Advertisement

Current Clinical Management of Metastatic Lung Cancer

  • Bryan J. Schneider
  • Suresh S. Ramalingam
Chapter

Abstract

Approximately 40% of patients with non-small cell lung cancer (NSCLC) and 70% of patients with small cell lung cancer (SCLC) present with advanced, hematogenously metastatic, incurable disease. Systemic chemotherapy is the mainstay of therapy in these patients with the primary goals of palliating symptoms, maintaining quality of life, and prolonging life. For patients with advanced NSCLC, standard treatment consists of two-drug, platinum-based chemotherapy with or without bevacizumab, a monoclonal antibody targeting the vascular endothelial growth factor which controls tumor angiogenesis. In NSCLC, second- and third-line therapy with chemotherapy or epidermal growth factor receptor inhibitors has also been shown to provide a survival benefit. Recent studies have begun to define specific clinical, histological, and molecular characteristics that can help identify subsets of patients with NSCLC who will or will not respond to particular chemotherapeutic or molecularly targeted agents. For patients with extensive-stage SCLC, initial platinum-based chemotherapy yields impressive response rates, but long-term survival remains extremely limited. Despite extensive knowledge of the biology of SCLC, studies of molecularly targeted therapies have yet to demonstrate any significant clinical benefits in this disease.

Keywords

Vascular Endothelial Growth Factor Epidermal Growth Factor Receptor Small Cell Lung Cancer Epidermal Growth Factor Receptor Mutation Advanced NSCLC 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2007. CA Cancer J Clin 2007; 57:43–66.PubMedCrossRefGoogle Scholar
  2. 2.
    Govindan R, Page N, Morgensztern D, et al. Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database. J Clin Oncol 2006; 24:4539–4544.PubMedCrossRefGoogle Scholar
  3. 3.
    Ramalingam S, Belani CP. State-of-the-art chemotherapy for advanced non-small cell lung cancer. Semin Oncol 2004; 31:68–74.PubMedCrossRefGoogle Scholar
  4. 4.
    Albain KS, Crowley JJ, LeBlanc M, et al. Survival determinants in extensive-stage non-small-cell lung cancer: the Southwest Oncology Group experience. J Clin Oncol 1991; 9:1618–1626.PubMedGoogle Scholar
  5. 5.
    Langer C, Li S, Schiller J, et al. Randomized phase II trial of paclitaxel plus carboplatin or gemcitabine plus cisplatin in Eastern Cooperative Oncology Group performance status 2 non-small-cell lung cancer patients: ECOG 1599. J Clin Oncol 2007; 25:418–423.PubMedCrossRefGoogle Scholar
  6. 6.
    Bunn PA, Jr. Chemotherapy for advanced non-small-cell lung cancer: who, what, when, why? J Clin Oncol 2002; 20:23S–33S.PubMedGoogle Scholar
  7. 7.
    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; 346:92–98.PubMedCrossRefGoogle Scholar
  8. 8.
    Scagliotti G, Parikh P, von Pawel J, et al. Phase III study of pemetrexed plus cisplatin versus gemcitabine plus cisplatin in chemonaive patients with locally advanced or metastatic non-small cell lung cancer. J Thorac Oncol 2007; 2:S306.CrossRefGoogle Scholar
  9. 9.
    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; 16:2459–2465.PubMedGoogle Scholar
  10. 10.
    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; 18:122–130.PubMedGoogle Scholar
  11. 11.
    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 2000; 18:3390–3399.PubMedGoogle Scholar
  12. 12.
    Rosell R, Gatzemeier U, Betticher DC, et al. Phase III randomised trial comparing paclitaxel/carboplatin with paclitaxel/cisplatin in patients with advanced non-small-cell lung cancer: a cooperative multinational trial. Ann Oncol 2002; 13:1539–1549.PubMedCrossRefGoogle Scholar
  13. 13.
    Hotta K, Matsuo K, Ueoka H, et al. Meta-analysis of randomized clinical trials comparing Cisplatin to Carboplatin in patients with advanced non-small-cell lung cancer. J Clin Oncol 2004; 22:3852–3859.PubMedCrossRefGoogle Scholar
  14. 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 2001; 19:3210–3218.PubMedGoogle Scholar
  15. 15.
    Fossella F, Pereira JR, Von Pawel J, et al. Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 Study Group. J Clin Oncol 2003; 16:3016–3024.CrossRefGoogle Scholar
  16. 16.
    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 1994; 12:360–367.PubMedGoogle Scholar
  17. 17.
    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; 18:623–631.PubMedGoogle Scholar
  18. 18.
    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 2003; 21:3909–3917.PubMedCrossRefGoogle Scholar
  19. 19.
    Treat J, Belani CP, Edelman M, et al. A randomized phase III trial of gemcitabine in combination with carboplatin or paclitaxel versus paclitaxel plus carboplatin in advanced non-small cell lung cancer: Update of the Alpha Oncology Trial. J Clin Oncol 2005; 23:1096.CrossRefGoogle Scholar
  20. 20.
