Jens Peter Klußmann

Basics of tumor development and importance of human papilloma virus (HPV) for head and neck cancer.

Head and Neck Squamous Cell Carcinomas (HNSCC) are the 6th most common cancers worldwide. While incidence rates for cancer of the hypopharynx and larynx are decreasing, a significant increase in cancer of the oropharynx (OSCC) is observed. Classical risk factors for HNSCC are smoking and alcohol. It has been shown for 25 to 60% of OSCC to be associated with an infection by oncogenic human papilloma viruses (HPV). The development of “common” cancer of the head and neck is substantially enhanced by an accumulation of genetic changes, which lead to an inactivation of tumor suppressor genes or activation of proto-oncogenes. A more or less uniform sequence of different DNA-damages leads to genetic instability. In this context, an early and frequent event is deletion on the short arm of chromosome 9, which results in inactivation of the p16-gene. In contrast, for HPV-induced carcinogenesis, expression of the viral proteins E6 and E7 is most important, since they lead to inactivation of the cellular tumor-suppressor-proteins p53 and Rb. The natural route of transoral infection is a matter of debate; peroral HPV-infections might be frequent and disappear uneventfully in most cases. Smoking seems to increase the probability for developing an HPV-associated OSCC. The association of HNSCC with HPV can be proven with established methods in clinical diagnostics. In addition to classical prognostic factors, diagnosis of HPV-association may become important for selection of future therapies. Prognostic relevance of HPV probably surmounts many known risk-factors, for example regional metastasis. Until now, no other molecular markers are established in clinical routine. Future therapy concepts may vary for the two subgroups of patients, particularly patients with HPV-associated OSCC may take advantage of less aggressive treatments. Finally, an outlook will be given on possible targeted therapies.

Definitive radiochemotherapy of advanced head and neck cancer with carboplatin and paclitaxel

PurposeTo report outcome and toxicity of concurrent radiochemotherapy with carboplatin and paclitaxel in advanced squamous cell carcinomas of the oropharynx and hypopharynx.Patients and MethodsAdvanced inoperable carcinomas of the oropharynx and hypopharynx were treated with either hyper-fractionated, accelerated radiotherapy (50.0 Gy/2.0 with concomitant boost to 69.2 Gy/1.6) or conventional fractionated radiotherapy (70.2–72 Gy/1.8) concurrent with paclitaxel 40 mg/m2 and carboplatin AUC 1 weekly for 6 weeks. Acute and long-term toxicity was measured according to WHO- and CTC-criteria.ResultsA total of 84 patients were included between 2000 and 2008. Median follow-up time of patients alive was 36 months. Conventionally fractionated radiotherapy was given to 16 patients, while 68 patients were treated with concomitant boost. Finally, 88.1% of patients received full dose paclitaxel. Acute mucositis ≥ grade 3 was present in 51.2% of patients, while 6% of patients experienced ≥ grade 3 leucopenia and thrombopenia. A supportive gastric feeding tube was implanted in 89.1% of patients. Overall survival after 2 years was 46.3%, progression-free survival after 2 years was 41.0%. There was no significant survival difference between the different radiotherapy protocols.ConclusionConcomitant carboplatin and paclitaxel is feasible and effective in advanced carcinomas of the head and neck.ZielZiel der Arbeit war die Untersuchung der Effektivität und Toxizität einer simultanen Radiochemotherapie mit Carboplatin und Paclitaxel bei fortgeschrittenen inoperablen Oropharynx- und Hypopharynxkarzinomen.Patienten und MethodenFortgeschrittene und inoperable Karzinome von Oropharynx und Hypopharynx wurden entweder mit einer simultanen hyperfraktioniert-akzelerierten (50,0 Gy/2,0 mit „concomitant boost“ bis 69,2 Gy/1,6) oder einer konventionell fraktionierten Radiochemotherapie (70,2–72 Gy/1,.8) zusammen mit Paclitaxel (40 mg/m2) und Carboplatin (AUC 1) für insgesamt 6 Wochen behandelt. Die Akut- und Spättoxizitäten wurde jeweils nach WHO- und CTC-Kriterien dokumentiert.ErgebnisseZwischen 2000 und 2008 wurden insgesamt 84 Patienten behandelt. Die mediane Nachbeobachtungszeit aller lebenden Patienten betrug 36 Monate. 68 Patienten erhielten ein ccb-Protokoll; 16 Patienten wurden mit konventioneller Fraktionierung bestrahlt. 88,1% der Patienten erhielten die geplante volle Paclitaxeldosierung. Eine akute Mukositis Grad 3 oder höher trat bei 51,2% der Patienten auf; die Rate an Grad-3-Leukopenien und -Thrombopenien lag bei 6%. Eine PEG-Sonde wurde bei 89,1% der Patienten implantiert. Die 2-Jahres-Gesamtüberlebenswahrscheinlichkeit lag bei 46,3%; das progressionsfreie Überleben nach 2 Jahren betrug 41,0%. Zwischen den verschiedenen Radiotherapieprotokollen gab es keine Unterschiede in der Überlebenswahrscheinlichkeit.SchlussfolgerungDie kombinierte Radiochemotherapie mit Carboplatin und Paclitaxel bei fortgeschrittenen Kopf-Hals-Tumoren ist sicher durchführbar und effektiv.

