Das Medizinportal


Klassische und molekulare Diagnostik

Claudia Kayser, Martin Werner, Department für Pathologie, Institut für Klinische Pathologie, Universitätsklinikum Freiburg (Seiten 9-12)

  1. Barnes L, Eveson, J.W., Reichart, P., Sidransky, D. Pathology and Genetics of Head and Neck Tumours. Lyon: IARCPress International Agency for Research on Cancer (IARC); 2005.
  2. Wittekind C, Meyer, H.-J. TNM: Klassifikation maligner Tumoren. 7 vol. Weinheim: WILEY-VCH Verlag; 2010.
  3. Parkin DM, Whelan S. L., Ferlay J., Teppo L., Thomas D. B. Cancer Incidence in Five Continents. 8 vol. Lyon; 2003.
  4. Blot WJ, McLaughlin JK, Winn DM et al. Smoking and drinking in relation to oral and pharyngeal cancer. Cancer Res. 1988;48:3282-7.
  5. Gillison ML, Koch WM, Capone RB et al. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst. 2000;92:709-20.
  6. Garbuglia AR. Human papillomavirus in head and neck cancer. Cancers (Basel). 2014;6:1705-26.
  7. Blitzer GC, Smith MA, Harris SL, Kimple RJ. Review of the clinical and biologic aspects of human papillomavirus-positive squamous cell carcinomas of the head and neck. Int J Radiat Oncol Biol Phys. 2014;88:761-70.
  8. Platz H, Fries R, Hudec M. Retrospective DOSAK Study on carcinomas of the oral cavity: results and consequences. J Maxillofac Surg. 1985;13:147-53.
  9. Chiesa F, Mauri S, Tradati N et al. Surfing prognostic factors in head and neck cancer at the millennium. Oral Oncol. 1999;35:590-6.
  10. Shroyer KR, Greer RO, Fankhouser CA, McGuirt WF, Marshall R. Detection of human papillomavirus DNA in oral verrucous carcinoma by polymerase chain reaction. Mod Pathol. 1993;6:669-72.
  11. Eneroth CM. Salivary gland tumors in the parotid gland, submandibular gland, and the palate region. Cancer. 1971;27:1415-8.
  12. Ron E, Saftlas AF. Head and neck radiation carcinogenesis: epidemiologic evidence. Otolaryngol Head Neck Surg. 1996;115:403-8.
  13. Goode RK, Auclair PL, Ellis GL. Mucoepidermoid carcinoma of the major salivary glands: clinical and histopathologic analysis of 234 cases with evaluation of grading criteria. Cancer. 1998;82:1217-24.
  14. Skalova A, Lehtonen H, von Boguslawsky K, Leivo I. Prognostic significance of cell proliferation in mucoepidermoid carcinomas of the salivary gland: clinicopathological study using MIB 1 antibody in paraffin sections. Hum Pathol. 1994;25:929-35.
  15. Yoo J, Robinson RA. H-ras gene mutations in salivary gland mucoepidermoid arcinomas. Cancer. 2000;88:518-23.
  16. Gibbons MD, Manne U, Carroll WR, Peters GE, Weiss HL, Grizzle WE. Molecular differences in mucoepidermoid carcinoma and adenoid cystic carcinoma of the major salivary glands. Laryngoscope. 2001;111:1373-8.
  17. Castle JT, Thompson LD, Frommelt RA, Wenig BM, Kessler HP. Polymorphous low grade adenocarcinoma: a clinicopathologic study of 164 cases. Cancer. 1999;86:207-19.
  18. Gnepp DR. Malignant mixed tumors of the salivary glands: a review. Pathol Annu. 1993;28 Pt 1:279-328.
  19. Tortoledo ME, Luna MA, Batsakis JG. Carcinomas ex pleomorphic adenoma and malignant mixed tumors. Histomorphologic indexes. Arch Otolaryngol. 1984;110:172-6.
  20. Szanto PA, Luna MA, Tortoledo ME, White RA. Histologic grading of adenoid cystic carcinoma of the salivary glands. Cancer. 1984;54:1062-9.
  21. Nascimento AG, Amaral AL, Prado LA, Kligerman J, Silveira TR. Adenoid cystic carcinoma of salivary glands. A study of 61 cases with clinicopathologic correlation. Cancer. 1986;57:312-9.
  22. Queimado L, Reis A, Fonseca I et al. A refined localization of two deleted regions in chromosome 6q associated with salivary gland carcinomas. Oncogene. 1998;16:83-8.
  23. Skalova A, Starek, Kucerova V, Szepe P, Plank L. Salivary duct carcinoma--a highly aggressive salivary gland tumor with HER-2/neu oncoprotein overexpression. Pathol Res Pract. 2001;197:621-6.
  24. Austin DF, Reynolds, P. Laryngeal cancer. 2nd ed. New York: Oxford University Press; 1996.
  25. Brownson RC, Chang JC. Exposure to alcohol and tobacco and the risk of laryngeal cancer. Arch Environ Health. 1987;42:192-6.
  26. Flanders WD, Rothman KJ. Interaction of alcohol and tobacco in laryngeal cancer. Am J Epidemiol. 1982;115:371-9.
  27. Maier H, Dietz A, Gewelke U, Heller WD, Weidauer H. Tobacco and alcohol and the risk of head and neck cancer. Clin Investig. 1992;70:320-7.
  28. Bryne M, Jenssen N, Boysen M. Histological grading in the deep invasive front of T1 and T2 glottic squamous cell carcinomas has high prognostic value. Virchows Arch. 1995;427:277-81.
