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.)

Many patients with recurrent non-small cell lung cancer (NSCLC) are eligible for clinical trials. Radiation therapy may provide excellent palliation of symptoms from a localized tumor mass.

Patients who present with a solitary cerebral metastasis after resection of a primary NSCLC lesion and who have no evidence of extracranial tumor can achieve prolonged disease-free survival with surgical excision of the brain metastasis and postoperative whole-brain radiation therapy.[1,2] Unresectable brain metastases in this setting may be treated with radiosurgery.[3] Because of the small potential for long-term survival, radiation therapy should be delivered by conventional methods in daily doses of 1.8 Gy to 2.0 Gy. Because of the high risk of toxic effects observed with such treatments, higher daily doses over a shorter period of time (i.e., hypofractionated schemes) should be avoided.[4] Most patients who are not suitable for surgical resection should receive conventional whole-brain radiation therapy. Selected patients with good performance status (PS) and small metastases can be considered for stereotactic radiosurgery.[5]

Approximately 50% of patients treated with resection and postoperative radiation therapy will develop recurrence in the brain; some of these patients will be suitable for additional treatment.[6] In those selected patients with good PS and without progressive metastases outside of the brain, treatment options include reoperation or stereotactic radiosurgery.[3,6] For most patients, additional radiation therapy can be considered; however, the palliative benefit of this treatment is limited.[7][Level of evidence: 3iiiDiii]

A solitary pulmonary metastasis from an initially resected bronchogenic carcinoma is unusual. The lung is frequently the site of second primary malignancies in patients with primary lung cancers. Whether the new lesion is a new primary cancer or a metastasis may be difficult to determine. Studies have indicated that in most patients the new lesion is a second primary tumor, and after its resection some patients may achieve long-term survival. Thus, if the first primary tumor has been controlled, the second primary tumor should be resected, if possible.[8,9]

The use of chemotherapy has produced objective responses and small improvement in survival for patients with metastatic disease.[10][Level of evidence: 1iiA] In studies that have examined symptomatic response, improvement in subjective symptoms has been reported to occur more frequently than objective response.[11,12] Informed patients with good PS and symptomatic recurrence can be offered treatment with a platinum-based chemotherapy regimen for palliation of symptoms. For patients who have relapsed after platinum-based chemotherapy, second-line therapy can be considered. Two prospective randomized studies have shown an improvement in survival with the use of docetaxel compared with vinorelbine, ifosfamide, or best supportive care;[13,14] however, criteria for the selection of appropriate patients for second-line treatment are not well defined.[15] A randomized phase III trial of 571 patients designed to demonstrate the noninferiority of pemetrexed compared with docetaxel showed no difference in response rates, progression-free survival, or overall survival (OS).[16][Level of evidence: 1iiA]

A phase II study of erlotinib (i.e., 150 mg orally, daily) in patients with epidermal growth factor receptor (EGFR)-expressing NSCLC previously treated with platinum-based chemotherapy reported an objective response rate of 12.3% (95% confidence interval [CI], 5.1%–23.7%).[17][Level of evidence: 3iiiDiv] Drug-related cutaneous rash and diarrhea were observed in 75% and 56% of patients, respectively. A preliminary report of a randomized, placebo-controlled trial indicated that erlotinib prolongs survival in NSCLC patients after first-line or second-line chemotherapy compared with placebo.[18] In this trial of 731 patients, the median OS was 6.7 months versus 4.7 months (hazard ratio [HR] = 0.73; 95% CI, 0.6–0.87; P = .001). The median progression-free survival was 2.23 months versus 1.84 months (HR = 0.6; 95% CI, 0.51–0.73; P < .001).[18][Level of evidence: 1iiA] When used in combination with carboplatin/paclitaxel [19] or cisplatin/gemcitabine, [20] erlotinib was not found to improve response rates, progression-free survival, or OS in previously untreated patients with advanced or metastatic NSCLC.[19,20][Level of evidence: 1iiA]

Gefitinib induces responses in 9.6% to 19% of NSCLC patients treated previously with platinum and taxane chemotherapy.[21,22][Level of evidence: 3iiiDiv] Additionally, a randomized phase III trial evaluating gefitinib versus placebo in 1,692 previously treated NSCLC patients showed that gefitinib does not improve OS (HR = 0.89; P = .11; median 5.6 vs. 5.1 months for gefitnib and placebo, respectively).[23][Level of evidence: 1iiA] In addition, in two randomized trials comparing the addition of gefitinib with standard platinum combination chemotherapy, no improvement in response rates, progression-free survival, or OS was shown.[24,25][Level of evidence: 1iiA]