Humane Papillomaviren bei Kopf-Hals-Karzinomen

ZusammenfassungTranslationale Forschung beschreibt Schnittstellen zwischen präklinischer Forschung und einer zielgerichteten kurz- bis mittelfristigen Entwicklung hin zu klinischen Standards. Es existieren 2 verschiedene Gruppen von Oropharynxkarzinomen: die einen werden durch Risikofaktoren wie Rauchen und Alkohol, die anderen durch Infektion mit humanen Papillomaviren (HPV) verursacht. Bei Patienten mit HPV-assoziierten Tumoren ist die Prognose signifikant besser, in der Wahl der Behandlung spielt dies jedoch bisher kaum eine Rolle. Aktuell werden der reduzierte Einsatz von Radio-/Chemotherapie oder Operationen sowie der Einsatz einer zielgerichteten multimodalen Therapie untersucht. In diesem Artikel werden die natürliche HPV-Infektion und ihre karzinogene Bedeutung, Signalwege und neue, potenziell therapeutisch relevante molekulare Targets dargestellt. Die Identifikation einer distinkten Tumorentität des Oropharynx kann die Entwicklung neuer Strategien zur Prävention und Therapie HPV-assoziierter Tumoren in naher Zukunft voranbringen.AbstractTranslational research refers to the interfaces between preclinical research and targeted short- and medium-term developments through to clinical standards. There are two distinct groups of oropharyngeal malignancies: those caused by tobacco and alcohol abuse and those caused by HPV infection. Although the prognosis of patients in the latter group is significantly better, this is not taken into consideration in the choice of treatment. However, less intensive use of radiotherapy, chemotherapy, or surgery, as well as targeted multimodal therapeutic approaches, is under research. This article summarizes the main events in the HPV life cycle, with emphasis on carcinogenic mechanisms and potential new molecular targets. Identifying distinct tumor entities of the oropharynx enables the design and development of new preventive and therapeutic strategies to reduce the incidence and mortality of HPV-associated oropharyngeal cancers in the near future.Translational research refers to the interfaces between preclinical research and targeted short- and medium-term developments through to clinical standards. There are two distinct groups of oropharyngeal malignancies: those caused by tobacco and alcohol abuse and those caused by HPV infection. Although the prognosis of patients in the latter group is significantly better, this is not taken into consideration in the choice of treatment. However, less intensive use of radiotherapy, chemotherapy, or surgery, as well as targeted multimodal therapeutic approaches, is under research. This article summarizes the main events in the HPV life cycle, with emphasis on carcinogenic mechanisms and potential new molecular targets. Identifying distinct tumor entities of the oropharynx enables the design and development of new preventive and therapeutic strategies to reduce the incidence and mortality of HPV-associated oropharyngeal cancers in the near future.