  29. Gallo O, Bianchi S, Giannini A, Boccuzzi S, Calzolari A, Fini-Storchi O. Lack of detection of human papillomavirus (HPV) in transformed laryngeal keratoses by in situ hybridization (ISH) technique. Acta Otolaryngol. 1994;114:213-7.
  30. Lie ES, Karlsen F, Holm R. Presence of human papillomavirus in squamous cell laryngeal carcinomas. A study of thirty-nine cases using polymerase chain reaction and in situ hybridization. Acta Otolaryngol. 1996;116:900-5.
  31. Lindeberg H, Krogdahl A. Laryngeal cancer and human papillomavirus: HPV is absent in the majority of laryngeal carcinomas. Cancer Lett. 1999;146:9-13.
  32. Slootweg PJ, Hordijk GJ, Schade Y, van Es RJ, Koole R. Treatment failure and margin status in head and neck cancer. A critical view on the potential value of molecular pathology. Oral Oncol. 2002;38:500-3.
  33. Yilmaz T, Hosal AS, Gedikoglu G, Onerci M, Gursel B. Prognostic significance of vascular and perineural invasion in cancer of the larynx. Am J Otolaryngol. 1998;19:83-8.
  34. Yu MC, Yuan JM. Epidemiology of nasopharyngeal carcinoma. Semin Cancer Biol. 2002;12:421-9.
  35. Poirier S, Ohshima H, de-The G, Hubert A, Bourgade MC, Bartsch H. Volatile nitrosamine levels in common foods from Tunisia, south China and Greenland, high-risk areas for nasopharyngeal carcinoma (NPC). Int J Cancer. 1987;39:293-6.
  36. Dolcetti R, Menezes J. Epstein-Barr virus and undifferentiated nasopharyngeal carcinoma: new immunobiological and molecular insights on a long-standing etiopathogenic association. Adv Cancer Res. 2003;87:127-57.
  37. Raab-Traub N. Epstein-Barr virus in the pathogenesis of NPC. Semin Cancer Biol. 2002;12:431-41.
  38. Chan AS, To KF, Lo KW et al. High frequency of chromosome 3p deletion in histologically normal nasopharyngeal epithelia from southern Chinese. Cancer Res. 2000;60:5365-70.
  39. Pathmanathan R, Prasad U, Sadler R, Flynn K, Raab-Traub N. Clonal proliferations of cells infected with Epstein-Barr virus in preinvasive lesions related to nasopharyngeal carcinoma. N Engl J Med. 1995;333:693-8.
  40. Chen CL, Hsu MM. Second primary epithelial malignancy of nasopharynx and nasal cavity after successful curative radiation therapy of nasopharyngeal carcinoma. Hum Pathol. 2000;31:227-32.
  41. Sisson GA, Beck, S.P. Cancer of the nasal and paranasal sinuses. New York; 1981.
  42. Robin PE, Powell DJ, Stansbie JM. Carcinoma of the nasal cavity and paranasal sinuses: incidence and presentation of different histological types. Clin Otolaryngol Allied Sci. 1979;4:431-56.
  43. Batsakis JG, Suarez P. Schneiderian papillomas and carcinomas: a review. Adv Anat Pathol. 2001;8:53-64.
  44. Barnes L, Brandwein M, Som PM. Surgical Pathology of the Head and Neck. 2nd ed. New York: Marcel Dekker Inc; 2001.
  45. Jeng YM, Sung MT, Fang CL et al. Sinonasal undifferentiated carcinoma and nasopharyngeal-type undifferentiated carcinoma: two clinically, biologically, and histopathologically distinct entities. Am J Surg Pathol. 2002;26:371-6.
  46. Zong Y, Liu K, Zhong B, Chen G, Wu W. Epstein-Barr virus infection of sinonasal lymphoepithelial carcinoma in Guangzhou. Chin Med J (Engl). 2001;114:132-6.
  47. Cerilli LA, Holst VA, Brandwein MS, Stoler MH, Mills SE. Sinonasal undifferentiated carcinoma: immunohistochemical profile and lack of EBV association. Am J Surg Pathol. 2001;25:156-63.
  48. Lopategui JR, Gaffey MJ, Frierson HF, Jr. et al. Detection of Epstein-Barr viral RNA in sinonasal undifferentiated carcinoma from Western and Asian patients. Am J Surg Pathol. 1994;18:391-8.
  49. Mills SE, Fechner RE, Cantrell RW. Aggressive sinonasal lesion resembling normal intestinal mucosa. Am J Surg Pathol. 1982;6:803-9.
  50. Macbeth R. Malignant Disease of the Paranasal Sinuses. J Laryngol Otol. 1965;79:592-612.
  51. Franchi A, Gallo O, Santucci M. Clinical relevance of the histological classification of sinonasal intestinal-type adenocarcinomas. Hum Pathol. 1999;30:1140-5.
  52. Franquemont DW, Fechner RE, Mills SE. Histologic classification of sinonasal intestinal-type adenocarcinoma. Am J Surg Pathol. 1991;15:368-75.
  53. Saber AT, Nielsen LR, Dictor M, Hagmar L, Mikoczy Z, Wallin H. K-ras mutations in sinonasal adenocarcinomas in patients occupationally exposed to wood or leather dust. Cancer Lett. 1998;126:59-65.
  54. Gallo O, Franchi A, Fini-Storchi I et al. Prognostic significance of c-erbB-2 oncoprotein expression in intestinal-type adenocarcinoma of the sinonasal tract. Head Neck. 1998;20:224-31.
  55. Perez P, Dominguez O, Gonzalez S, Trivino A, Suarez C. ras gene mutations in ethmoid sinus adenocarcinoma: prognostic implications. Cancer. 1999;86:255-64.

