Drugs

, Volume 76, Issue 8, pp 831–840 | Cite as

Management of NSCLC Disease Progression After First-Line EGFR Tyrosine Kinase Inhibitors: What Are the Issues and Potential Therapies?

  • Raffaele Califano
  • Ourania Romanidou
  • Giannis Mountzios
  • Lorenza Landi
  • Federico Cappuzzo
  • Fiona Blackhall
Current Opinion

Abstract

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) represent the standard of care for advanced non-small cell lung cancer (NSCLC) patients whose tumor harbors an activating EGFR mutation. The vast majority of patients will experience disease control with an EGFR-TKI but inevitably all patients will progress, often within a year of treatment. There is no current standard of care for this scenario but, in clinical practice, most of the patients will be offered platinum-based doublet chemotherapy. In some situations, continuation of the EGFR-TKI beyond radiological progression, with or without use of local treatments in case of oligo-progressive disease, represents a reasonable therapeutic option. The aim of this review is to describe the different treatment strategies that have been developed to tackle progression on EGFR-TKIs, including specific clinical scenarios and novel agents designed to tackle the common T790M resistance mutation.

Keywords

Epidermal Growth Factor Receptor Gefitinib Erlotinib Epidermal Growth Factor Receptor Mutation Overall Response Rate 
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.

Notes

Compliance with Ethical Standards

Funding

None.

Conflict of interest

R Califano: Consulting fees and honoraria from Roche, Astrazeneca, Lilly Oncology and Boehringer Ingelheim; Support to travel to meetings from Roche, Astrazeneca, Lilly Oncology and Boehringer Ingelheim. Payment for lectures from Roche, Astrazeneca, Lilly Oncology and Boehringer Ingelheim.

F Blackhall: Consulting fees and honoraria from Roche, Astrazeneca, Lilly Oncology and Boehringer Ingelheim; Support to travel to meetings from Roche, Astrazeneca, Lilly Oncology and Boehringer Ingelheim.

G Mountzios: consulting fees from Boehringer Ingelheim.

R Romanidou, F Cappuzzo and L Landi declare no relevant conflicts of interest.