Objective response rates to erlotinib and gefitinib are higher in patients who have never smoked, in females, and in patients with adenocarcinoma and bronchioloalveolar carcinoma.[26-30] Responses may be associated with mutations around the tyrosine kinase domain of the EGFR receptor [27-29] and with the absence of K-RAS mutations.[30][Level of evidence: 3iiiDiii]

Treatment options:

1. Palliative radiation therapy.[31]



2. Chemotherapy alone.

   For patients who have not received chemotherapy previously, the following regimens are associated with similar survival outcomes:

   • Cisplatin plus vinblastine plus mitomycin.[32]
   • Cisplatin plus vinorelbine.[33]
   • Cisplatin plus paclitaxel.[34,35]
   • Cisplatin plus gemcitabine.[35,36]
   • Carboplatin plus paclitaxel.[35,37,38]
   • Cisplatin plus docetaxel.[35,39]

   For patients who have received platinum chemotherapy previously:

   • Docetaxel.[14,16]
   • Pemetrexed.[16]
   • Erlotinib after failure of both platinum-based and docetaxel chemotherapies.[18]



3. Surgical resection of isolated cerebral metastasis (highly selected patients).[6]



4. Laser therapy or interstitial radiation therapy for endobronchial lesions.[40]



5. Stereotactic radiosurgery (highly selected patients).[3,5]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with recurrent 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

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2. 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]
   
   
3. Loeffler JS, Kooy HM, Wen PY, et al.: The treatment of recurrent brain metastases with stereotactic radiosurgery. J Clin Oncol 8 (4): 576-82, 1990.  [PUBMED Abstract]
   
   
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18. Shepherd FA, Pereira J, Ciuleanu TE, et al.: A randomized placebo-controlled trial of erlotinib in patients with advanced non-small cell lung cancer (NSCLC) following failure of 1st line or 2nd line chemotherapy. A National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) trial. [Abstract] J Clin Oncol 22 (Suppl 14): A-7022, 622s, 2004. 
    
    
19. Herbst RS, Prager D, Hermann R, et al.: TRIBUTE - A phase III trial of erlotinib HCI (OSI-774) combined with carboplatin and paclitaxel (CP) chemotherapy in advanced non-small cell lung cancer (NSCLC). [Abstract] J Clin Oncol 22 (Suppl 14): A-7011, 619s, 2004. 
    
    
20. Gatzemeier U, Pluzanska A, Szczesna A, et al.: Results of a phase III trial of erlotinib (OSI-774) combined with cisplatin and gemcitabine (GC) chemotherapy in advanced non-small cell lung cancer (NSCLC). [Abstract] J Clin Oncol 22 (Suppl 14): A-7010, 619s, 2004. 
    
    
21. Kris MG, Natale RB, Herbst RS, et al.: Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA 290 (16): 2149-58, 2003.  [PUBMED Abstract]
    
    
22. Fukuoka M, Yano S, Giaccone G, et al.: Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer. J Clin Oncol 21 (12): 2237-46, 2003.  [PUBMED Abstract]
    
    
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24. Herbst RS, Giaccone G, Schiller JH, et al.: Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial--INTACT 2. J Clin Oncol 22 (5): 785-94, 2004.  [PUBMED Abstract]
    
    
25. Giaccone G, Herbst RS, Manegold C, et al.: Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial--INTACT 1. J Clin Oncol 22 (5): 777-84, 2004.  [PUBMED Abstract]
    
    
26. Miller VA, Kris MG, Shah N, et al.: Bronchioloalveolar pathologic subtype and smoking history predict sensitivity to gefitinib in advanced non-small-cell lung cancer. J Clin Oncol 22 (6): 1103-9, 2004.  [PUBMED Abstract]
    
    
27. Paez JG, Jänne PA, Lee JC, et al.: EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304 (5676): 1497-500, 2004.  [PUBMED Abstract]
    
    
28. Lynch TJ, Bell DW, Sordella R, et al.: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350 (21): 2129-39, 2004.  [PUBMED Abstract]
    
    
29. Pao W, Miller V, Zakowski M, et al.: EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 101 (36): 13306-11, 2004.  [PUBMED Abstract]
    
    
30. Pao W, Wang TY, Riely GJ, et al.: KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med 2 (1): e17, 2005.  [PUBMED Abstract]
    
    
31. 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]
    
    
32. 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]
    
    
33. 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]
    
    
34. 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]
    
    
35. 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]
    
    
36. 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]
    
    
37. 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]
    
    
38. 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]
    
    
39. 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]
    
    
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