Chirurgische Therapie

Tobias Kroll, Claus Wittekindt, Jens Peter Klußmann, Klinik für Hals-Nasen-Ohrenheilkunde, Kopf-Halschirurgie und plastische Operationen des Universitätsklinikums Gießen & Marburg, Standort Gießen, Justus-Liebig-Universität Gießen (Seiten 14-17)

  1. Boyle P., Ferlay J.: Cancer incidence and mortality in Europe, 2004. Ann Oncol. 2005 Mar;16(3):481-8. Epub 2005 Feb 17
  2. Wittekindt C, Wagner S, Mayer CS, Klussmann JP.: Basics of tumor development and importance of human papilloma virus (HPV) for head and neck cancer. GMS Curr Top Otorhinolaryngol Head Neck Surg. 2012;11:Doc09
  3. Tan G, Tang X, Tang F: The role of microRNAs in nasopharyngeal carcinoma. Tumour Biol. 2015 Jan;36(1):69-79. doi: 10.1007/s13277-014-2847-3
  4. Wittekindt C, Weber A, Weidenbach H. Pathologie und Prognosefaktoren von Plattenepithelkarzinomen des Kopf-Hals-Bereiches. Der Onkologe 2001; 7:498–504
  5. Sharma SJ, Linke JJ, Kroll T, Klußmann JP, Guntinas-Lichius O, Wittekindt C.: [Current practice of tumour endoscopy in German ENT-clinics]. Laryngorhinootologie. 2013 Mar;92(3):166-9
  6. Reske SN, Dankerl A, Glatting G, Mottaghy FM, Blumstein NM.: [Significance of PET for ENT-tumors]. Laryngorhinootologie. 2004 Jun;83(6):391-406; quiz 407-10
  7. Canis M, Ihler F, Martin A, Matthias C, Steiner W.: Transoral laser microsurgery for T1a glottic cancer: Review of 404 cases. Head Neck. 2014 Mar 13. doi: 10.1002/hed.23688
  8. Welkoborsky HJ, Deichmüller C, Bauer L, Hinni ML.: Reconstruction of large pharyngeal defects with microvascular free flaps and myocutaneous pedicled flaps. Curr Opin Otolaryngol Head Neck Surg. 2013 Aug;21(4):318-27
  9. Volk GF, Pantel M, Streppel M, Guntinas-Lichius O.: Reconstruction of complex peripheral facial nerve defects by a combined approach using facial nerve interpositional graft and hypoglossal-facial jump nerve suture. Laryngoscope. 2011 Nov;121(11):2402-5
  10. Robert-Koch-Institut (Hrsg) und die Gesellschaft der epidemiologischen Krebsregister in Deutschland e.V. (Hrsg). (2010) Krebs in Deutschland 2005- 2006. Ha?ufigkeiten und Trends, 7. Ausgabe. Berlin, 2010

Strahlentherapeutische Behandlungsstrategien

Corinna Macht, Lars Schüttrumpf, Anna A. Friedl, Ute Ganswindt, Klinik und Poliklinik für Strahlentherapie und Radioonkologie der Ludwig-Maximilians-Universität München und Klinische Kooperationsgruppe „Personalisierte Radiotherapie von Kopf-Hals-Tumoren“ am Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (Seiten 18-20)