References

  1. 1.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5–29.CrossRefPubMedGoogle Scholar
  2. 2.
    Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947–57.CrossRefPubMedGoogle Scholar
  3. 3.
    Han JY, Park K, Kim SW, Lee DH, Kim HY, Kim HT, et al. First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung. J Clin Oncol. 2012;30(10):1122–8.Google Scholar
  4. 4.
    Inoue A, Kobayashi K, Maemondo M, Sugawara S, Oizumi S, Isobe H, et al. Updated overall survival results from a randomized phase III trial comparing gefitinib with carboplatin-paclitaxel for chemo-naive non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002). Ann Oncol. 2013;24(1):54–9.CrossRefPubMedGoogle Scholar
  5. 5.
    Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, et al. Gefitinib or chemotherapy for non small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362(25):2380–8.CrossRefPubMedGoogle Scholar
  6. 6.
    Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 2010;11(2):121–8.CrossRefPubMedGoogle Scholar
  7. 7.
    Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011;12(8):735–42.CrossRefPubMedGoogle Scholar
  8. 8.
    Sequist LV, Yang JC-H, Yamamoto N, O’Byrne K, Hirsh V, Mok T, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31(27):3327–34.Google Scholar
  9. 9.
    Wu YL, Zhou C, Hu CP, Feng J, Lu S, Huang Y, et al. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol. 2014;15(2):213–22.CrossRefPubMedGoogle Scholar
  10. 10.
    Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13(3):239–46.CrossRefPubMedGoogle Scholar
  11. 11.
    Masters GA, Temin S, Azzoli CG, Giaccone G, Baker S, Brahmer JR, et al. Systemic therapy for stage IV non–small-cell lung cancer: american society of clinical oncology clinical practice guideline update. J Clin Oncol. 2015;31:2015.Google Scholar
  12. 12.
    Reck M, Popat S, Reinmuth N, De Ruysscher D, Kerr KM, Peters S. Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;11:2014.Google Scholar
  13. 13.
    Cortot AB, Janne PA. Molecular mechanisms of resistance in epidermal growth factor receptor-mutant lung adenocarcinomas. Eur Respir Rev. 2014;23(133):356–66.CrossRefPubMedGoogle Scholar
  14. 14.
    Yu HA, Arcila ME, Rekhtman N, Sima CS, Zakowski MF, Pao W, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013;19(8):2240–7.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011;3(75):75ra26.Google Scholar
  16. 16.
    Pao W, Miller VA, Politi KA, Riely GJ, Somwar R, Zakowski MF, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2005;2(3):e73.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Yun CH, Mengwasser KE, Toms AV, Woo MS, Greulich H, Wong KK, et al. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci. 2008;105(6):2070–5.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Park K, Yu C, Kim S, et al. First-line erlotinib therapy until and beyond response evaluation criteria in solid tumors progression in asian patients with epidermal growth factor receptor mutation–positive non–small-cell lung cancer: The aspiration study. JAMA Oncol. 2016;2(3):305–12.CrossRefPubMedGoogle Scholar
  19. 19.
    Van Assche K, Vandecasteele K, Ferdinande L, Lievens Y, Surmont V. EGFR mutation positive stage IV non-small-cell lung cancer: treatment beyond progression. Front Oncol. 2014;4:350. doi: 10.3389/fonc.2014.00350 PubMedPubMedCentralGoogle Scholar
  20. 20.
    Costa DB, Nguyen KS, Cho BC, Sequist LV, Jackman DM, Riely GJ, et al. Effects of erlotinib in EGFR mutated non-small cell lung cancers with resistance to gefitinib. Clin Cancer Res. 2008;14(21):7060–7.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Kaira K, Naito T, Takahashi T, Ayabe E, Shimoyama R, Kaira R, et al. Pooled analysis of the reports of erlotinib after failure of gefitinib for non-small cell lung cancer. Lung Cancer. 2010;68(1):99–104.CrossRefPubMedGoogle Scholar
  22. 22.
    Katayama T, Shimizu J, Suda K, Onozato R, Fukui T, Ito S, et al. Efficacy of erlotinib for brain and leptomeningeal metastases in patients with lung adenocarcinoma who showed initial good response to gefitinib. J Thorac Oncol. 2009;4(11):1415–9.CrossRefPubMedGoogle Scholar
