Low PTEN expression is associated with worse overall survival in head and neck squamous cell carcinoma patients treated with chemotherapy and cetuximab.

BACKGROUND: Platinum-based chemotherapy associated with cetuximab is the first-line treatment for inoperable recurrence or metastatic head and neck squamous cell carcinoma (HNSCC). There is no established biomarker for cetuximab efficacy in HNSCC. The PI3K pathway is one of the most frequently altered pathways in HNSCC. Loss of phosphatase and tensin homolog (PTEN) expression occurs in up to 30 % of cases. METHODS: This was a retrospective analysis of data from 61 patients with inoperable recurrence or metastatic HNSCC treated with cetuximab. PTEN, epidermal growth factor receptor and p16 expression were analyzed by immunohistochemistry and tested for association with clinical outcomes. RESULTS: Median overall survival was 11.4 months and progression-free survival was 6.9 months. Low PTEN expression was present in 26.2 % of patients and identified patients with worse prognosis. p16 was positive in only 8.5 % of tumors. CONCLUSIONS: Low PTEN expression in patients treated with cetuximab plus chemotherapy emerged as a prognostic biomarker and should be evaluated for its predictive role for cetuximab efficacy.

[Proton Pump Inhibitor and High-dose Methotrexate: Two Cases Reports]. / Inhibiteurs de pompe à proton et méthotrexate haute dose : à propos de deux cas.

Methotrexate (MTX) is a cytotoxic agent prescribed at high dose in treatment of malignancy. Association of MTX to proton pump inhibitor (PPI) is not recommended if doses are more than 20 mg per weeks and only to take into account for smaller doses. Review relate some cases of delayed elimination of methotrexate in patients taking PPI, which increase risk of toxic event. However, currently there is no status quo on interaction between PPI and MTX according to available data. We report two clinical cases illustrating one more time a toxic event to MTX in presence of PPI. In absence of risk/benefit ratio set correctly, an assessment of appropriateness of PPI prescription before MTX therapy can limit an iatrogenic risk.

Xerostomia after radiotherapy. What matters--mean total dose or dose to each parotid gland?

PURPOSE: Xerostomia is a debilitating side effect of radiotherapy in patients with head and neck cancer. We undertook a prospective study of the effect on xerostomia and outcomes of sparing one or both parotid glands during radiotherapy for patients with squamous cell carcinoma of the head and neck. METHODS AND MATERIALS: Patients with locally advanced squamous cell carcinoma of the head and neck received definitive (70 Gy in 2 Gy fractions) or adjuvant (60-66 Gy in 2 Gy fractions) curative-intent radiotherapy using helical tomotherapy with concurrent chemotherapy if appropriate. Group A received < 26 Gy to the left and right parotids and group B received < 26 Gy to either parotid. RESULTS: The study included 126 patients; 114 (55 in group A and 59 in group B) had follow-up data. There were no statistically significant differences between groups in disease stage. Xerostomia was significantly reduced in group A vs. group B (p = 0.0381). Patients in group A also had significantly less dysphagia. Relapse-free and overall survival were not compromised in group A: 2-year relapse-free survival was 86% vs. 72% in group B (p = 0.361); 2-year overall survival was 88% and 76%, respectively (p = 0.251). CONCLUSION: This analysis suggests that reducing radiotherapy doses to both parotid glands to < 26 Gy can reduce xerostomia and dysphagia significantly without compromising survival. Sparing both parotids while maintaining target volume coverage and clinical outcome should be the treatment goal and reporting radiotherapy doses delivered to the individual parotids should be standard practice.

The evolving role of selective neck dissection for head and neck squamous cell carcinoma.

Neck dissection is an important part of the surgical treatment of head and neck squamous cell carcinoma (HNSCC). The historical concept of neck dissection implied the removal of all lymph node-bearing tissue in the neck, which began in the late nineteenth century. However, more conservative variations of neck dissection have been performed and promoted as well. Anatomic, pathologic, clinical investigations, and prospective studies have demonstrated that the lymphatic dissemination of HNSCC occurs in predictable patterns. Supported by these studies, selective neck dissection (SND), which consists of the removal of select levels of lymph nodes in the neck that have the highest risk of harboring undetected metastases, has become widely accepted in the treatment of the clinically uninvolved neck. More recently, evidence supports using SND in a therapeutic setting in selected cases of HNSCC with limited metastatic disease. Additionally, even more targeted dissections referred to as super-selective neck dissection have been explored for selected patients undergoing elective node dissection for supraglottic cancer and as an adjuvant therapy for salvage of residual lymphadenopathy confined to a single neck level following chemoradiation. In the future, the trend to tailor treatment to individual patients and to limit toxicity and morbidity may further increase the use of SND. The indications have to be guided by further research, in relation with non-surgical treatment options while optimizing oncological effectiveness.