    Alberola V, Camps C, Provencio M, et al. Cisplatin plus gemcitabine versus a cisplatin-based triplet versus nonplatinum sequential doublets in advanced non-small-cell lung cancer: a Spanish Lung Cancer Group phase III randomized trial. J Clin Oncol 2003; 21:3207–3213.PubMedCrossRefGoogle Scholar
  21. 21.
    Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 2004; 22:1589–1597.PubMedCrossRefGoogle Scholar
  22. 22.
    Schmid M, Malicki D, Nobori T, et al. Homozygous deletions of methylthioadenosine phosphorylase (MTAP) are more frequent than p16INK4A (CDKN2) homozygous deletions in primary non-small cell lung cancers. Oncogene 1998; 17:2669–2675.PubMedCrossRefGoogle Scholar
  23. 23.
    Schmid M, Sen M, Rosenbach MD, et al. A methylthioadenosine phosphorylase (MTAP) fusion transcript identifies a new gene on chromosome 9p21 that is frequently deleted in cancer. Oncogene 2000; 19:5747–5754.PubMedCrossRefGoogle Scholar
  24. 24.
    Chattopadhyay S, Zhao R, Tsai E, et al. The effect of a novel transition state inhibitor of methylthioadenosine phosphorylase on pemetrexed activity. Mol Cancer Ther 2006; 5:2549–2555.PubMedCrossRefGoogle Scholar
  25. 25.
    Rosell R, Taron M, Barnadas A, et al. Nucleotide excision repair pathways involved in Cisplatin resistance in non-small-cell lung cancer. Cancer Control 2003; 10:297–305.PubMedGoogle Scholar
  26. 26.
    Lord RV, Brabender J, Gandara D, et al. Low ERCC1 expression correlates with prolonged survival after cisplatin plus gemcitabine chemotherapy in non-small cell lung cancer. Clin Cancer Res 2002; 8:2286–2291.PubMedGoogle Scholar
  27. 27.
    Cobo M, Isla D, Massuti B, et al. Customizing cisplatin based on quantitative excision repair cross-complementing 1 mRNA expression: a phase III trial in non-small-cell lung cancer. J Clin Oncol 2007; 25:2747–2754.PubMedCrossRefGoogle Scholar
  28. 28.
    Simon G, Sharma A, Li X, et al. Feasibility and efficacy of molecular analysis-directed individualized therapy in advanced non-small-cell lung cancer. J Clin Oncol 2007; 25:2741–2746.PubMedCrossRefGoogle Scholar
  29. 29.
    Shepherd FA, Dancey J, Ramlau R, et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 2000; 18:2095–2103.PubMedGoogle Scholar
  30. 30.
    Fossella FV, DeVore R, Kerr RN, et al. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol 2000; 18:2354–2362.PubMedGoogle Scholar
  31. 31.
    Ramlau R, Gervais R, Krzakowski M, et al. Oral topotecan demonstrates clinical activity in relapsed non-small cell lung cancer. Results from an open-label, phase III study comparing oral topotecan to intravenous docetaxel. J Clin Oncol 2005; 23:625.Google Scholar
  32. 32.
    Krzakowski M, Douillard J, Ramlau R, et al. Phase III study of vinflunine versus docetaxel in patients with advanced non-small cell lung cancer previously treated with a platinum-containing regimen. J Clin Oncol 2007; 25:387s.Google Scholar
  33. 33.
    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 2003; 21:2237–2246.PubMedCrossRefGoogle Scholar
  34. 34.
    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 2003; 290:2149–2158.PubMedCrossRefGoogle Scholar
  35. 35.
    Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 2005; 366:1527–1537.PubMedCrossRefGoogle Scholar
  36. 36.
    Perez-Soler R, Chachoua A, Hammond LA, et al. Determinants of tumor response and survival with erlotinib in patients with non–small-cell lung cancer. J Clin Oncol 2004; 22:3238–3247.PubMedCrossRefGoogle Scholar
  37. 37.
    Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005; 353:123–132.PubMedCrossRefGoogle Scholar
  38. 38.
    Hanna N, Lilenbaum R, Ansari R, et al. Phase II trial of cetuximab in patients with previously treated non-small-cell lung cancer. J Clin Oncol 2006; 24:5253–5258.PubMedCrossRefGoogle Scholar
  39. 39.
    Sirotnak FM, Zakowski MF, Miller VA, et al. Efficacy of cytotoxic agents against human tumor xenografts is markedly enhanced by coadministration of ZD1839 (Iressa), an inhibitor of EGFR tyrosine kinase. Clin Cancer Res 2000; 6:4885–4892.PubMedGoogle Scholar
  40. 40.
    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 2004; 22:785–794.PubMedCrossRefGoogle Scholar
  41. 41.
    Herbst RS, Prager D, Hermann R, et al. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol 2005; 23:5892–5899.PubMedCrossRefGoogle Scholar
  42. 42.
