Risk profiling based on p16 and HPV DNA more accurately predicts location of disease relapse in patients with oropharyngeal squamous cell carcinoma.

BACKGROUND: In the era of precision medicine and HPV-related oropharyngeal squamous cell carcinoma (OPSCC), it is relevant to assess the risk of not only survival, but also the risk of local, regional, or distant treatment failure. The UICC 8th edition uses the surrogate marker p16 to stratify for HPV association but discordance between p16 status and HPV association has been shown. The purpose of this study was to develop a prognostic model to predict the risk of local, regional, and distant metastases and non-cancer-related death for patients with OPSCC, test the prognostic relevance of adding HPV DNA and p16 status, and validate the findings in an independent external dataset. PATIENTS AND METHODS: Consecutive patients diagnosed with OPSCC and treated with curative radiotherapy with or without cisplatin in eastern Denmark from 2000 to 2014 were included. Characteristics included age, gender, TNM stage, smoking habits, performance status, and HPV status assessed with p16 and HPV DNA. The information was used to develop a prognostic model for first site of failure with four competing events: recurrence in T-, N-, and M-site, and death with no evidence of disease. RESULTS: Overall 1243 patients were eligible for the analysis. A prognostic model with the four events was developed and externally validated in an independent dataset with a heterogeneously treated patient population from another institution. The individual prognostication from the competing risk analysis is displayed in a user friendly online tool (https://rasmussen.shinyapps.io/OPSCCmodelHPV_p16/). Replacing p16 status with the combined variable HPV/p16 status influenced the HR and patients with HPV-/p16+ had significantly higher HR of M-site recurrence than HPV+/p16+ with a HR = 2.56; CI [1.30; 5.02]; P = 0.006 (P = 0.013 in the validation cohort). CONCLUSION: Patients with HPV-/p16+ have significantly higher risk of M-site recurrence and could potentially be relevant candidates for clinical trials testing systemic treatments in combination with conventional treatments.

[HPV-associated oropharyngeal cancer-incidence, trends, diagnosis, and treatment]. / Das HPV-getriebene Oropharynxkarzinom ­ Inzidenz, Trends, Diagnose und Therapie.

A rising incidence of oropharyngeal squamous cell carcinoma (OPSCC) is reported by many countries worldwide and OPSCC associated with human papillomavirus (HPV) has been recently defined as a new class of head and neck cancers. Besides tobacco and alcohol consumption, HPV is an accepted risk and prognostic factor for OPSCC. Although the incidence increase of HPV-associated OPSCC is convincing, cancer registry studies and studies based on cohorts often have drawbacks regarding data linkage to comparable experimental data, comparable anatomical definitions or HPV diagnostics. Patients with HPV-associated OPSCC have remarkably better prognosis and the tumors differ from HPV-negative OPSCC with respect to molecular and genetic aspects. Nevertheless, choice of therapy is independent of HPV, and rather is subject to the individual patient's condition, local preference and anatomic characteristics. New concepts emerge in immune-checkpoint oncology, which might be a valuable add-on to established concepts. Also, treatment de-escalation (e.g., by reduction of radiation dosage) might be suitable for patients with certain risk profiles. Prophylactic vaccination can contribute to reducing HPV-induced disease, likewise OPSCC. Prerequisite is a high rate of vaccination, which is currently not sufficient in Germany. Because of currently low vaccination rates and the rather long time between initial infection and HPV-induced carcinogenesis, reduction of incidence increase or prevalence of HPV-associated OPSCC is not expected in the near future.

[Update on HPV-associated head and neck cancer-highlights of the 2018 ASCO Annual Meeting]. / Update zu HPV-assoziierten Kopf-Hals-Karzinomen ­ Highlights der ASCO-Jahrestagung 2018.