Praxis der Tumorendoskopie an deutschen HNO-Kliniken

BACKGROUND Second primary carcinomas (SPC) essentially influence therapy and the outcome in head and neck cancer. This study presents the current status of tumour endoscopy in German ENT-clinics. MATERIAL AND METHODS A standardised questionnaire regarding indication, time of event, examined anatomical region and technique of tumour endoscopy was compiled, sent to all German ENT-clinics (n=159) and subsequently analysed. RESULTS In 94-100% of the clinics, tumour endoscopy is being conducted when primary carcinoma lies within oral cavity, pharynx, larynx or is a CUP-syndrome. In 80%, 2-stage surgical procedure is preferred. Nasal cavity and tracheobronchial system (47%, 74%) are often not included in the examination. When primary cancer is seen, in 7% of the clinics a standardised biopsy of unsuspicious anatomic areas is conducted. In CUP-syndrome, unsuspicious surfaces within the pharynx do not undergo routine biopsy in 10-20% of the clinics. In tracheobronchoscopy (63.0%) and esophagoscopy (93.3%) rigid scopes are mainly used. 65% of the clinics conduct endoscopy as follow-up care. CONCLUSION Practice of tumour endoscopy in German ENT-clinics is widespread but does not follow standardised mechanisms. Current international literature shows that there is no common consensus on value and techniques of tumour endoscopy, however, due to highly developed radiological diagnostics, risks of rigid endoscopies and unknown incidence of second primary tumours it is discussed more and more negative. To establish future guidelines, controlled studies or analysis of large populations seem to be necessary.

HPV – Das andere Kopf-Hals-Karzinom

Head and neck cancer is the sixth most common cancer with over 500000 annually reported incident cases worldwide. Besides major risk factors tobacco and alcohol, oropharyngeal squamous cell carcinomas (OSCC) show increased association with human papillomavirus (HPV). HPV-associated and HPV-negative OSCC are 2 different entities regarding biological characteristics, therapeutic response, and patient prognosis. In HPV OSCC, viral oncoprotein activity, as well as genetic (mutations and chromosomal aberrations) and epigenetic alterations plays a key role during carcinogenesis. Based on improved treatment response, the introduction of therapy de-intensification and targeted therapy is discussed for patients with HPV OSCC. A promising targeted therapy concept is immunotherapy. The use of checkpoint inhibitors (e.g. anti-PD1) is currently investigated. By means of liquid biopsies, biomarkers such as viral DNA or tumor mutations in the will soon be available for disease monitoring, as well as detection of treatment failure. By now, primary prophylaxis of HPV OSCC can be achieved by vaccination of girls and boys.

Spontane Knochenregeneration nach keratozystischem odontogenem Tumor@@@Spontaneous bone regeneration following ceratocystic odontogenic tumor

ZusammenfassungEin Patient stellte sich mit einem keratozystischen odontogenen Tumor des linken Sinus maxillaris vor. Radiologisch fanden sich ausgedehnte druckbedingte knöcherne Atrophien der Kieferhöhlenwände. Es erfolgte eine endoskopische Zystektomie des Tumors und die anschließende klinische Nachsorge. Im Verlauf wurde eine erneute radiologische Untersuchung durchgeführt, in der sich eine nahezu vollständige Rekonturierung der Kieferhöhlenwände zeigte. Knöcherne Rekonstruktionen im Rahmen von schonenden Ersteingriffen, wie der Enukleation, sollten bei der Möglichkeit spontaner Knochenregeneration zurückhaltend indiziert werden.AbstractA patient presents with a keratocystic odontogenic tumour of the left maxillary sinus. In computed tomography scans, extensive pressure-induced osseous atrophy of the sinus walls is detected. Endoscopic cystectomy of the tumour was performed, with subsequent clinical follow-up. A second computed tomography scan revealed almost complete regeneration of the sinus walls. Where spontaneous regeneration of osseous structures is possible, restraint should be exercised when assessing indications for bony reconstruction during initial conservative surgery such as enucleation.A patient presents with a keratocystic odontogenic tumour of the left maxillary sinus. In computed tomography scans, extensive pressure-induced osseous atrophy of the sinus walls is detected. Endoscopic cystectomy of the tumour was performed, with subsequent clinical follow-up. A second computed tomography scan revealed almost complete regeneration of the sinus walls. Where spontaneous regeneration of osseous structures is possible, restraint should be exercised when assessing indications for bony reconstruction during initial conservative surgery such as enucleation.