    Rosell R, Daniel C, Ramlau R, et al. Randomized phase II study of cetuximab in combination with cisplatin and vinorelbine vs. CV alone in the first-line treatment of patients with epidermal growth factor receptor (EGFR)-expressing advanced non-small-cell lung cancer. Proc Am Soc Clin Oncol 2004; 23:618.Google Scholar
  43. 43.
    Thienelt CD, Bunn PA, Jr., Hanna N, et al. Multicenter phase I/II study of cetuximab with paclitaxel and carboplatin in untreated patients with stage IV non-small-cell lung cancer. J Clin Oncol 2005; 23:8786–8793.PubMedCrossRefGoogle Scholar
  44. 44.
    Belani CP, Ramalingam S, Schreeder R, et al. Phase II study of cetuximab in combination with carboplatin and docetaxel for patients with advanced/metastatic non-small cell lung cancer. J Clin Oncol 2007; 25:420s.Google Scholar
  45. 45.
    Crawford J, Swanson P, Prager D, et al. Panitumumab, a fully human antibody, combined with paclitaxel and carboplatin versus paclitaxel and carboplatin alone for first line advanced non-small cell lung cancer: a primary analysis. Eur J Cancer 2005; 3:324.Google Scholar
  46. 46.
    Scartozzi M, Bearzi I, Berardi R, et al. Epidermal growth factor receptor (EGFR) status in primary colorectal tumors does not correlate with EGFR expression in related metastatic sites: implications for treatment with EGFR-targeted monoclonal antibodies. J Clin Oncol 2004; 22:4772–4778.PubMedCrossRefGoogle Scholar
  47. 47.
    Hirsch FR, Gandara D, McCoy J, et al. Increased EGFR gene copy number detected by FISH is associated with increased sensitivity to gefitinib in patients with bronchioloalveolar carcinoma (S0126). J Clin Oncol 2005; 23:628.Google Scholar
  48. 48.
    Hirsch FR, Varella-Garcia M, McCoy J, et al. Increased epidermal growth factor receptor gene copy number detected by fluorescence in situ hybridization associates with increased sensitivity to gefitinib in patients with bronchioloalveolar carcinoma subtypes: a Southwest Oncology Group study. J Clin Oncol 2005; 23:6838–6845.PubMedCrossRefGoogle Scholar
  49. 49.
    Hirsch FR, Varella-Garcia M, Bunn PA, Jr., et al. Epidermal growth factor receptor in non-small-cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis. J Clin Oncol 2003; 21:3798–3807.PubMedCrossRefGoogle Scholar
  50. 50.
    Tsao MS, Sakurada A, Cutz JC, et al. Erlotinib in lung cancer – molecular and clinical predictors of outcome. N Engl J Med 2005; 353:133–144.PubMedCrossRefGoogle Scholar
  51. 51.
    Douillard JY, Kim ES, Hirsch V, et al. Gefitinib versus docetaxel in patients with locally advanced or metastatic non-small cell lung cancer pre-treated with platinum-based chemotherapy: a randomized, open-label phase III study (INTEREST). J Thorac Oncol 2007; 2:S305.CrossRefGoogle Scholar
  52. 52.
    Crino L, Zatloukal P, Reck M, et al. Gefitinib versus vinorelbine in chemonaive elderly patients with advanced non-small cell lung cancer (INVITE): a randomized phase II study. J Thorac Oncol 2007; 2:S341.CrossRefGoogle Scholar
  53. 53.
    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 2004; 350:2129–2139.PubMedCrossRefGoogle Scholar
  54. 54.
    Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004; 304:1497–1500.PubMedCrossRefGoogle Scholar
  55. 55.
    Paz-Ares L, Sanchez JM, García-Velasco A, et al. A prospective phase II trial of erlotinib in advanced non-small cell lung cancer patients with mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR). J Clin Oncol 2006; 24:369s.CrossRefGoogle Scholar
  56. 56.
    Cappuzzo F, Toschi L, Trisolini R, et al. Clinical and biological effects of gefitinib in EGFR FISH positive/phospho-akt positive or never smoker non-small cell lung cancer: Preliminary results of the ONCOBELL trial. J Clin Oncol 2006; 24:369s.Google Scholar
  57. 57.
    Kris MG, Pao W, Zakowski MF, et al. Prospective trial with preoperative gefitinib to correlate lung cancer response with EGFR exon 19 and 21 mutations and to select patients for adjuvant therapy. J Clin Oncol 2006; 24:369s.CrossRefGoogle Scholar
  58. 58.
    Mukohara T, Engelman JA, Hanna NH, et al. Differential effects of gefitinib and cetuximab on non-small-cell lung cancers bearing epidermal growth factor receptor mutations. J Natl Cancer Inst 2005; 97:1185–1194.PubMedCrossRefGoogle Scholar
  59. 59.
    Eberhard DA, Johnson BE, Amler LC, et al. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol 2005; 23:5900–5909.PubMedCrossRefGoogle Scholar
  60. 60.
    Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 2005; 352:786–792.PubMedCrossRefGoogle Scholar
  61. 61.
    Engelman JA, Zejnullahu K, Mitsudomi T, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 2007; 316:1039–1043.PubMedCrossRefGoogle Scholar
  62. 62.