Rising incidence rates in human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) and a significantly improved prognosis have brought this entity into scientific focus. At this year's American Society of Clinical Oncology (ASCO) Annual Meeting, 291 studies with the keyword "HPV" were presented, the majority of which were in head and neck cancer. Due to high rates of late toxicities after conventional therapy, de-intensified treatment concepts are being increasingly discussed, although data from prospective phase III studies were not presented. Retrospective data on the latest TNM staging (downstaging in many HPV-associated patients) and other risk stratification systems were presented. HPV diagnostics based solely on p16 immunohistochemistry were discussed. Many groups presented work on the HPV association and its prognostic relevance not only in oropharyngeal carcinoma, but also in oral cavity, hypopharyngeal, and locally advanced laryngeal squamous cell carcinoma. New prognostic biomarkers such as methylation signatures appear to be promising. New data suggest equal survival rates in HPV-associated stage I OPSCC treated with surgery alone in comparison to patients who received adjuvant therapy after surgery. A possible negative effect on overall survival in stage III HPV-associated OPSCC with a cisplatin dose ≤200 mg/m2 was discussed. Results of de-escalation studies are urgently awaited, in order to be able to treat HPV-associated OPSCC patients as precisely and as specifically as possible and ensure long-term quality of life.

Patient's perspective on long-term complications after superficial parotidectomy for benign lesions: Prospective analysis of a 2-year follow-up.

OBJECTIVE: Evaluation of patients' perspective on long-term complications after superficial parotidectomy for benign lesions. DESIGN: A prospective nonrandomized controlled multicenter study. SETTING: Three university-based tertiary referral centers (Departments of Otorhinolaryngology of Cologne, Jena and Giessen; all in Germany). PARTICIPANTS: 130 adult patients, who underwent a primary superficial parotidectomy for benign tumors of the parotid gland, were consecutively included from 09/2010 to 05/2012. 61 patients completed every follow-up examination. MAIN OUTCOME MEASURES: Complications were evaluated using the validated German-language questionnaire Parotidectomy Outcome Inventory 8 at six, 12 and 24 months after surgery. Pain intensity was assessed on a numeric rating scale (NRS) at each follow-up visit. RESULTS: At 6 months after surgery, 90% characterized hypoesthesia as the most disturbing problem, followed by fear of revision surgery (57%) and scar (56%). Facial palsy (14%) posed the minor problem. Hypoesthesia improved significantly during the follow-up period (all P < .05), but still posed a problem for 78% of the patients after 2 years. Pain, which initially bothered 53% of the patients, significantly decreased, whereas impairment due to Frey's syndrome significantly increased during the follow-up (6 vs 24 months; P = .002 and P = .001, respectively). Scar, substance loss, xerostomia, facial palsy, and anxiety affected patients with unvarying severity during the 2 years (all P > .05). CONCLUSIONS: From patients' perspective, sensation loss posed the major subjective problem after superficial parotidectomy. Appearance of the scar, and fear of revision surgery impaired more than 50% of the patients in their daily life without significant improvement during the 2 years postoperatively. Although superficial parotidectomy is a highly standardized and safe procedure, limited parotidectomy for proven benign parotid salivary gland neoplasms is more likely to result in patients with minimal or no displeasing complications.

[The innate immune system in oropharyngeal squamous cell carcinoma : Immune modulation by HPV]. / Das angeborene Immunsystem beim Oropharynxkarzinom : Immunmodulation durch HPV.