  23. 23.
    Oh IJ, Ban HJ, Kim KS, Kim YC. Retreatment of gefitinib in patients with non-small-cell lung cancer who previously controlled to gefitinib: a single-arm, open-label, phase II study. Lung Cancer. 2012;77(1):121–7.CrossRefPubMedGoogle Scholar
  24. 24.
    Grommes C, Oxnard GR, Kris MG, Miller VA, Pao W, Holodny AI, et al. “Pulsatile” high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer. Neuro Oncol. 2011;13(12):1364–9.Google Scholar
  25. 25.
    Yu HA, Sima CS, Huang J, Solomon SB, Rimner A, Paik P, et al. Local therapy with continued EGFR tyrosine kinase inhibitor therapy as a treatment strategy in EGFR-mutant advanced lung cancers that have developed acquired resistance to EGFR tyrosine kinase inhibitors. J Thorac Oncol. 2013;8(3):346–51.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Conforti F, Catania C, Toffalorio F, Duca M, Spitaleri G, Barberis M, et al. EGFR tyrosine kinase inhibitors beyond focal progression obtain a prolonged disease control in patients with advanced adenocarcinoma of the lung. Lung Cancer. 2013;81(3):440–4.CrossRefPubMedGoogle Scholar
  27. 27.
    Shukuya T, Takahashi T, Naito T, Kaira R, Ono A, Nakamura Y, et al. Continuous EGFR-TKI administration following radiotherapy for non-small cell lung cancer patients with isolated CNS failure. Lung Cancer. 2011;74(3):457–61.CrossRefPubMedGoogle Scholar
  28. 28.
    Weickhardt AJ, Scheier B, Burke JM, Gan G, Lu X, Bunn PA Jr, et al. Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non-small-cell lung cancer. J Thorac Oncol. 2012;7(12):1807–14.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Matikas A, Mistriotis D, Georgoulias V, Kotsakis A. Current and future approaches in the management of non–small-cell lung cancer patients with resistance to EGFR TKIs. Clin Lung Cancer. 2015;16(4):252–61.CrossRefPubMedGoogle Scholar
  30. 30.
    Chmielecki J, Foo J, Oxnard GR, Hutchinson K, Ohashi K, Somwar R, et al. Optimization of dosing for EGFR-mutant non–small cell lung cancer with evolutionary cancer modeling. Sci Transl Med. 2011;3(90):90ra59.Google Scholar
  31. 31.
    Chaft JE, Oxnard GR, Sima CS, Kris MG, Miller VA, Riely GJ. Disease flare after tyrosine kinase inhibitor discontinuation in patients with EGFR-mutant lung cancer and acquired resistance to erlotinib or gefitinib: implications for clinical trial design. Clin Cancer Res. 2011;17(19):6298–303.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Goldberg SB, Oxnard GR, Digumarthy S, Muzikansky A, Jackman DM, Lennes IT, et al. Chemotherapy with erlotinib or chemotherapy alone in advanced non-small cell lung cancer with acquired resistance to EGFR tyrosine kinase inhibitors. Oncologist. 2013;18(11):1214–20.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Soria J-C, Wu Y-L, Nakagawa K, Kim S-W, Yang J-J, Ahn M-J, et al. Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib (IMPRESS): a phase 3 randomised trial. Lancet Oncol. 2015;16(8):990–8.CrossRefPubMedGoogle Scholar
  34. 34.
    Soria J, Kim SW, Wu YL, Nakagawa K, Yang JJ, Ahn MJ, et al. Gefitinib/chemotherapy vs chemotherapy in EGFR mutation-positive NSCLC resistant to first-line gefitinib: IMPRESS T790M subgroup. J Thorac Oncol. 2015;10(Supplement 2):S207.Google Scholar
  35. 35.
    Wu Y-L, Lee JS, Thongprasert S, Yu C-J, Zhang L, Ladrera G, et al. Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non-small-cell lung cancer (FASTACT-2): a randomised, double-blind trial. Lancet Oncol. 2013;. doi: 10.1016/S1470-2045(13)70254-7.PubMedCentralGoogle Scholar
  36. 36.
    Miller VA, Hirsh V, Cadranel J, Chen YM, Park K, Kim SW, et al. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet Oncol. 2012;13(5):528–38.CrossRefPubMedGoogle Scholar
  37. 37.
    Sequist LV, Besse B, Lynch TJ, Miller VA, Wong KK, Gitlitz B, et al. Neratinib, an irreversible Pan-ErbB receptor tyrosine kinase inhibitor: results of a phase II trial in patients with advanced non–small-cell lung cancer. J Clin Oncol. 2010;28(18):3076–83.CrossRefPubMedGoogle Scholar