    Taguchi F, Solomon B, Gregorc V, et al. Mass spectrometry to classify non-small-cell lung cancer patients for clinical outcome after treatment with epidermal growth factor receptor tyrosine kinase inhibitors: a multicohort cross-institutional study. J Natl Cancer Inst 2007; 99:838–846.PubMedCrossRefGoogle Scholar
  63. 63.
    Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med 2003; 9:669–676.PubMedCrossRefGoogle Scholar
  64. 64.
    Ferrara N. Vascular endothelial growth factor as a target for anticancer therapy. Oncologist 2004; 9 Suppl 1:2–10.PubMedCrossRefGoogle Scholar
  65. 65.
    Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004; 350:2335–2342.PubMedCrossRefGoogle Scholar
  66. 66.
    Johnson DH, Fehrenbacher L, Novotny WF, et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 2004; 22:2184–2191.PubMedCrossRefGoogle Scholar
  67. 67.
    Sandler A, Gray R, Perry MC, et al. Paclitaxel–carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006; 355:2542–2550.PubMedCrossRefGoogle Scholar
  68. 68.
    Manegold C, von Pawel J, Zatloukal P, et al. Randomised, double-blind multicentre phase III study of bevacizumab in combination with cisplatin and gemcitabine in chemotherapy-naïve patients with advanced or recurrent non-squamous non-small cell lung cancer: BO17704. J Clin Oncol 2007; 25:388s.Google Scholar
  69. 69.
    Natale RB, Bodkin D, Govindan R, et al. ZD6474 versus gefitinib in patients with advanced NSCLC: Final results from a two-part, double-blind, randomized phase II trial. J Clin Oncol 2006; 24:364s.Google Scholar
  70. 70.
    Socinski MA, Novello S, Sanchez JM, et al. Efficacy and safety of sunitinib in previously treated, advanced non-small cell lung cancer: Preliminary results of a multicenter phase II trial. J Clin Oncol 2006; 24:364s.CrossRefGoogle Scholar
  71. 71.
    Gatzemeier U, Blumenschein G, Fosella F, et al. Phase II trial of single-agent sorafenib in patients with advanced non-small cell lung carcinoma. J Clin Oncol 2006; 24:364s.Google Scholar
  72. 72.
    Schiller JH, Flaherty KT, Redlinger M, et al. Sorafenib combined with carboplatin/paclitaxel for advanced non-small cell lung cancer: A phase I subset analysis. J Clin Oncol 2006; 24:412s.CrossRefGoogle Scholar
  73. 73.
    Dowlati A, Gray R, Johnson DH, et al. Prospective correlative assessment of biomarkers in E4599 randomized phase II/III trial of carboplatin and paclitaxel ± bevacizumab in advanced non-small cell lung cancer. J Clin Oncol 2006; 24:370s.CrossRefGoogle Scholar
  74. 74.
    Schenkein DP. Use of proteasome inhibition in the treatment of lung cancer. Clin Lung Cancer 2004; 6 Suppl 2:S89–S96.PubMedCrossRefGoogle Scholar
  75. 75.
    Fanucchi MP, Fossella F, Fidias P, et al. Bortezomib + docetaxel in previously treated patients with advanced non-small cell lung cancer: A phase 2 study. J Clin Oncol 2005; 23:629.Google Scholar
  76. 76.
    Davies AM, McCoy J, Lara PN, et al. Bortezomib + gemcitabine /carboplatin results in encouraging survival in advanced non-small cell lung cancer: Results of a phase II Southwest Oncology Group trial (S0339). J Clin Oncol 2006; 24:368s.CrossRefGoogle Scholar
  77. 77.
    Lorch JH, Thomas TO, Schmoll HJ. Bortezomib inhibits cell–cell adhesion and cell migration and enhances epidermal growth factor receptor inhibitor-induced cell death in squamous cell cancer. Cancer Res 2007; 67:727–734.PubMedCrossRefGoogle Scholar
  78. 78.
    Marks PA, Richon VM, Rifkind RA. Histone deacetylase inhibitors: inducers of differentiation or apoptosis of transformed cells. J Natl Cancer Inst 2000; 92:1210–1216.PubMedCrossRefGoogle Scholar
  79. 79.
    Kelly WK, Richon VM, O‘Connor O, et al. Phase I clinical trial of histone deacetylase inhibitor: suberoylanilide hydroxamic acid administered intravenously. Clin Cancer Res 2003; 9:3578–3588.PubMedGoogle Scholar
  80. 80.
    Bali P, Pranpat M, Swaby R, et al. Activity of suberoylanilide hydroxamic Acid against human breast cancer cells with amplification of her-2. Clin Cancer Res 2005; 11:6382–6389.PubMedCrossRefGoogle Scholar
  81. 81.
    Kim MS, Blake M, Baek JH, et al. Inhibition of histone deacetylase increases cytotoxicity to anticancer drugs targeting DNA. Cancer Res 2003; 63:7291–7300.PubMedGoogle Scholar
  82. 82.