[MIF in head and neck cancer: a new therapeutic target ?]. / Le MIF dans les cancers des voies aéro-digestives supérieures: une nouvelle thérapie ciblée?

Macrophage migration inhibitory factor is a critical proinflammatory cytokine produced by cells of innate and adaptive immune system. MIF plays a key role in cell cycle regulation and in the pathogenesis of many cancers. Recently, MIF has been studied in the upper aerodigestive tract cancer for its involvement in tumor progression, invasion, proliferation and cell motility. In addition, MIF appears to be a mediator in angiogenesis and in the development of metastasis and locoregional lymph node, which are often associated with a poor prognosis. The mechanisms of action responsible for MIF involvement in tumor progression are not completely elucidated. However, the main effects of MIF are mediated by the CD74 receptor. MIF binding to its receptor is responsible for the activation of several signaling pathways (ERK1/2 - MAPK, JAB1 - CSN5, PI3K - Akt), the inhibition of p53 and the stimulation of angiogenic factors including VEGF and IL-8. The overexpression of MIF also causes a reduction of the anti-tumor activity of the immune system. Finally, MIF could be an interesting biomarker in the diagnosis and monitoring of upper aerodigestive tract cancers. In this paper, we assess the state of knowledge of MIF involvement in upper aero-digestive tract cancers and we analyze the therapeutic perspectives.

Functional outcome in patients with advanced head and neck cancer: surgery and reconstruction with free flaps versus primary radiochemotherapy.

The objective was to compare functional outcome in patients with advanced head and neck cancer (HNC) treated with (a) surgical resection and reconstruction with microvascular free flaps (MVFF) followed by radiochemotherapy versus (b) primary radiochemotherapy (RCT) on the basis of the International Classification of Functioning, Disability and Health (ICF) from WHO. This was a cross-sectional, multi-institutional study. The outcome measures included ICF Core Sets for HNC, the EORTC-QLQ, modules c30 + hn35 and the University of Washington-Quality of life Questionnaire (UW-QOL). Analyses included descriptive statistics, ranking exercises, and regression analyses in a cumulative logit model; 27 patients were treated with MVFF and 22 with RCT. Global Quality of life scores suggested a slightly better functional outcome for the surgical approach. The majority of ICF categories (81/93, 87%) did not show a difference in functional outcome between the two treatment approaches. In the remaining 12 ICF categories, n = 3 body structures were more affected in the MVFF group, while n = 3 body functions, and n = 6 activities/participations were more problematic in the RCT group. This included oral swallowing and weight maintenance functions as well as social relationships, acquiring a job, and economic self-sufficiency. In addition, nine contextual environmental factors were more relevant to the RCT group. Both treatment approaches seemed appropriate to advanced HNC from the perspective of functional outcome. The influence of treatment modalities on the social and economic lives of cancer survivors needs to be explored further. In order to guide rehabilitation according to patients' needs, the ICF offers a multidimensional view comprising body structures, body functions, and activities and participation in life.

[Nanomedicine in otorhinolaryngology--future prospects]. / Nanomedizin in der HNO-Heilkunde--ein Ausblick.

BACKGROUND: Nanotechnology becomes more and more important in the world of today. Equally, it does generally in medicine and of course specifically in otorhinolaryngology. Essentially, there are the following fields: Diagnostics, new therapies and agents, drug delivery and medical implants. MATERIAL AND METHODS: An extensive literature research on nanomedicine in otorhinolaryngology was carried out in the standard online medical reference databases "PubMed/Medline" and "Web of Science". Furthermore, we are giving an overview of the work of the Department of Otorhinolaryngology, Head and Neck Surgery, Section of Experimental Oncology and Nanomedicine (SEON), University Hospital Erlangen. RESULTS: A lot of new and innovative studies on nanotechnology in diagnostics and therapy were recovered. Depending on the variety in otorhinolaryngology, there are numerous versatile approaches, according to the different areas. The main part is engaged in drug delivery. CONCLUSIONS: The efforts to exploit the potential of nanotechnology in otorhinolaryngology are multifaceted, innovative and seminal. The best perspective of success is attributed to nanoparticulate drug delivery systems.