Based on clinical and experimental data, oropharyngeal squamous cell carcinomas (OPSCC) associated with human papillomavirus (HPV) have been recognized as a distinct entity of head and neck cancers. However, outside of clinical trials, HPV status currently has no impact on treatment. The natural replication cycle of HPV takes place in epithelial cells, and is thus spatially separated from cytotoxic immune cells in the epidermis. Dendritic cells (Langerhans cells, LC), however, are frequent in this upper dermal layer. The ability of LC to process antigens, migrate, and, ultimately activate T cells is inhibited by the activity of the viral oncoproteins (E5-E7). Downregulation of functional human leukocyte antigen I (HLA-I) epithelial cell surface expression contributes to LC inhibition. However, due to their absence in upper skin layers, corresponding activation of natural killer (NK) cells via missing-self recognition is not relevant. Genome-wide analyses have revealed specific expression signatures for HPV-associated OPSCC that are distinct from HPV-negative cancers. Interestingly, aberrations in HLA-I genes were common in HPV-associated OPSCC. Our own findings indicate more frequent infiltration of HPV-associated OPSCC by CD56-positive (CD56+) NK cells, which might be related to HLA-I downregulation during HPV-associated carcinogenesis. In patients with OPSCC, CD56 positivity correlates with improved prognosis after conventional therapy. This could be evidence for HPV-associated OPSCC being especially eligible for novel immune-based therapies and an indication that immunological data should be included in the design of clinical trials.

A two-arm multicenter phase II trial of one cycle chemoselection split-dose docetaxel, cisplatin and 5-fluorouracil (TPF) induction chemotherapy before two cycles of split TPF followed by curative surgery combined with postoperative radiotherapy in patients with locally advanced oral and oropharyngeal squamous cell cancer (TISOC-1).

BACKGROUND: Induction chemotherapy (ICT) with docetaxel, cisplatin and fluorouracil (TPF) followed by radiotherapy is an effective treatment option for locally advanced head and neck cancer. This phase II study investigated the effectivity of a split-dose TPF ICT before surgery for locally advanced resectable (stage III/IVA) oral and oropharyngeal cancer. PATIENTS AND METHODS: Patients received TPF split on two dosages on days 1 and 8 per cycle (30 mg/m2 docetaxel, 40 mg/m2 cisplatin, 2000 mg/m2 fluorouracil per week). Responders (reduction tumor volume ≥30% after first cycle) received three 3-week cycles and non-responders only one cycle before surgery and postoperative radio(chemo)therapy (RCT). The primary endpoint was progression-free survival rate after 24 months. Secondary endpoints were amongst others overall survival, histopathological response to ICT, toxicity, quality of life and swallowing function. RESULTS: Fifty-four patients (91% stage IVA, 87% male, 72% oropharyngeal cancer, 70% responders) were eligible for a per-protocol analysis. The progression-free survival rate after 24 months was 88.5% for responders and 60.6% for non-responders (P = 0.005). The overall survival rate after 24 months was 97.3% for responders and 73.7% for non-responders (P = 0.032). The rate of histopathological complete remission of the primary tumor was higher in responders (P = 0.015). High-risk classification for postoperative RCT was lower in responders (P < 0.0001). The most common grade 3+ adverse event was neutropenia in 26% of patients during ICT and mucositis in 13% during postoperative RCT. During treatment and follow-up quality of life and swallowing function was not different between responders and non-responders. CONCLUSION: Patients with oral and oropharyngeal cancer responding to split-dose TPF before surgery and postoperative RCT show good oncological results. The tri-modal treatment regime was well tolerated. ICT using tumor response as criterion for duration of ICT before surgery of oral and oropharyngeal cancer merits additional investigation in a phase III study. CLINICAL TRIAL NUMBER: NCT01108042.

[Human papillomavirus and squamous cell cancer of the head and neck region : Prognostic, therapeutic and prophylactic implications]. / Humane Papillomviren bei Plattenepithelkarzinomen der Kopf- und Halsregion : Relevanz für Prognose, Therapie und Prophylaxe.