    Ramalingam S, Parise RA, Egorin MJ, et al. Phase I study of vorinostat, a histone deacetylase (HDAC) inhibitor, in combination with carboplatin and paclitaxel for patients with advanced solid malignancies. J Clin Oncol 2006; 24:98s.Google Scholar
  83. 83.
    Witta SE, Gemmill RM, Hirsch FR, et al. Restoring E-cadherin expression increases sensitivity to epidermal growth factor receptor inhibitors in lung cancer cell lines. Cancer Res 2006; 66:944–950.PubMedCrossRefGoogle Scholar
  84. 84.
    Bjornsti MA, Houghton PJ. The TOR pathway: a target for cancer therapy. Nat Rev Cancer 2004; 4:335–348.PubMedCrossRefGoogle Scholar
  85. 85.
    Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev 2004; 18:1926–1945.PubMedCrossRefGoogle Scholar
  86. 86.
    Hudes G, Carducci M, Tomczak P, et al. A phase 3, randomized, 3-arm study of temsirolimus (TEMSR) or interferon-alpha (IFN) or the combination of TEMSR + IFN in the treatment of first-line, poor-risk patients with advanced renal cell carcinoma. J Clin Oncol 2006; 24:2s.CrossRefGoogle Scholar
  87. 87.
    Papadimitrakopoulou V, Blumenschein G, Rollins M, et al. A phase I/II study investigating the combination of RAD001 (everolimus) and erlotinib as 2nd /3rd line therapy in patients with advanced non-small cell lung cancer previously treated with chemotherapy. J Clin Oncol 2006; 24:670s.Google Scholar
  88. 88.
    Herbst RS, Heymach JV, O‘Reilly MS, et al. Vandetanib (ZD6474): an orally available receptor tyrosine kinase inhibitor that selectively targets pathways critical for tumor growth and angiogenesis. Expert Opin Investig Drugs 2007; 16:239–249.PubMedCrossRefGoogle Scholar
  89. 89.
    Heymach J, Johnson B, Prager D, et al. A phase II trial of ZD6474 plus docetaxel in patients with previously treated NSCLC: Follow-up results. J Clin Oncol 2006; 24:368s.Google Scholar
  90. 90.
    Herbst RS, O‘Neill VJ, Fehrenbacher L, et al. Phase II study of efficacy and safety of bevacizumab in combination with chemotherapy or erlotinib compared with  chemotherapy alone for treatment of recurrent or refractory non small-cell lung cancer. J Clin Oncol 2007; 25:4743–4750.PubMedCrossRefGoogle Scholar
  91. 91.
    Roth BJ, Johnson DH, Einhorn LH, et al. Randomized study of cyclophosphamide, doxorubicin, and vincristine versus etoposide and cisplatin versus alternation of these two regimens in extensive small-cell lung cancer: a phase III trial of the Southeastern Cancer Study Group. J Clin Oncol 1992; 10:282–291.PubMedGoogle Scholar
  92. 92.
    Skarlos DV, Samantas E, Kosmidis P, et al. Randomized comparison of etoposide–cisplatin vs. etoposide–carboplatin and irradiation in small-cell lung cancer. A Hellenic Co-operative Oncology Group study. Ann Oncol 1994; 5:601–607.PubMedGoogle Scholar
  93. 93.
    Noda K, Nishiwaki Y, Kawahara M, et al. Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med 2002; 346:85–91.PubMedCrossRefGoogle Scholar
  94. 94.
    Hanna N, Bunn PA, Jr., Langer C, et al. Randomized phase III trial comparing irinotecan/cisplatin with etoposide/cisplatin in patients with previously untreated extensive-stage disease small-cell lung cancer. J Clin Oncol 2006; 24:2038–2043.PubMedCrossRefGoogle Scholar
  95. 95.
    Mavroudis D, Papadakis E, Veslemes M, et al. A multicenter randomized clinical trial comparing paclitaxel–cisplatin–etoposide versus cisplatin–etoposide as first-line treatment in patients with small-cell lung cancer. Ann Oncol 2001; 12:463–470.PubMedCrossRefGoogle Scholar
  96. 96.
    Niell HB, Herndon JE, 2nd, Miller AA, et al. Randomized phase III intergroup trial of etoposide and cisplatin with or without paclitaxel and granulocyte colony-stimulating factor in patients with extensive-stage small-cell lung cancer: Cancer and Leukemia Group B Trial 9732. J Clin Oncol 2005; 23:3752–3759.PubMedCrossRefGoogle Scholar
  97. 97.
    Reck M, von Pawel J, Macha HN, et al. Randomized phase III trial of paclitaxel, etoposide, and carboplatin versus carboplatin, etoposide, and vincristine in patients with small-cell lung cancer. J Natl Cancer Inst 2003; 95:1118–1127.PubMedCrossRefGoogle Scholar
  98. 98.
    Loehrer PJ, Sr., Ansari R, Gonin R, et al. Cisplatin plus etoposide with and without ifosfamide in extensive small-cell lung cancer: a Hoosier Oncology Group study. J Clin Oncol 1995; 13:2594–2599.PubMedGoogle Scholar
  99. 99.