  38. 38.
    Reckamp KL, Giaccone G, Camidge DR, Gadgeel SM, Khuri FR, Engelman JA, et al. A phase 2 trial of dacomitinib (PF-00299804), an oral, irreversible pan-HER (human epidermal growth factor receptor) inhibitor, in patients with advanced non–small cell lung cancer after failure of prior chemotherapy and erlotinib. Cancer. 2014;120(8):1145–54.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Regales L, Gong Y, Shen R, de Stanchina E, Vivanco I, Goel A, et al. Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer. J Clin Investig. 2009;119(10):3000–10.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Janjigian YY, Azzoli CG, Krug LM, Pereira LK, Rizvi NA, Pietanza MC, et al. Phase I/II trial of cetuximab and erlotinib in patients with lung adenocarcinoma and acquired resistance to erlotinib. Clin Cancer Res. 2011;17(8):2521–7.CrossRefPubMedGoogle Scholar
  41. 41.
    Janjigian YY, Smit EF, Groen HJM, Horn L, Gettinger S, Camidge DR, et al. Dual inhibition of EGFR with afatinib and cetuximab in kinase inhibitor-resistant EGFR-mutant lung cancer with and without T790M mutations. Cancer Discov. 2014;4(9):1036–45.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Ercan D, Choi HG, Yun C-H, Capelletti M, Xie T, Eck MJ, et al. EGFR mutations and resistance to irreversible pyrimidine-based EGFR inhibitors. Clin Cancer Res. 2015;21(17):3913–23.CrossRefPubMedGoogle Scholar
  43. 43.
    Herbst RS, O’Neill VJ, Fehrenbacher L, Belani CP, Bonomi PD, Hart 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(30):4743–50.Google Scholar
  44. 44.
    Herbst RS, Ansari R, Bustin F, Flynn P, Hart L, Otterson GA, et al. Efficacy of bevacizumab plus erlotinib versus erlotinib alone in advanced non-small-cell lung cancer after failure of standard first-line chemotherapy (BeTa): a double-blind, placebo-controlled, phase 3 trial. Lancet. 2011;377(9780):1846–54.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Scagliotti GV, Krzakowski M, Szczesna A, Strausz J, Makhson A, Reck M, et al. Sunitinib plus erlotinib versus placebo plus erlotinib in patients with previously treated advanced non–small-cell lung cancer: a phase III trial. J Clin Oncol. 2012;30(17):2070–8.CrossRefPubMedGoogle Scholar
  46. 46.
    Spigel DR, Burris HA, Greco FA, Shipley DL, Friedman EK, Waterhouse DM, et al. Randomized, double-blind, placebo-controlled, phase II trial of sorafenib and erlotinib or erlotinib alone in previously treated advanced non–small-cell lung cancer. J Clin Oncol. 2011;29(18):2582–9.CrossRefPubMedGoogle Scholar
  47. 47.
    Seto T, Kato T, Nishio M, Goto K, Atagi S, Hosomi Y, et al. Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study. Lancet Oncol. 2014;15(11):1236–44.CrossRefPubMedGoogle Scholar
  48. 48.
    Stahel R, Dafni U, Gautschi G, Felip E, Curioni-Fontecedro A, Peters S, et al. A phase II trial of erlotinib (E) and bevacizumab (B) in patients with advanced non-small-cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutations with and without T790M mutation. The Spanish Lung Cancer Group (SLCG) and the European Thoracic Oncology Platform (ETOP) BELIEF trial. Eur J Cancer. 2015;51:S711.CrossRefGoogle Scholar
  49. 49.
    Akbay EA, Koyama S, Carretero J, Altabef A, Tchaicha JH, Christensen CL, et al. Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors. Cancer Discov. 2013;3(12):1355–63.CrossRefPubMedGoogle Scholar
  50. 50.
    D’Incecco A, Andreozzi M, Ludovini V, Rossi E, Capodanno A, Landi L, et al. PD-1 and PD-L1 expression in molecularly selected non-small-cell lung cancer patients. Br J Cancer. 2015;112(1):95–102.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Rizvi NA, Chow LQM, Borghaei H, Shen Y, Harbison C, Alaparthy S, et al. Safety and response with nivolumab (anti-PD-1; BMS-936558, ONO-4538) plus erlotinib in patients (pts) with epidermal growth factor receptor mutant (EGFR MT) advanced NSCLC. ASCO Meeting Abstracts. 2014;32(15_suppl):8022.Google Scholar
  52. 52.