Spontaneous bone regeneration following ceratocystic odontogenic tumor

ZusammenfassungEin Patient stellte sich mit einem keratozystischen odontogenen Tumor des linken Sinus maxillaris vor. Radiologisch fanden sich ausgedehnte druckbedingte knöcherne Atrophien der Kieferhöhlenwände. Es erfolgte eine endoskopische Zystektomie des Tumors und die anschließende klinische Nachsorge. Im Verlauf wurde eine erneute radiologische Untersuchung durchgeführt, in der sich eine nahezu vollständige Rekonturierung der Kieferhöhlenwände zeigte. Knöcherne Rekonstruktionen im Rahmen von schonenden Ersteingriffen, wie der Enukleation, sollten bei der Möglichkeit spontaner Knochenregeneration zurückhaltend indiziert werden.AbstractA patient presents with a keratocystic odontogenic tumour of the left maxillary sinus. In computed tomography scans, extensive pressure-induced osseous atrophy of the sinus walls is detected. Endoscopic cystectomy of the tumour was performed, with subsequent clinical follow-up. A second computed tomography scan revealed almost complete regeneration of the sinus walls. Where spontaneous regeneration of osseous structures is possible, restraint should be exercised when assessing indications for bony reconstruction during initial conservative surgery such as enucleation.A patient presents with a keratocystic odontogenic tumour of the left maxillary sinus. In computed tomography scans, extensive pressure-induced osseous atrophy of the sinus walls is detected. Endoscopic cystectomy of the tumour was performed, with subsequent clinical follow-up. A second computed tomography scan revealed almost complete regeneration of the sinus walls. Where spontaneous regeneration of osseous structures is possible, restraint should be exercised when assessing indications for bony reconstruction during initial conservative surgery such as enucleation.

Spontane Knochenregeneration nach keratozystischem odontogenem Tumor

ZusammenfassungEin Patient stellte sich mit einem keratozystischen odontogenen Tumor des linken Sinus maxillaris vor. Radiologisch fanden sich ausgedehnte druckbedingte knöcherne Atrophien der Kieferhöhlenwände. Es erfolgte eine endoskopische Zystektomie des Tumors und die anschließende klinische Nachsorge. Im Verlauf wurde eine erneute radiologische Untersuchung durchgeführt, in der sich eine nahezu vollständige Rekonturierung der Kieferhöhlenwände zeigte. Knöcherne Rekonstruktionen im Rahmen von schonenden Ersteingriffen, wie der Enukleation, sollten bei der Möglichkeit spontaner Knochenregeneration zurückhaltend indiziert werden.AbstractA patient presents with a keratocystic odontogenic tumour of the left maxillary sinus. In computed tomography scans, extensive pressure-induced osseous atrophy of the sinus walls is detected. Endoscopic cystectomy of the tumour was performed, with subsequent clinical follow-up. A second computed tomography scan revealed almost complete regeneration of the sinus walls. Where spontaneous regeneration of osseous structures is possible, restraint should be exercised when assessing indications for bony reconstruction during initial conservative surgery such as enucleation.A patient presents with a keratocystic odontogenic tumour of the left maxillary sinus. In computed tomography scans, extensive pressure-induced osseous atrophy of the sinus walls is detected. Endoscopic cystectomy of the tumour was performed, with subsequent clinical follow-up. A second computed tomography scan revealed almost complete regeneration of the sinus walls. Where spontaneous regeneration of osseous structures is possible, restraint should be exercised when assessing indications for bony reconstruction during initial conservative surgery such as enucleation.

