum-based and nonplatinum-based chemotherapy. Outside of a clinical trial setting, chemotherapy should be given only to patients with good PS and evaluable tumor lesions, who desire such treatment after being fully informed of its anticipated risks and limited benefits.

Radiation therapy may be effective in palliating symptomatic local involvement with NSCLC, such as tracheal, esophageal, or bronchial compression; bone or brain metastases; pain; vocal cord paralysis; hemoptysis; or superior vena cava syndrome. In some cases, endobronchial laser therapy and/or brachytherapy has been used to alleviate proximal obstructing lesions.[16] In the rare patient with synchronous presentation of a resectable primary tumor in the lung and a single brain metastasis, surgical resection of the solitary brain lesion is indicated with resection of the primary tumor. Appropriate postoperative chemotherapy and/or radiation therapy of the primary tumor site (and with postoperative whole-brain radiation therapy delivered in daily fractions of 1.8 Gy to 2.0 Gy) is used to avoid long-term toxic effects to normal brain tissue.[17,18]

Thoracic radiation therapy is an effective treatment modality to relieve symptoms from intrathoracic disease, either after disease progression during chemotherapy or in patients who are not candidates for or decline chemotherapy. Most of these patients will have symptoms from the primary tumor and local regional metastases, including dyspnea, cough, and hemoptysis; however, there is no consensus on which fractionation scheme should be used. Although different multifraction regimens appear to provide similar symptom relief, [19,20] single-fraction radiation may be insufficient for symptom relief compared with hypofractionated or standard regimens, as evidenced in the NCIC-CTG-SC15 trial, for example.[21] Evidence is available of a modest increase in survival in patients with better PS given high-dose radiation therapy.[19,20]

In closely observed asymptomatic patients, treatment may often be appropriately deferred until symptoms or signs of a progressive tumor develop.

Treatment options:

1. External-beam radiation therapy, primarily for palliative relief of local symptomatic tumor growth.[19-21]



2. Chemotherapy. The following regimens are associated with similar survival outcomes:
   • Cisplatin plus vinblastine plus mitomycin, as evidenced in the EORTC-08975 trial, for example.[19,22-25]
   • Cisplatin plus vinorelbine.[3,14]
   • Cisplatin plus paclitaxel.[5,13]
   • Cisplatin plus docetaxel.[13,26,27]
   • Cisplatin plus gemcitabine.[13,28]
   • Carboplatin plus paclitaxel.[13,14,29]



3. Clinical trials evaluating the role of new chemotherapy regimens and other systemic agents. Initial results suggest newer nonplatinum-based chemotherapy regimens produce response and survival results like those produced by standard platinum-based regimens.[30] Further trials comparing platinum-based and nonplatinum-based regimens are ongoing.



4. Endobronchial laser therapy and/or brachytherapy for obstructing lesions.[16]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage IV non-small cell lung cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References

1. Weick JK, Crowley J, Natale RB, et al.: A randomized trial of five cisplatin-containing treatments in patients with metastatic non-small-cell lung cancer: a Southwest Oncology Group study. J Clin Oncol 9 (7): 1157-62, 1991.  [PUBMED Abstract]
   
   
2. O'Connell JP, Kris MG, Gralla RJ, et al.: Frequency and prognostic importance of pretreatment clinical characteristics in patients with advanced non-small-cell lung cancer treated with combination chemotherapy. J Clin Oncol 4 (11): 1604-14, 1986.  [PUBMED Abstract]
   
   
3. Le Chevalier T, Brisgand D, Douillard JY, et al.: Randomized study of vinorelbine and cisplatin versus vindesine and cisplatin versus vinorelbine alone in advanced non-small-cell lung cancer: results of a European multicenter trial including 612 patients. J Clin Oncol 12 (2): 360-7, 1994.  [PUBMED Abstract]
   
   
4. Johnson DH, Paul DM, Hande KR, et al.: Paclitaxel plus carboplatin in advanced non-small-cell lung cancer: a phase II trial. J Clin Oncol 14 (7): 2054-60, 1996.  [PUBMED Abstract]
   
   
5. 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 18 (3): 623-31, 2000.  [PUBMED Abstract]
   
   
6. Hotta K, Matsuo K, Ueoka H, et al.: Addition of platinum compounds to a new agent in patients with advanced non-small-cell lung cancer: a literature based meta-analysis of randomised trials. Ann Oncol 15 (12): 1782-9, 2004.  [PUBMED Abstract]
   
   
7. 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 (3): 173-81, 2002.  [PUBMED Abstract]
   
   
8. Perrone F, Gallo C, Gridelli C: Re: 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 (13): 1029-30; discussion 1030-1, 2002.  [PUBMED Abstract]
   
   
9. Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small-cell lung cancer. The Elderly Lung Cancer Vinorelbine Italian Study Group. J Natl Cancer Inst 91 (1): 66-72, 1999.  [PUBMED Abstract]
   
   
10. Gridelli C, Perrone F, Gallo C, et al.: Chemotherapy for elderly patients with advanced non-small-cell lung cancer: the Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial. J Natl Cancer Inst 95 (5): 362-72, 2003.  [PUBMED Abstract]
    
    
11. Hensing TA, Peterman AH, Schell MJ, et al.: The impact of age on toxicity, response rate, quality of life, and survival in patients with advanced, Stage IIIB or IV nonsmall cell lung carcinoma treated with carboplatin and paclitaxel. Cancer 98 (4): 779-88, 2003.  [PUBMED Abstract]
    