  1. Adelstein DJ et al.: An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol 2003, 21: 92 – 98
  2. Bernier J et al.: Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 2004, 350: 1945 – 1952
  3. Bernier J et al.: Adjuvant therapy in patients with resected poor-risk head and neck cancer, J Clin Oncol 2006, 24: 2629 – 2635
  4. Blanchard P et al.: Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): a comprehensive analysis by tumour site. Radiother Oncol 2011, 100: 33 -40
  5. Bonner JA et al.: Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med  2006, 354: 567 – 578
  6. Bourhis J et al.: Concomitant chemoradiotherapy versus acceleration of radiotherapy with or without concomitant chemotherapy in locally advanced head and neck carcinoma (GORTEC 99-02): an open-label phase 3 randomised trial. Lancet  2012, 13: 145 – 153
  7. Budach V et al.: Hyperfractionated accelerated chemoradiation with concurrent fluorouracil-mitomycin is more effective than dose-escalated hyperfractionated accelerated radiation therapy alone in locally advanced head and neck cancer: final results of the radiotherapy cooperative clinical trials group of the German Cancer Society 95-06 Prospective Randomized Trial. J Clin Oncol 2005, 23: 1125 – 1135
  8. Cooper JS et al.: Precisely defining high-risk operable head and neck tumors based on RTOG #85-03 and #88-24: targets for postoperative radiochemotherapy? Head and Neck 1998, 20: 588 – 594
  9. Cooper JS et al.: Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 2004, 350: 1937 -1944
  10. Fietkau R et al.: Postoperative concurrent radiochemotherapy versus radiotherapy in high-risk SCCA of the head and neck: Results of the German phase III trial ARO 96–3,  J Clin Oncol 2006, 24 (Suppl): # 5507
  11. Pignon JP et al.: Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-Analysis of Chemotherapy on Head and Neck Cancer. Lancet 2000, 355: 949 – 955
  12. Pignon JP et al.: Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. 2009, Radiother Oncol 92: 4 – 14
  13. Soo KC et al.: Surgery and adjuvant radiotherapy vs concurrent chemoradiotherapy in stage III/IV nonmetastatic squamous cell head and neck cancer: a randomised comparison. Br J Cancer 2005, 93(3):279-86
  14. Ramaekers BL et al.: Systematic review and meta-analysis of radiotherapy in various head and neck cancers: comparing photons, carbon-ions and protons. Cancer Treat Rev 2011, 37: 185 – 201
  15. Veldeman L et al.: Evidence behind use of intensity-modulated radiotherapy: a systematic review of comparative clinical studies. Lancet 2008, 9: 367 - 375

Aktuelle medikamentöse Therapiekonzepte

Rainald Knecht,Chia-Jung Busch, Klinik und Poliklinik für Hals-, Nasen- und Ohrenheilkunde, Kopf-Hals-Tumorzentrum des Universitären Cancer Center Hamburg, Universitätsklinikum Hamburg-Eppendorf (Seite 22-24)

  1. Forastiere AA, Goepfert H, Maor M et al. (2003) Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 349:2091-2098
  2. Forastiere AA, Zhang Q, Weber RS et al. (2013) Long-term results of RTOG 91-11: a comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 31:845-8523.      
  3. Budach V, Cho C-H, Sedlmaier B et al. (2012) Five years' results of the German ARO 04-01 trial of concurrent 72 Gy hyperfractionated accelerated radiation therapy (HART) plus once weekly cisplatinum/5-FU versus mitomycin C/5-FU in stage IV head and neck cancer. ASCO Meeting Abstracts 30:5512
  4. Lorch JH, Goloubeva O, Haddad RI et al. (2011) Induction chemotherapy with cisplatin and fluorouracil alone or in combination with docetaxel in locally advanced squamous-cell cancer of the head and neck: long-term results of the TAX 324 randomised phase 3 trial. Lancet Oncol 12:153-159
  5. Vermorken JB, Remenar E, Van Herpen C et al. (2007) Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med 357:1695-1704
  6. Posner MR, Hershock DM, Blajman CR et al. (2007) Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med 357:1705-1715
  7. Cohen EE, Karrison TG, Kocherginsky M et al. (2014) Phase III Randomized Trial of Induction Chemotherapy in Patients With N2 or N3 Locally Advanced Head and Neck Cancer. J Clin Oncol
  8. Haddad R, O'neill A, Rabinowits G et al. (2013) Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): a randomised phase 3 trial. Lancet Oncol 14:257-264
  9. Ghi MG, Paccagnella A, Ferrari D et al. (2014) Concomitant chemoradiation (CRT) or cetuximab/RT (CET/RT) versus induction Docetaxel/ Cisplatin/5-Fluorouracil (TPF) followed by CRT or CET/RT in patients with Locally Advanced Squamous Cell Carcinoma of Head and Neck (LASCCHN). A randomized phase III factorial study (NCT01086826). ASCO Meeting Abstracts 32:6004
  10. Kurzweg T, Mockelmann N, Laban S et al. (2012) Current treatment options for recurrent/metastatic head and neck cancer: a post-ASCO 2011 update and review of last year's literature. Eur Arch Otorhinolaryngol 269:2157-2167
  11. Vermorken JB, Mesia R, Rivera F et al. (2008) Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 359:1116-1127
  12. Vermorken JB, Eva Remenar, Ricardo Hitt, Andrzej Kawecki, Sylvie Rottey, Luise Knierim, Jeltje Schulten, Ricard Mesia (2014 ASCO Annual Meeting) Platinum-based chemotherapy (CT) plus cetuximab in recurrent or metastatic squamous cell carcinoma of the head and neck cancer (R/M-SCCHN): 5-year follow-up data for the extreme trial. J Clin Oncol 32:5s, 2014 (suppl; abstr 6021^)
  13. Keilholz U, Gauler TC, Dietz A et al. (2014) Cetuximab (C), fluorouracil (F), and cisplatin (P) alone or with docetaxel (D) for recurrent/metastatic (RM) head and neck cancer (HNSCC): First analysis of AIO trial # 1108. ASCO Meeting Abstracts 32:6018