Human papilloma viruses (HPV) are responsible for approximately half of all oropharyngeal squamous cell carcinomas (OPSCC) and incidence rates of HPV-associated OPSCC continue to increase substantially. The defined viral carcinogenesis permits development of specific diagnostic, therapeutic, and prophylactic approaches. Laboratory identification of HPV-associated OPSCC may be achieved by p16(INK4a) immunohistochemistry combined with HPV DNA detection by polymerase chain reaction (PCR) using tumor tissue. Patients with HPV-associated OPSCC have a relatively good prognosis; therefore, the HPV status plays an important role in patient guidance. Due to the relatively favorable prognosis, ongoing studies are evaluating whether less rigorous therapy for HPV-positive patients results in equally good cure rates. The criteria for patient selection are, however, still uncertain. Particularly markers for detection of HPV-positive patients with a high risk of treatment failure are lacking. Besides tumor stage and comorbidities, distinct genomic, epigenetic, and immunologic alterations are prognostically relevant for HPV-associated OPSCC, and might be of predictive value. Furthermore, the characteristic molecular alterations suggest the possibility of novel vigilant and specific therapy approaches. These may be inhibitors of the phosphatidylinositol 3­kinase (PI3K) pathway, which is frequently activated in HPV-associated OPSCC, and immunotherapeutic methods, e. g., therapeutic vaccination. Although prophylactic HPV vaccinations may also prevent development of HPV-associated OPSCC, foreseeable effects on OPSCC incidence will be low, given the low vaccination rates in Germany. This highlights the fact that interdisciplinary research networks should enhance the necessary activities related to HPV-associated OPSCC.

[Spontaneous bone regeneration following ceratocystic odontogenic tumor]. / Spontane Knochenregeneration nach keratozystischem odontogenem Tumor.

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.

[HPV-associated head and neck cancer : mutational signature and genomic aberrations]. / HPV-assoziierte Kopf­Hals­Karzinome : Mutationssignaturen und genomische Aberrationen.

A significantly increasing proportion of oropharyngeal head and neck carcinomas (OSCC) in North America and Europe are associated with human papillomavirus (HPV) infections. HPV-related OSCC is regarded as a distinct tumor type with regard to its cellular, biologic, and clinical characteristics. Patients with HPV-related OSCC have significantly better local control, but higher rates of regional lymph node and distant metastases as compared to patients with HPV-negative OSCC. Classical molecular genetic investigations demonstrated specific chromosomal aberration signatures in HPV-related OSCC, and recent developments in next generation sequencing (NGS) technology have rendered possible the sequencing of entire genomes, and thus detection of specific mutations, in just a few days. Initial data from The Cancer Genome Atlas (TCGA) project obtained by using genome-wide high throughput methods have confirmed that HPV-related OSCC contain fewer, albeit more specific mutations than HPV-negative tumors. Additionally, these data revealed the presence of specific-potentially therapeutically targetable-activating driver mutations in subgroups of HPV-positive OSCC, some of which have a prognostic impact. Specific targeted NGS technologies provide new possibilities for identification of diagnostic, prognostic, and predictive biomarkers and the development of personalized cancer treatment. Patients with HPV-positive tumors are likely to profit from these developments in the future, since the genetic alterations are relatively homogenous and frequently lead to signal pathway activation. There is an urgent need for network research activities to carry out the necessary basic research in prospective cohort studies.

[Surgical Simulation Models for Sialendoscopy]. / Trainingsmodelle für die Sialendoskopie.

OBJECTIVE: Different simulation models are in use to teach the technique of sialendoscopy. Only a few reports in literature deal with this topic with no comparison having been published, yet. We therefore asked sialendoscopy training course participants about our applied models by using a questionnaire. Material und Methods: A tube-, a pepper-, a porcine kidney-, and a pig head-model were developed as training models and used during 6 consecutive practical sialendoscopy courses from 2012 to 2014. Participants were asked to answer a questionnaire specifically designed to assess the value of the different training models. RESULTS: All respondents (n=61) rated all training models positively. However, porcine kidney- and pig head-models were described to be superior, especially with respect to realistic simulation. Intubation of the papilla can be practised sufficiently only in the pig head-model. The tube- and peppers-models have the advantage of being less expensive, easier to handle and cleaner. CONCLUSIONS: The models described are all useful in learning the sialendoscopy technique. However, they have distinct advantages and disadvantages making a combination of different models useful.