    Fukuoka M, Furuse K, Saijo N, et al. Randomized trial of cyclophosphamide, doxorubicin, and vincristine versus cisplatin and etoposide versus alternation of these regimens in small-cell lung cancer. J Natl Cancer Inst 1991; 83:855–861.PubMedCrossRefGoogle Scholar
  100. 100.
    Mavroudis D, Veslemes M, Kouroussis C, et al. Cisplatin–etoposide alternating with topotecan in patients with extensive stage small cell lung cancer. A multicenter phase II study. Lung Cancer 2002; 38:59–63.PubMedCrossRefGoogle Scholar
  101. 101.
    Jett JR, Hatfield AK, Hillman S, et al. Alternating chemotherapy with etoposide plus cisplatin and topotecan plus paclitaxel in patients with untreated, extensive-stage small cell lung carcinoma: a phase II trial of the North Central Cancer Treatment Group. Cancer 2003; 97:2498–2503.PubMedCrossRefGoogle Scholar
  102. 102.
    Frei E, 3rd, Canellos GP. Dose: a critical factor in cancer chemotherapy. Am J Med 1980; 69:585–594.PubMedCrossRefGoogle Scholar
  103. 103.
    Johnson DH, DeLeo MJ, Hande KR, et al. High-dose induction chemotherapy with cyclophosphamide, etoposide, and cisplatin for extensive-stage small-cell lung cancer. J Clin Oncol 1987; 5:703–709.PubMedGoogle Scholar
  104. 104.
    Ihde DC, Mulshine JL, Kramer BS, et al. Prospective randomized comparison of high-dose and standard-dose etoposide and cisplatin chemotherapy in patients with extensive-stage small-cell lung cancer. J Clin Oncol 1994; 12:2022–2034.PubMedGoogle Scholar
  105. 105.
    Steward WP, von Pawel J, Gatzemeier U, et al. Effects of granulocyte-macrophage colony-stimulating factor and dose intensification of V-ICE chemotherapy in small-cell lung cancer: a prospective randomized study of 300 patients. J Clin Oncol 1998; 16:642–650.PubMedGoogle Scholar
  106. 106.
    Murray N, Shah A, Osoba D, et al. Intensive weekly chemotherapy for the treatment of extensive-stage small-cell lung cancer. J Clin Oncol 1991; 9:1632–1638.PubMedGoogle Scholar
  107. 107.
    Furuse K, Fukuoka M, Nishiwaki Y, et al. Phase III study of intensive weekly chemotherapy with recombinant human granulocyte colony-stimulating factor versus standard chemotherapy in extensive-disease small-cell lung cancer. The Japan Clinical Oncology Group. J Clin Oncol 1998; 16:2126–2132.PubMedGoogle Scholar
  108. 108.
    Murray N, Livingston RB, Shepherd FA, et al. Randomized study of CODE versus alternating CAV/EP for extensive-stage small-cell lung cancer: an Intergroup Study of the National Cancer Institute of Canada Clinical Trials Group and the Southwest Oncology Group. J Clin Oncol 1999; 17:2300–2308.PubMedGoogle Scholar
  109. 109.
    Sculier JP, Paesmans M, Bureau G, et al. Multiple-drug weekly chemotherapy versus standard combination regimen in small-cell lung cancer: a phase III randomized study conducted by the European Lung Cancer Working Party. J Clin Oncol 1993; 11:1858–865.PubMedGoogle Scholar
  110. 110.
    Humblet Y, Symann M, Bosly A, et al. Late intensification chemotherapy with autologous bone marrow transplantation in selected small-cell carcinoma of the lung: a randomized study. J Clin Oncol 1987; 5:1864–1873.PubMedGoogle Scholar
  111. 111.
    Leyvraz S, Perey L, Rosti G, et al. Multiple courses of high-dose ifosfamide, carboplatin, and etoposide with peripheral-blood progenitor cells and filgrastim for small-cell lung cancer: A feasibility study by the European Group for Blood and Marrow Transplantation. J Clin Oncol 1999; 17:3531–3539.PubMedGoogle Scholar
  112. 112.
    Rizzo JD, Elias AD, Stiff PJ, et al. Autologous stem cell transplantation for small cell lung cancer. Biol Blood Marrow Transplant 2002; 8:273–280.PubMedCrossRefGoogle Scholar
  113. 113.
    Lebeau B, Chastang C, Allard P, et al. Six vs twelve cycles for complete responders to chemotherapy in small cell lung cancer: definitive results of a randomized clinical trial. The “Petites Cellules” Group. Eur Respir J 1992; 5:286–290.PubMedGoogle Scholar
  114. 114.
    Giaccone G, Dalesio O, McVie GJ, et al. Maintenance chemotherapy in small-cell lung cancer: long-term results of a randomized trial. European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group. J Clin Oncol 1993; 11:1230–1240.PubMedGoogle Scholar
  115. 115.