Atemwegsmanagement und Schmerztherapie in der palliativen Situation

Sven Koscielny, Universitätsklinik und Poliklinik für HNO-Heilkunde, Universitätsklinikum  Jena (Seite 26-28)


  1. Büntzel J. Palliativmedizin in der HNO-Heilkunde. HNO 2014; 62:335–341
  2. Diddee R, Shaw IR. Acquired tracheo-oesophageal fistula in adults. Anaesthesia, Critical Care & Pain 2006; 6: 105-108
  3. Haberland B, Christof Müller-Busch H. Leitlinien in der Palliativmedizin– Ein Überblick zum Stand von Empfehlungen. Palliativmedizin 2010; S2: 6-11
  4. Hartenstein R. Palliativmedizin als Alternative zur aktiven Sterbehilfe. Onkologe 2003; 9:434–438
  5. Hauser U, Hoffmann TK, Balló H, Sarbia M, Bier H. Die palliativ-chirurgische Behandlung von Tracheostomarezidiven mit der Argon-Plasma-Koagulation (APC). HNO 2003; 51:473–479
  6. Klemm E, Nowack A. Kompendium der Tracheotomie. Springer Heidelberg 2012
  7. Koscielny S, Beleites E, Schumann G. Moderne Möglichkeiten der palliativen chirurgischen Therapien bei inkurablenKopf-Hals-Tumoren. Onkologe 2003; 8:165–168
  8. Schweigert M, Posada-Gonzalez M, Dubecz A, Öfner D, Muschweck H, Stein HJ. Recurrent oesophageal cancer complicated by tracheo-oesophageal fistula: improved palliation by means of parallel tracheal and oesophageal stenting. Interactive Cardiovascular and Thoracic Surgery 2013; 18(2). DOI: 10.1093/icvts/ivt466
  9. www.bostonscientific.com/en-US/products/stents--pulmonary.html
  10. www.leufen-medical.de



Literatur Update „Zielgerichtete Therapie: Tyrosinkinaseinhibitoren in der klinischen Onkologie“

Stefan Schmidt, Günther Gastl,  Universitätsklinik für Innere Medizin V, Schwerpunkt Hämatologie & Onkologie, Innsbruck, Österreich (Seiten 41-46)