    
12. Maestu I, Gómez-Aldaraví L, Torregrosa MD, et al.: Gemcitabine and low dose carboplatin in the treatment of elderly patients with advanced non-small cell lung cancer. Lung Cancer 42 (3): 345-54, 2003.  [PUBMED Abstract]
    
    
13. Schiller JH, Harrington D, Belani CP, et al.: Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 346 (2): 92-8, 2002.  [PUBMED Abstract]
    
    
14. Kelly K, Crowley J, Bunn PA Jr, 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 (13): 3210-8, 2001.  [PUBMED Abstract]
    
    
15. Sandler AB, Gray R, Brahmer J, et al.: Randomized phase II/III trial of paclitaxel (P) plus carboplatin (C) with or without bevacizumab (NSC # 704865) in patients with advanced non-squamous non-small cell lung cancer (NSCLC): an Eastern Cooperative Oncology Group (ECOG) Trial - E4599. [Abstract] J Clin Oncol 23 (Suppl 16): A-LBA4, 2s, 2005. 
    
    
16. Miller JI Jr, Phillips TW: Neodymium:YAG laser and brachytherapy in the management of inoperable bronchogenic carcinoma. Ann Thorac Surg 50 (2): 190-5; discussion 195-6, 1990.  [PUBMED Abstract]
    
    
17. Mandell L, Hilaris B, Sullivan M, et al.: The treatment of single brain metastasis from non-oat cell lung carcinoma. Surgery and radiation versus radiation therapy alone. Cancer 58 (3): 641-9, 1986.  [PUBMED Abstract]
    
    
18. DeAngelis LM, Mandell LR, Thaler HT, et al.: The role of postoperative radiotherapy after resection of single brain metastases. Neurosurgery 24 (6): 798-805, 1989.  [PUBMED Abstract]
    
    
19. Macbeth F, Toy E, Coles B, et al.: Palliative radiotherapy regimens for non-small cell lung cancer. Cochrane Database Syst Rev (3): CD002143, 2001.  [PUBMED Abstract]
    
    
20. Sundstrøm S, Bremnes R, Aasebø U, et al.: Hypofractionated palliative radiotherapy (17 Gy per two fractions) in advanced non-small-cell lung carcinoma is comparable to standard fractionation for symptom control and survival: a national phase III trial. J Clin Oncol 22 (5): 801-10, 2004.  [PUBMED Abstract]
    
    
21. Bezjak A, Dixon P, Brundage M, et al.: Randomized phase III trial of single versus fractionated thoracic radiation in the palliation of patients with lung cancer (NCIC CTG SC.15). Int J Radiat Oncol Biol Phys 54 (3): 719-28, 2002.  [PUBMED Abstract]
    
    
22. Veeder MH, Jett JR, Su JQ, et al.: A phase III trial of mitomycin C alone versus mitomycin C, vinblastine, and cisplatin for metastatic squamous cell lung carcinoma. Cancer 70 (9): 2281-7, 1992.  [PUBMED Abstract]
    
    
23. Danson S, Middleton MR, O'Byrne KJ, et al.: Phase III trial of gemcitabine and carboplatin versus mitomycin, ifosfamide, and cisplatin or mitomycin, vinblastine, and cisplatin in patients with advanced nonsmall cell lung carcinoma. Cancer 98 (3): 542-53, 2003.  [PUBMED Abstract]
    
    
24. Pfister DG, Johnson DH, Azzoli CG, et al.: American Society of Clinical Oncology treatment of unresectable non-small-cell lung cancer guideline: update 2003. J Clin Oncol 22 (2): 330-53, 2004.  [PUBMED Abstract]
    
    
25. Smit EF, van Meerbeeck JP, Lianes P, et al.: Three-arm randomized study of two cisplatin-based regimens and paclitaxel plus gemcitabine in advanced non-small-cell lung cancer: a phase III trial of the European Organization for Research and Treatment of Cancer Lung Cancer Group--EORTC 08975. J Clin Oncol 21 (21): 3909-17, 2003.  [PUBMED Abstract]
    
    
26. Kubota K, Watanabe K, Kunitoh H, et al.: Phase III randomized trial of docetaxel plus cisplatin versus vindesine plus cisplatin in patients with stage IV non-small-cell lung cancer: the Japanese Taxotere Lung Cancer Study Group. J Clin Oncol 22 (2): 254-61, 2004.  [PUBMED Abstract]
    
    
27. Georgoulias V, Ardavanis A, Agelidou A, et al.: Docetaxel versus docetaxel plus cisplatin as front-line treatment of patients with advanced non-small-cell lung cancer: a randomized, multicenter phase III trial. J Clin Oncol 22 (13): 2602-9, 2004.  [PUBMED Abstract]
    
    
28. 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 (1): 122-30, 2000.  [PUBMED Abstract]
    
    
29. Belani CP, Barstis J, Perry MC, et al.: Multicenter, randomized trial for stage IIIB or IV non-small-cell lung cancer using weekly paclitaxel and carboplatin followed by maintenance weekly paclitaxel or observation. J Clin Oncol 21 (15): 2933-9, 2003.  [PUBMED Abstract]
    
    
30. Kosmidis P, Mylonakis N, Nicolaides C, et al.: Paclitaxel plus carboplatin versus gemcitabine plus paclitaxel in advanced non-small-cell lung cancer: a phase III randomized trial. J Clin Oncol 20 (17): 3578-85, 2002.  [PUBMED Abstract]
    
    

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