[Negative pressure pulmonary edema after peritonsillar abscess tonsillectomy]. / Pulmonales Negativdrucködem nach Abszesstonsillektomie.

We report on a 19-year-old patient who developed negative pressure pulmonary edema (NPPE) with respiratory insufficiency following abscess tonsillectomy. NPPE is an unpredictable and life-threatening postoperative complication characterized by respiratory insufficiency. It may arise immediately after extubation or later in the postoperative period. NPPE is frequently observed after laryngospasm or in combination with space-occupying lesions in the pharynx and larynx. Treatment comprises the immediate correction of hypoxemia, preferably by noninvasive respiratory support using continuous positive airway pressure (CPAP), although in some cases reintubation is necessary.

Updated S2K AWMF guideline for the diagnosis and follow-up of obstructive sialadenitis--relevance for radiologic imaging.

The interdisciplinarily developed German S2k AWMF guideline for the treatment of obstructive sialadenitis represents a new standard in the guideline program of the AWMF, the German Society for Consultants and the clinical disciplines working in the field of diseases of the head and neck region. In the last few years new diagnostic and therapeutic possibilities have been established in obstructive chronic Sialadenitis offering individually optimized therapeutic strategies. Only a few years ago extirpation of the whole affected gland was the only relevant therapy option. Nowadays therapeutic options such as interventional sialendoscopy and extracorporeal shock-wave lithotripsy (ESWL) are available in combination with marsupialization or incision of the duct. If possible the focus is on preserving the main glandular duct. In the following article the relevant aspects for the diagnostic radiologic procedures are presented.

Optimising the pre-treatment process before mobile ear surgery for chronic suppurative otitis media in Wolisso and Attat, Ethiopia.

BACKGROUND: Chronic suppurative otitis media is a major cause of long-standing hearing impairment in many Sub-Saharan African countries. METHODS: Attempts were made to optimise the pre-treatment process before mobile ear surgery for chronic suppurative otitis media in Wolisso, a semi-urban community in the Oromia region, and in Attat, a rural community in the Gurage region, both in the south-west of Ethiopia, between 2008 and 2010. This included special training for ENT nurses, and the use of a strict scheduling regime and improved topical treatment. RESULTS AND CONCLUSION: This strategy allowed effective middle-ear surgery to be carried out using simple means and with a mobile ear surgery team, the latter of which is only transiently but regularly on site.

[The new S2k AWMF guideline for the treatment of obstructive sialadenitis in commented short form]. / Die neue S2k AWMF Leitlinie zur Behandlung der obstruktiven Sialadenitis in kommentierter Kurzform.

A new and interdisciplinary S2k AWMF guideline for the treatment of obstructive sialadenitis has been published. There have been several technical achievements, for instance in the field of ultrasonography, via sialendoscopy, or by MR-sialography, that have increased the possibilities for diagnosis and treatment of patients with obstructive sialadenitis. In the past, the treatment of choice in case of unsuccessful medical treatment was a complete extirpation of the affected salivary gland. Nowadays, using a variety of modern treatment options (like sialendoscopy, or extracorporeal shock-waves lithotripsy sometimes combined with salivary duct incision), it is possible in most patients, especially in cases of sialolithiasis, to preserve the affected gland. A functional recovery after gland-sparing surgery is described but more data is needed to finally evaluate the long-time results. The new guideline describes all relevant steps to diagnose an obstructive sialadenitis and values all diagnostic tools critically. Finally, all recommendable therapy options are described and valued, too.

[Current practice of tumour endoscopy in German ENT-clinics]. / 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.

[Sialendoscopy--learning curve and nation-wide survey in German ENT-departments]. / Sialendoskopie--Lernkurve und Verbreitung in deutschen HNO-Kliniken.