    Garon E, Wolf B, Lisberg A, Kim K, Horton J, Kamranpour N, et al. Prior TKI therapy in NSCLC EGFR mutant patients associates with lack of response to anti-PD-1 treatment. J Thorac Oncol. 2015;10(9):S269.Google Scholar
  53. 53.
    Hellmann M, Garon E, Gandhi L, Hui R, Zhang J, Rangwala R, et al. Efficacy of pembrolizumab in key subgroups of patients withadvanced NSCLC. J Thorac Oncol. 2015;10(9):S270.Google Scholar
  54. 54.
    Cross DAE, Ashton SE, Ghiorghiu S, Eberlein C, Nebhan CA, Spitzler PJ, et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 2014;4(9):1046–61.Google Scholar
  55. 55.
    Jänne PA, Yang JC-H, Kim D-W, Planchard D, Ohe Y, Ramalingam SS, et al. AZD9291 in EGFR inhibitor-resistant non–small-cell lung cancer. N Engl J Med. 2015;372(18):1689–99.CrossRefPubMedGoogle Scholar
  56. 56.
    Ramalingam SS, Yang JC-H, Lee CK, Kurata T, Kim D-W, John T, et al. AZD9291, a mutant-selective EGFR inhibitor, as first-line treatment for EGFR mutation-positive advanced non-small cell lung cancer (NSCLC): Results from a phase 1 expansion cohort. ASCO Meeting Abstracts. 2015;33(15_suppl):8000.Google Scholar
  57. 57.
    FDA. OSIRMETINIB. 11/13/2015 [cited 2016 04/04/2016]; Available from: http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm472565.htm.
  58. 58.
    Walter AO, Sjin RTT, Haringsma HJ, Ohashi K, Sun J, Lee K, et al. Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC. Cancer Discov. 2013;3(12):1404–15.Google Scholar
  59. 59.
    Sequist LV, Soria J-C, Goldman JW, Wakelee HA, Gadgeel SM, Varga A, et al. Rociletinib in EGFR-mutated non–small-cell lung cancer. N Engl J Med. 2015;372(18):1700–9.CrossRefPubMedGoogle Scholar
  60. 60.
    Wakelee H, Sequist L, Gadgeel S, Soria J, Goldman J, Yu H, et al. Rociletinib in NSCLC patients with negative central testing for T790M in TIGER-X. J Thorac Oncol. 2015;10(9):S271.Google Scholar
  61. 61.
    Sequist LV, Goldman JW, Wakelee HA, Camidge DR, Yu HA, Varga A, et al. Efficacy of rociletinib (CO-1686) in plasma-genotyped T790M-positive non-small cell lung cancer (NSCLC) patients (pts). ASCO Meeting Abstracts. 2015;33(15_suppl):8001.Google Scholar
  62. 62.
    Park K, Lee J-S, Lee KH, Kim J-H, Min YJ, Cho JY, et al. Updated safety and efficacy results from phase I/II study of HM61713 in patients (pts) with EGFR mutation positive non-small cell lung cancer (NSCLC) who failed previous EGFR-tyrosine kinase inhibitor (TKI). ASCO Meeting Abstracts. 2015;33(15_suppl):8084.Google Scholar
  63. 63.
    Yu HA, Oxnard GR, Spira AI, Horn L, Weiss J, Feng Y, et al. Phase I dose escalation study of ASP8273, a mutant-selective irreversible EGFR inhibitor, in subjects with EGFR mutation positive NSCLC. ASCO Meeting Abstracts. 2015;33(15_suppl):8083.Google Scholar
  64. 64.
    Goto Y, Nokihara H, Murakami H, Shimizu T, Seto T, Krivoshik AP, et al. ASP8273, a mutant-selective irreversible EGFR inhibitor in patients (pts) with NSCLC harboring EGFR activating mutations: Preliminary results of first-in-human phase I study in Japan. ASCO Meeting Abstracts. 2015;33(15_suppl):8014.Google Scholar
  65. 65.
    Tan DS-W, Seto T, Leighl NB, Riely GJ, Sequist LV, Felip E, et al. First-in-human phase I study of EGF816, a third generation, mutant-selective EGFR tyrosine kinase inhibitor, in advanced non-small cell lung cancer (NSCLC) harboring T790M. ASCO Meeting Abstracts. 2015;33(15_suppl):8013.Google Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Raffaele Califano
    • 1
    • 2
  • Ourania Romanidou
    • 3
  • Giannis Mountzios
    • 4
  • Lorenza Landi
    • 5
  • Federico Cappuzzo
    • 5
  • Fiona Blackhall
    • 1
    • 6
  1. 1.Department of Medical OncologyThe Christie NHS Foundation TrustManchesterUK
  2. 2.Department of Medical OncologyUniversity Hospital of South Manchester NHS Foundation TrustManchesterUK
  3. 3.Medical Oncology UnitPapageorgiou General HospitalThessalonikiGreece
  4. 4.Department of Medical OncologyUniversity of Athens School of MedicineAthensGreece
  5. 5.Istituto Toscano Tumori, Ospedale Civile di Livorno,LeghornItaly
  6. 6.University of ManchesterManchesterUK

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