    Ettinger DS, Finkelstein DM, Abeloff MD, et al. A randomized comparison of standard chemotherapy versus alternating chemotherapy and maintenance versus no maintenance therapy for extensive-stage small-cell lung cancer: a phase III study of the Eastern Cooperative Oncology Group. J Clin Oncol 1990; 8:230–240.PubMedGoogle Scholar
  116. 116.
    Beith JM, Clarke SJ, Woods RL, et al. Long-term follow-up of a randomised trial of combined chemoradiotherapy induction treatment, with and without maintenance chemotherapy in patients with small cell carcinoma of the lung. Eur J Cancer 1996; 32A:438–443.PubMedCrossRefGoogle Scholar
  117. 117.
    Hanna NH, Sandier AB, Loehrer PJ, Sr., et al. Maintenance daily oral etoposide versus no further therapy following induction chemotherapy with etoposide plus ifosfamide plus cisplatin in extensive small-cell lung cancer: a Hoosier Oncology Group randomized study. Ann Oncol 2002; 13:95–102.PubMedCrossRefGoogle Scholar
  118. 118.
    Schiller JH, Adak S, Cella D, et al. Topotecan versus observation after cisplatin plus etoposide in extensive-stage small-cell lung cancer: E7593–a phase III trial of the Eastern Cooperative Oncology Group. J Clin Oncol 2001; 19:2114–2122.PubMedGoogle Scholar
  119. 119.
    Onoda S, Masuda N, Seto T, et al. Phase II trial of amrubicin for treatment of refractory or relapsed small-cell lung cancer: Thoracic Oncology Research Group Study 0301. J Clin Oncol 2006; 24:5448–5453.PubMedCrossRefGoogle Scholar
  120. 120.
    Kudoh S, Yoshimura N, Kimura T. A phase II trial of amrubicin for recurrent or refractory small cell lung cancer. J Clin Oncol 2006; 24:671s.CrossRefGoogle Scholar
  121. 121.
    Mekhail T, Gettinger S, Blumenschein G. A phase II trial of VNP40101M in patients with relapsed or refractory small cell lung cancer with or without brain metastases. J Clin Oncol 2007; 25:439s.Google Scholar
  122. 122.
    Bentzion D, Lipatov O, Polyakov I. A phase II study of picoplatin as second line therapy for patients with small cell lung cancer who have resistant or refractory disease or have relapsed within 180 days of completing first-line, platinum-containing chemotherapy. J Clin Oncol 2007; 25:439s.Google Scholar
  123. 123.
    Lucchi M, Mussi A, Fontanini G, et al. Small cell lung carcinoma: the angiogenic phenomenon. Eur J Cardiothorac Surg 2002; 21:1105–1110.PubMedCrossRefGoogle Scholar
  124. 124.
    D’Amato RJ, Loughnan MS, Flynn E, et al. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci USA 1994; 91:4082–4085.PubMedCrossRefGoogle Scholar
  125. 125.
    Pujol JL, Breton JL, Gervais R, et al. Phase III double-blind, placebo-controlled study of thalidomide in extensive-disease small-cell lung cancer after response to chemotherapy: an intergroup study FNCLCC cleo04 IFCT 00-01. J Clin Oncol 2007; 25:3945–3951.PubMedCrossRefGoogle Scholar
  126. 126.
    Arnold AM, Seymour L, Smylie M, et al. Phase II study of vandetanib or placebo in small-cell lung cancer patients after complete or partial response to induction chemotherapy with or without radiation therapy: National Cancer Institute of Canada Clinical Trials Group Study BR.20. J Clin Oncol 2007; 25:4278–4284.PubMedCrossRefGoogle Scholar
  127. 127.
    Ready N, Dudek A, Wang X, et al. CALGB 30306: A phase II study of cisplatin, irinotecan and bevacizumab for untreated extensive stage small cell lung cancer. J Clin Oncol 2007; 25:400s.Google Scholar
  128. 128.
    Sandler A, Szwaric S, Dowlati A, et al. A phase II study of cisplatin plus etoposide plus bevacizumab for previously untreated extensive stage small cell lung cancer (E3501): A trial of the Eastern Cooperative Oncology Group. J Clin Oncol 2007; 25:400s.Google Scholar
  129. 129.
    Khokha R, Denhardt DT. Matrix metalloproteinases and tissue inhibitor of metalloproteinases: a review of their role in tumorigenesis and tissue invasion. Invasion Metastasis 1989; 9:391–405.PubMedGoogle Scholar
  130. 130.
    Shepherd FA, Giaccone G, Seymour L, et al. Prospective, randomized, double-blind, placebo-controlled trial of marimastat after response to first-line chemotherapy in patients with small-cell lung cancer: a trial of the National Cancer Institute of Canada-Clinical Trials Group and the European Organization for Research and Treatment of Cancer. J Clin Oncol 2002; 20:4434–4439.PubMedCrossRefGoogle Scholar
  131. 131.