Ich kriege kaum noch Luft durch das linke Nasenloch

Ein 18-Jähriger stellte sich mit einseitiger Behinderung der Nasenatmung vor. Die Beschwerden waren seit einem halben Jahr progredient. Sinusitis-typische Symptome wurden nicht angegeben. Was war die Ursache?

Definitive radiochemotherapy of advanced head and neck cancer with carboplatin and paclitaxel@@@Definitive Radiochemotherapie fortgeschrittener Kopf-Hals-Tumoren mit Carboplatin und Paclitaxel: A phase II study

PurposeTo report outcome and toxicity of concurrent radiochemotherapy with carboplatin and paclitaxel in advanced squamous cell carcinomas of the oropharynx and hypopharynx.Patients and MethodsAdvanced inoperable carcinomas of the oropharynx and hypopharynx were treated with either hyper-fractionated, accelerated radiotherapy (50.0 Gy/2.0 with concomitant boost to 69.2 Gy/1.6) or conventional fractionated radiotherapy (70.2–72 Gy/1.8) concurrent with paclitaxel 40 mg/m2 and carboplatin AUC 1 weekly for 6 weeks. Acute and long-term toxicity was measured according to WHO- and CTC-criteria.ResultsA total of 84 patients were included between 2000 and 2008. Median follow-up time of patients alive was 36 months. Conventionally fractionated radiotherapy was given to 16 patients, while 68 patients were treated with concomitant boost. Finally, 88.1% of patients received full dose paclitaxel. Acute mucositis ≥ grade 3 was present in 51.2% of patients, while 6% of patients experienced ≥ grade 3 leucopenia and thrombopenia. A supportive gastric feeding tube was implanted in 89.1% of patients. Overall survival after 2 years was 46.3%, progression-free survival after 2 years was 41.0%. There was no significant survival difference between the different radiotherapy protocols.ConclusionConcomitant carboplatin and paclitaxel is feasible and effective in advanced carcinomas of the head and neck.ZielZiel der Arbeit war die Untersuchung der Effektivität und Toxizität einer simultanen Radiochemotherapie mit Carboplatin und Paclitaxel bei fortgeschrittenen inoperablen Oropharynx- und Hypopharynxkarzinomen.Patienten und MethodenFortgeschrittene und inoperable Karzinome von Oropharynx und Hypopharynx wurden entweder mit einer simultanen hyperfraktioniert-akzelerierten (50,0 Gy/2,0 mit „concomitant boost“ bis 69,2 Gy/1,6) oder einer konventionell fraktionierten Radiochemotherapie (70,2–72 Gy/1,.8) zusammen mit Paclitaxel (40 mg/m2) und Carboplatin (AUC 1) für insgesamt 6 Wochen behandelt. Die Akut- und Spättoxizitäten wurde jeweils nach WHO- und CTC-Kriterien dokumentiert.ErgebnisseZwischen 2000 und 2008 wurden insgesamt 84 Patienten behandelt. Die mediane Nachbeobachtungszeit aller lebenden Patienten betrug 36 Monate. 68 Patienten erhielten ein ccb-Protokoll; 16 Patienten wurden mit konventioneller Fraktionierung bestrahlt. 88,1% der Patienten erhielten die geplante volle Paclitaxeldosierung. Eine akute Mukositis Grad 3 oder höher trat bei 51,2% der Patienten auf; die Rate an Grad-3-Leukopenien und -Thrombopenien lag bei 6%. Eine PEG-Sonde wurde bei 89,1% der Patienten implantiert. Die 2-Jahres-Gesamtüberlebenswahrscheinlichkeit lag bei 46,3%; das progressionsfreie Überleben nach 2 Jahren betrug 41,0%. Zwischen den verschiedenen Radiotherapieprotokollen gab es keine Unterschiede in der Überlebenswahrscheinlichkeit.SchlussfolgerungDie kombinierte Radiochemotherapie mit Carboplatin und Paclitaxel bei fortgeschrittenen Kopf-Hals-Tumoren ist sicher durchführbar und effektiv.