  1. Porter AC, Vaillantcourt RR. Tyrosine kinase receptor-activated signal transduction pathway which lead to oncogenesis. Oncogene 1998;17:1343-52
  2. Traxler P. Tyrosine kinases as targets in cancer therapy – successes and failures. Expert Opin Ther Targets 2003;2:215-34
  3. Müller D, Totzke F, Beisenherz-Huss C, Kubbutat MHG. Wirkmechanismen von Tyrosinkinase-Inhibitoren. Forum Onkologische Pflege 2011;2:19-22
  4. Tsai, CJ, Nussinov R. The molecular basis of targeting protein kinases in cancer therapeutics. Semin Cancer Biol 2013;23:235-42
  5. Kolibaba KS. Druker BJ. Protein tyrosine kinases and cancer. Biochem Biophys Acta 1997;1333(3):F217-48
  6. Deininger M, Buchdunger E, Druker, BJ. The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood 2005;105:2640-2653.
  7. Kosaka T, Yatabe Y, Endoh H, et al. Mutations of the epidermal growth factor receptor gene in lung cancer: biological an clinical implications. Cancer Res 2004;64(24):8919-23
  8. Robertson SC, Tynan J, Donoghue DJ. RTK mutations and human syndroms: When good receptors turn bad. Trends Genet 2000;16:265-271
  9. O'Brien SG, Guilhot F, Larson RA, et al. IRIS Investigators. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003;348:994-1004.
  10. Lipinski Ca. Lead- and drug-like compounds: The rule-of-five revolution. Drug Discov Today 2004;1:337-41
  11. Lipinski CA. Chris Lipinski discusses life and chemistry after the Role of Five. Drug Discov Today 2003;8:12-16
  12. Veber DF, Johnson SR, Chen HY, et al. Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem 2002;45:2615-23
  13. Johnson LN. Protein kinase inhibitors: Contributions from structure to clinical compounds. Q Rev Biophys 2009;42:1-40
  14. Hojjat-Farsangi M. Small-molecule inhibitors of the receptor tyrosine kinases: promising tools for targeted cancer therapies. Int J Mol Sci 2014;15:13768-801
  15. Nagar B, Bornmann WG, Pellicena P, et al. Crystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD173955 and imatinib (STI-571). Cancer Res 2003;62(15):4236-43
  16. Takano T, Ohe Y, Sakamoto H, et al. Epidermal growth factor receptor gene mutations and increased copy numbers predivt gefitinib sensitivity in patients with recurrent non-samll-cell lung cancer. J Clin Oncol 2005;23(28):6829-37
  17. Motzer RJ, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007;356(2):115-2
  18. Demetri GD, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomized controlled trial. Lancet. 2006;368:1329–38
  19. Raymond E, et al. Sunitinib maleate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011 Feb 10;364(6):501-13
  20. Escudier B, et al. Sorafenib for treatment of renal cell carcinoma: Final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial. J Clin Oncol 2009;27(20):3312-8
  21. Llovet JM, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378-90
  22. Brose MS, Nutting CM, Jarzab B, et al. DECISION investigators. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet. 2014; 384:319-28.
  23. Motzer RJ, et al. Randomized, open-label, phase III trial of pazopanib versus sunitinib in first-line treatment of patients with metastatic renal cell carcinoma (MRCC): results of the COMPARZ trial. Ann Oncol 2012;23(suppl. 9):LBA8_PR
  24. van der Graaf WT, et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2012;379(9829):1879-86
  25. Rini BI, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomized phase 3 trial. Lancet 2011;378(9807):1931-9
  26. Reck M, Kaiser R, Mellemgaard A et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol 2014;15:143–55
  27. Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381:303-12.
  28. Demetri GD, Reichardt P, Kang YK et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 2013;381(9863):295-302
  29. Wells SA Jr, Robinson BG, Gagel RF, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol. 2012 Jan 10;30(2):134-41
  30. Elisei R, Schlumberger MJ, Müller SP, et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. 2013 Oct 10;31(29):3639-46.
  31. Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med. 2015; 372:621-30
  32. Mok TS, Wu YL, Thongprasert S et al.: Gefitinib or carboplatin/paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009, 361: 947-957
  33. Zhou C, Wu YL, Chen G 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: 735-742
  34. Rosell R, Carcereny E, Gervais R et al. on behalf of the Spanish Lung Cancer Group in collaboration with the Groupe Français de Pneumo-Cancérologie and the Associazione Italiana Oncologia Toracica: 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: 239-246
  35. Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013;31:3327-34
  36. Yang YC, Hirsh V, Schuler M et al. Symptom control and quality of life in LUX-Lung 3: a phase III study of afatinib or cisplatin/pemetrexed in patients with advanced lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013;31:3342-50
  37. Malcolm J. Moore, David Goldstein, John Hamm. Erlotinib Plus Gemcitabine Compared With Gemcitabine Alone in Patients With Advanced Pancreatic Cancer: A Phase III Trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007;25(15):1960–6.
  38. Verma S, Miles D, Gianni L, et al. for the EMILIA Study Group. Trastuzumab Emtansine for HER2-Positive Advanced Breast Cancer. N Engl J Med 2012; 367:1783-1791
  39. Blackwell KL, Burstein HJ, Storniolo AM, et al. Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 Study. J Clin Oncol 2012;30:2585-92
  40. Blackwell KL, Burstein HJ, Storniolo AM, et al. Randomized Study of Lapatinib Alone or in Combination With Trastuzumab in Women With ErbB2-Positive,Trastuzumab-Refractory Metastatic Breast Cancer. J Clin Oncol 2010; 28:1124-1130
  41. Shaw AT, Kim DW, Nakagawa K, et al: Crizotinib versus chemotherapy in advanced ALK-Positive lung cancer. N Engl J Med 2013;368(25),2385–2394 
  42. Shaw AT, Kim DW, Mehra R, et al.: Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med 2014, 370: 1189-1197
  43. Kantarjian H, Shah NP, Hochhaus A, et al: Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 362:2260-70, 2010
  44. Saglio G, Kim DW, Issaragrisil S, et al: Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med 362:2251-9, 2010
  45. Cortes JE, Kim DW, Kantarjian HM, et al: Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: results from the BELA trial. J Clin Oncol 2012;30:3486-92
  46. Cortes JE, Kim DW, Pinilla-Ibarz J, et al: A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med 2013;369:1783-96
  47. Cortes et al, Blood 2014: Long-term follow-up of ponatinib and safety in the phase II PACE trial. Abstract #3135
  48. Demetri GD, von Mehren M, Blanke CD et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002; 347:472-480
  49. Harrison C, Kiladjian JJ, Al2Ali HK et al.: JAK Inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med 2012;366: 787-798
  50. Verstovsek S, Mesa RA, Gotlib J et al.: A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med 2012;366:799-807
  51. Byrd JC1, Brown JR, O'Brien S. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia.N Engl J Med. 2014;371(3):213-23