BACKGROUND: Sialendoscopy is an established, minimal-invasive technique to diagnose and treat obstructive diseases of major salivary glands. Knowledge on learning curve and distribution in Germany is limited. MATERIAL UND METHODS: An 11 item questionnaire on Sialendoscopy was sent to all 159 German ent-hospitals. To determine the learning curve, all patients that underwent sialendoscopy during a 1-year-period after invention of sialendoscopy in our department were prospectively followed and evaluated. RESULTS: Sialendoscopy is currently performed in a minority (24%) of ent-departments in Germany. Denial was justified by technical problems, a lack of cost-benefit and small number of patients in descending order. A significant reduction of intervention time (61.0 ± 32.7 min to 43.2 ± 33.6 min, p=0.013) and less frequent aborted operations were noted after comparison of the first vs. the second half amount of interventions as indicators of a learning curve. Complications were not found to be significantly raised in the first half of interventions. CONCLUSION: The fact that sialendoscopy is provided in only a minority of ent-departments will in the future most likely be overcome by technical improvements. A learning curve has to be anticipated.

[Postoperative pain assessment after middle ear surgery]. / Postoperativer Schmerz nach Mittelohrchirurgie.

BACKGROUND: The purpose of this work was to assess postoperative pain management after middle ear surgery. MATERIALS AND METHODS: In a prospective clinical study, 73 adults were evaluated on the first postoperative day after middle ear surgery using the questionnaire of the Germany-wide project QUIPS (quality improvement in postoperative pain management). The main outcome measures were patients' characteristics, pain parameters, outcome, and pain therapy process parameters. RESULTS: Overall, pain on the first postoperative day was mild. Pain management consisted predominately of premedication with midazolam, remifentanil intraoperatively, metamizole in the recovery room and on the ward. Otherwise healthy patients suffered significantly more from pain than patients with reduced general condition in univariate and multivariate analyses. About half of the patients demanded pain relief on the ward. Despite immediate pain management with nonopioids and/or opioids, these patients had significantly more maximal pain and were less satisfied with overall pain therapy than patients not demanding pain therapy. DISCUSSION: QUIPS is a simple tool to evaluate the quality of in-hospital postoperative pain management following ear surgery. Pain on the first postoperative day seems to be moderate but should be improved for patients demanding more analgetics despite baseline pain therapy on the ward.

[Basics of tumor development and importance of human papilloma virus (HPV) for head and neck cancer]. / Grundlagen der Tumorentstehung und die Bedeutung Humaner Papillomaviren (HPV) bei Kopf-Hals-Karzinomen.

Head and Neck Squamous Cell Carcinoma (HNSCC) are the 6th most common cancers worldwide. While the incidence of larynx-hypopharynx carcinoma decreases, actually an increase in oropharyngeal squamous cell carcinoma (OSCC) is observed. Classical risk factors for HNSCC are smoking and alcohol. Though, it was shown recently for 25 to 60% of OSCC, to be associated with an infection by oncogenic human papilloma virus (HPV). The development of "common" head-neck-tumors is substantially enhanced by an accumulation of genetic changes, which lead to an inactivation of tumor suppressor genes or to an 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. On the contrary, for HPV-induced carcinogenesis, expression of the viral proteins E6 and E7 is most important, since E6 and E7 lead to inactivation of the cellular tumor-suppressor-proteins p53 and Rb. The process of natural transoral infection is not yet clear. However, as a matter of fact peroral HPV-infection is not seldom and in most cases such an infection heals completely and uneventfully. Smoking seems to increases the probability for developing an HPV-associated tumor. The association of HNSCC with HPV can be proven with established methods in clinical diagnostics. In addition to classical prognostic factors, diagnosis of an HPV-association may become important for future therapies. Prognostic relevance of HPV probably surmounts many known risk-factors, for instance regional metastasis. Until now, no other molecular markers are established in clinical routine. Future therapy concepts may vary for the two subgroups of patients, especially patients with HPV-associated OSCC may take advantage of a less aggressive postoperative treatment. Finally an outlook will be given on possible target-aimed therapies, of which so far only antibodies against EGF-receptors are established in clinical practice.