    Krystal GW, DeBerry CS, Linnekin D, et al. Lck associates with and is activated by Kit in a small cell lung cancer cell line: inhibition of SCF-mediated growth by the Src family kinase inhibitor PP1. Cancer Res 1998; 58:4660–4666.PubMedGoogle Scholar
  132. 132.
    Krystal GW, Carlson P, Litz J. Induction of apoptosis and inhibition of small cell lung cancer growth by the quinoxaline tyrphostins. Cancer Res 1997; 57:2203–2208.PubMedGoogle Scholar
  133. 133.
    Johnson BE, Fischer T, Fischer B, et al. Phase II study of imatinib in patients with small cell lung cancer. Clin Cancer Res 2003; 9:5880–5887.PubMedGoogle Scholar
  134. 134.
    Dy GK, Miller AA, Mandrekar SJ, et al. A phase II trial of imatinib (ST1571) in patients with c-kit expressing relapsed small-cell lung cancer: a CALGB and NCCTG study. Ann Oncol 2005; 16:1811–1816.PubMedCrossRefGoogle Scholar
  135. 135.
    Schneider BJ, Gadgeel S, Ramnath N, et al. Phase II trial of imatinib maintenance therapy after irinotecan and cisplatin in patients with c-kit positive extensive stage small cell lung cancer. J Clin Oncol 2006; 24:674s.Google Scholar
  136. 136.
    Dole M, Nunez G, Merchant AK, et al. Bcl-2 inhibits chemotherapy-induced apoptosis in neuroblastoma. Cancer Res 1994; 54:3253–3259.PubMedGoogle Scholar
  137. 137.
    Smith MR, Abubakr Y, Mohammad R, et al. Antisense oligodeoxyribonucleotide down-regulation of bcl-2 gene expression inhibits growth of the low-grade non-Hodgkin’s lymphoma cell line WSU-FSCCL. Cancer Gene Ther 1995; 2:207–212.PubMedGoogle Scholar
  138. 138.
    Leung S, Miyake H, Zellweger T, et al. Synergistic chemosensitization and inhibition of progression to androgen independence by antisense Bcl-2 oligodeoxynucleotide and paclitaxel in the LNCaP prostate tumor model. Int J Cancer 2001; 91:846–50.PubMedCrossRefGoogle Scholar
  139. 139.
    Rudin CM, Otterson GA, Mauer AM, et al. A pilot trial of G3139, a bcl-2 antisense oligonucleotide, and paclitaxel in patients with chemorefractory small-cell lung cancer. Ann Oncol 2002; 13:539–455.PubMedCrossRefGoogle Scholar
  140. 140.
    Rudin CM, Kozloff M, Hoffman PC, et al. Phase I study of G3139, a bcl-2 antisense oligonucleotide, combined with carboplatin and etoposide in patients with small-cell lung cancer. J Clin Oncol 2004; 22:1110–1117.PubMedCrossRefGoogle Scholar
  141. 141.
    Rudin CM, Salgia R, Wang XF, et al. CALGB 30103: A randomized phase II study of carboplatin and etoposide with or without G3139 in patients with extensive stage small cell lung cancer. J Clin Oncol 2005; 23:662s.CrossRefGoogle Scholar
  142. 142.
    D‘Amico D, Carbone D, Mitsudomi T, et al. High frequency of somatically acquired p53 mutations in small-cell lung cancer cell lines and tumors. Oncogene 1992; 7:339–46.PubMedGoogle Scholar
  143. 143.
    Brezicka T, Bergman B, Olling S, et al. Reactivity of monoclonal antibodies with ganglioside antigens in human small cell lung cancer tissues. Lung Cancer 2000; 28:29–36.PubMedCrossRefGoogle Scholar
  144. 144.
    Giaccone G, Debruyne C, Felip E, et al. Phase III study of adjuvant vaccination with Bec2/bacille Calmette-Guerin in responding patients with limited-disease small-cell lung cancer (European Organisation for Research and Treatment of Cancer 08971-08971B; Silva Study). J Clin Oncol 2005; 23:6854–6864.PubMedCrossRefGoogle Scholar
  145. 145.
    Ohe Y, Ohashi Y, Kubota K, et al. Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: Four-Arm Cooperative Study in Japan. Ann Oncol 2007; 18:317–323.PubMedCrossRefGoogle Scholar
  146. 146.
    Schiller J, Larson T, Ou S, et al. Efficacy and safety of axitinib (AG-013736) in patients with advanced non-small cell lung cancer: A phase II trial. J Clin Oncol 2007; 25:386s.Google Scholar
  147. 147.
    Gauler T, Besse B, Meric J, et al. Phase II open-label study to investigate efficacy and safety of PTK787/ZK 222584 orally administered once daily or twice daily at 1,250 mg as second-line monotherapy in patients with stage IIIB/IV non-small cell lung cancer. J Clin Oncol 2007; 25:394s.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Division of Hematology/Oncology Department of Internal MedicinePresbyterian-Weill Cornell Medical CenterNew YorkUSA
  2. 2.Emory University School of Medicine, Emory Winship Cancer InstituteAtlantaUSA

Personalised recommendations