  52. Furman RR1, Sharman JP, Coutre SE. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370(11):997-1007
  53. Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2013;369(6):507-16. 
  54. Gopal AK, Kahl BS, de Vos S. PI3K? inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014;370(11):1008-18
  55. Deininger MW, Goldman JM, Melo JV. The molecular biology of chronic myeloid leukemia. Blood 2000;96(10):3343-56.
  56. Deininger M, O'Brien SG, Guilhot F, Goldman JM, Hochhaus A, Hughes TP, et al. International Randomized Study of Interferon Vs STI571 (IRIS) 8-Year Follow up: Sustained Survival and Low Risk for Progression or Events in Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Treated with Imatinib. ASH Annual Meeting Abstracts 2009;114(22):1126.
  57. Hehlmann R. How I treat CML blast crisis. Blood 2012;120(4):737-47.
  58. Sinclair A, Latif AL, Holyoake TL. Targeting survival pathways in chronic myeloid leukaemia stem cells. Br J Pharmacol 2013;169(8):1693-707.
  59. Cortes JE, Saglio G, Baccarani M, Kantarjian HM, Mayer J, Boqu+® Cn, et al. Final Study Results of the Phase 3 Dasatinib Versus Imatinib in Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Trial (DASISION, CA180-056). Blood 2014;124(21):152.
  60. Larson RA, Kim DW, Issaragrilsil S, le Coutre P, Dorlhiac Llacer PE, Etienne G, et al. Efficacy and Safety of Nilotinib (NIL) vs Imatinib (IM) in Patients (pts) With Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP): Long-Term Follow-Up (f/u) of ENESTnd. Blood 2014;124(21):4541.
  61. Apperley JF. Part I: mechanisms of resistance to imatinib in chronic myeloid leukaemia. Lancet Oncol 2007;8(11):1018-29.
  62. Soverini S, Branford S, Nicolini FE, Talpaz M, Deininger MW, Martinelli G, et al. Implications of BCR-ABL1 kinase domain-mediated resistance in chronic myeloid leukemia. Leuk Res 2014;38(1):10-20.
  63. Frankfurt O, Licht JD. Ponatinib--a step forward in overcoming resistance in chronic myeloid leukemia. Clin Cancer Res 2013;19(21):5828-34.
  64. Muller MC, Cross NC, Erben P, Schenk T, Hanfstein B, Ernst T, et al. Harmonization of molecular monitoring of CML therapy in Europe. Leukemia 2009;23(11):1957-63.
  65. Cross NC, Hochhaus A, Muller MC. Molecular monitoring of chronic myeloid leukemia: principles and interlaboratory standardization. Ann Hematol 2015;94(Supplement 2):219-25.
  66. Cross NC, White HE, Muller MC, Saglio G, Hochhaus A. Standardized definitions of molecular response in chronic myeloid leukemia. Leukemia 2012;26(10):2172-5.
  67. Foroni L, Wilson G, Gerrard G, Mason J, Grimwade D, White HE, et al. Guidelines for the measurement of BCR-ABL1 transcripts in chronic myeloid leukaemia. Br J Haematol 2011;153(2):179-90.
  68. Cross NC. Standardisation of molecular monitoring for chronic myeloid leukaemia. Best Pract Res Clin Haematol 2009;22(3):355-65.
  69. Baccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, Apperley JF, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood 2013;122(6):872-84.
  70. Yahng SA, Jang EJ, Choi SY, Lee SE, Kim SH, Kim DW. Prognostic discrimination for early chronic phase chronic myeloid leukemia in imatinib era: comparison of Sokal, Euro, and EUTOS scores in Korean population. Int J Hematol 2014;100(2):132-40.
  71. Pavlik T, Janousova E, Mayer J, Indrak K, Jarosova M, Klamova H, et al. Current survival measures reliably reflect modern sequential treatment in CML: correlation with prognostic stratifications. Am J Hematol 2013;88(9):790-7.
  72. Breccia M, Alimena G. The pros and cons of new prognostic eutos score for chronic myeloid leukemia patients. Leuk Res 2013;37(11):1436-7.
  73. Breccia M, Finsinger P, Loglisci G, Latagliata R, Mancini M, Salaroli A, et al. The EUTOS score identifies chronic myeloid leukeamia patients with poor prognosis treated with imatinib first or second line. Leuk Res 2012;36(9):e209-e210.
  74. Cortes JE, Talpaz M, Kantarjian H. Ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med 2014;370(6):577.
  75. Mahon FX. Discontinuation of tyrosine kinase therapy in CML. Ann Hematol 2015 Apr;94(Supplement 2):187-93.
  76. Rousselot P, Charbonnier A, Cony-Makhoul P, Agape P, Nicolini FE, Varet B, et al. Loss of major molecular response as a trigger for restarting tyrosine kinase inhibitor therapy in patients with chronic-phase chronic myelogenous leukemia who have stopped imatinib after durable undetectable disease. J Clin Oncol 2014;32(5):424-30.
  77. Mahon FX, Rea D, Guilhot J, Guilhot F, Huguet F, Nicolini F, et al. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol 2010;11(11):1029-35.
  78. Legros L, Rousselot P, Giraudier S, Tulliez M, Huguet F, Nicolini FE, et al. Second attempt to discontinue imatinib in CP-CML patients with a second sustained complete molecular response. Blood 2012;120(9):1959-60.
  79. Giles FJ, O'Dwyer M, Swords R. Class effects of tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia. Leukemia 2009;23(10):1698-707.
  80. Montani D, Seferian A, Savale L, Simonneau G, Humbert M. Drug-induced pulmonary arterial hypertension: a recent outbreak. Eur Respir Rev 2013;22(129):244-50.
  81. Breccia M, Tiribelli M, Alimena G. Tyrosine kinase inhibitors for elderly chronic myeloid leukemia patients: a systematic review of efficacy and safety data. Crit Rev Oncol Hematol 2012;84(1):93-100.
  82. Giles FJ, Mauro MJ, Hong F, Ortmann CE, McNeill C, Woodman RC, et al. Rates of peripheral arterial occlusive disease in patients with chronic myeloid leukemia in the chronic phase treated with imatinib, nilotinib, or non-tyrosine kinase therapy: a retrospective cohort analysis. Leukemia 2013;27(6):1310-5.
  83. Kim TD, Rea D, Schwarz M, Grille P, Nicolini FE, Rosti G, et al. Peripheral artery occlusive disease in chronic phase chronic myeloid leukemia patients treated with nilotinib or imatinib. Leukemia 2013;27(6):1316-21.
  84. Mauro MJ, Cortes JE, Hochhaus A, Baccarani M, Hughes TP, Guilhot F, et al. Ponatinib Efficacy and Safety in Patients with the T315I Mutation: Long-Term Follow-up of Phase 1 and Phase 2 (PACE) Trials. Blood 2014 Dec 5;124(21):4552.
  85. Kantarjian HM, Cortes JE, Kim DW, Khoury HJ, Brümmendorf TH, Porkka K, et al. Bosutinib safety and management of toxicity in leukemia patients with resistance or intolerance to imatinib and other tyrosine kinase inhibitors. Blood 2013;123(9):1309-18.
  86. Cortes JE, Saglio G, Baccarani M, Kantarjian HM, Mayer J, Boqu+® Cn, et al. Final Study Results of the Phase 3 Dasatinib Versus Imatinib in Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Trial (DASISION, CA180-056). Blood 2014;124(21):152.
  87. Valent P, Hadzijusufovic E, Schernthaner GH, Wolf D, Rea D, le CP. Vascular safety issues in CML patients treated with BCR/ABL1 kinase inhibitors. Blood 2015;125(6):901-6.
  88. Aichberger KJ, Herndlhofer S, Schernthaner GH, Schillinger M, Mitterbauer-Hohendanner G, Sillaber C, et al. Progressive peripheral arterial occlusive disease and other vascular








Interview „Der Einfluss von Bisphosphonaten auf das Überleben von Patientinnen mit Tumorzellen im Knochenmark“

mit Prof. Dr. med. Ingo Diel, Mannheim (Seiten 36/37)


  1. Mansi JL et al. Outcome of primary-breast-cancer patients with micrometastases: a long-term follow-up study. Lancet 1999;354:197–202.
  2. Braun S et al. Cytokeratin-positive cells in the bone marrow and survival of patients with stage I, II, or III breast cancer. N Engl J Med 2000;342:525–533.
  3. Gerber B et al. Simultaneous immunohistochemical detection of tumor cells in lymph nodes and bone marrow aspirates in breast cancer and its correlation with other prognostic factors. J Clin Oncol 2001;19:960–971.
  4. Pierga J-Y et al. Clinical significance of immunocytochemical detection of tumor cells using digital microscopy in peripheral blood and bone marrow of breast cancer patients. Clin Cancer Res 2004;10:1392–1400.
  5. Wiedswang G et al. Detection of isolated tumor cells in bone marrow is an independent prognostic factor in breast cancer. J Clin Oncol 2003;21:3469–3478.
  6. Gebauer G et al. Epithelial cells in bone marrow of breast cancer patients at time of primary surgery: clinical outcome during long-term follow-up. J Clin Oncol 2001;19:3669–3674.
  7. Diel IJ et al. Micrometastatic breast cancer cells in bone marrow at primary surgery: prognostic value in comparison with nodal status. J Natl Cancer Inst 1996;88:1652–1658.
  8. Yu JJ. et al. Bone marrow micrometastases and adjuvant treatment of breast cancer. Breast J 2004;10:181–185.
  9. Braun S et al. A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med 2005;353:793–802.
  10. Diel IJ. et al. Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med 1998;339:357–363.
  11. Kasimir-Bauer S et al. Different prognostic value of circulating and disseminated tumor cells in primary breast cancer. Influence of bisphosphonate intake? San Antonio Breast Cancer Symposium 2014; P 04-01-07, Poster.
  12. Mathiesen RR et al. Persistence of disseminated tumor cells after neoadjuvant treatment for locally advanced breast cancer predicts poor survival. Breast Cancer Research 2012;14:R117.
  13. Wiedswang G et al. Isolated tumor cells in bone marrow three years after diagnosis in disease-free breast cancer patients predict unfavorable clinical outcome. Clin Cancer Res 2004;10:5342–5348.
  14. Janni W et al. The persistence of isolated tumor cells in bone marrow from patients with breast carcinoma predicts an increased risk for recurrence. Cancer 2005;103:884–891.
  15. Janni W et al. Persistence of disseminated tumor cells in the bone marrow of breast cancer patients predicts increased risk for relapse - a European pooled analysis. Clin Cancer Res 2011;17:2967–2976.
  16. Rack B et al. Circulating tumor cells predict survival in early average-to-high risk breast cancer patients. J Natl Cancer Inst 2014;106, doi: 10.1093/jnci/dju066.
  17. Diel IJ et al. Adjuvant oral clodronate improves the overall survival of primary breast cancer patients with micrometastases to the bone marrow: a long-term follow-up. Ann Oncol 2008;19:2007–2011.
  18. Powles T et al. Randomized, placebo-controlled trial of clodronate in patients with primary operable breast cancer. J Clin Oncol 2002;20:3219–3224.
  19. Powles T et al. Reduction in bone relapse and improved survival with oral clodronate for adjuvant treatment of operable breast cancer [ISRCTN83688026]. Breast Cancer Res 2006;8:R13.