[First experiences with ultrasound guided subclavian vein port placement in ENT]. / Erste Erfahrungen in der sonografisch kontrollierten Portanlage der V. subclavia in der HNO.

BACKGROUND: Description of ultrasound guided port placement in the subclavian vein in ENT and discussion of clinical advantages and disadvantages. MATERIALS AND METHODS: 50 Patients underwent ultrasound guided port placement. The catheter tip was placed over subclavian vein or jugular vein between the superior vena cava and the right atrium. Correct placement was confirmed radiographically. All patients received ports prior to chemotherapy and were followed up in our institution. RESULTS: Port placement was successful in all 50 cases. In 2 cases the suclavian vein could not be punctured. The internal and external jugular veins were used as alternatives in one case each. Subcutaneous hematoma was observed in 4 cases, in 2 cases revision was required. In one case a discrete pneumothorax was observed in radiographic imaging. However, further treatment was not required. During the application of chemotherapy one case of catheter infection was observed and one case of catheter thrombosis. Thrombosis followed incorrect use of the catheter in an external department. In both cases the port catheter was removed. In one further case removal of the catheter was performed after completion of the chemotherapy. In total 3 different port catheter systems were used. CONCLUSION: Ultrasound guided placement of port catheters in the subclavian vein is a simple procedure for ENT settings. Complication rates were very low, application of chemotherapy is simple and quality of life for the oncologic patient is increased.

[Current strategies in radiotherapy of head- and neck cancer]. / Aktuelle Fortschritte in der Strahlentherapie von Kopf-Hals-Tumoren.

Over the last 20 years there was a dramatic change in therapeutic options for head and neck tumors mainly due to improvements in surgical and radiotherapeutic techniques and in the increasing use of multimodal therapy. Especially for locally advanced tumors, one can achieve long lasting disease free intervals in a large proportion of patients. The following article will focus on the novel techniques in radiation oncology and combined radiochemotherapy giving an overview without too many technical details.

[Capillary ENT hemangioma].

Capillary hemangioma is considered to be one of the most widespread (frequently occurring) vascular ENT tumours. These neoplasms are usually localized in the nasal cavity, sometimes in the larynx or pharynx, and rarely in the outer or middle ear. The principal method for the treatment of this pathology is surgical intervention. Tumour destruction by laser and radiowave radiation finding wide application for the removal of hemangiomas does not substantially lighten the work of a surgeon; moreover the use of these tools is fraught with a high risk of serious intra- and postoperative complications. In an attempt to avoid or reduce bleeding in the course of surgical intervention we used for the first time hemostatic TachoComb and a Fibro-Vein solution. The mode of using these preparations is described in much detail because it determines to a large degree the efficacy and safety of the treatment. The possibility to combine the surgical intervention with the application of TachoComb and a Fibro-Vein solution is considered; also, the advantages of radiowave-induced destruction of hemangiomas are emphasized.

Dysphagia. Impact on quality of life after radio(chemo)therapy of head and neck cancer.

BACKGROUND: In the past, xerostomia was considered one of the most important determining factors of quality of life (QoL) after radiotherapy (RT) of the head and neck region. In addition, more recent studies have shown that RT-induced dysphagia has an essential influence on the QoL. PATIENTS AND METHODS: Between September 2005 and August 2007, 35 patients with locally advanced squamous cell carcinoma of the head and neck region were included in the prospective study. Patients were treated by IMAT (intensity-modulated arc therapy) or IMRT (intensity-modulated radiotherapy) planned on 3D imaging. A total of 28 patients (80%) received concomitant chemotherapy. The evaluation of QoL (EORTC QLQ-C30, H&N C-35) and toxicities (CTC 2.0) were assessed at the beginning of, during, and after RT as well as up to 12 months after the end of therapy. RESULTS: At the end of therapy, 86% of the patients experienced difficulties in swallowing (62% CTC II-III°). Twelve months after the end of treatment, 15% still suffered from dysphagia CTC II-III°. Concomitant chemotherapy exacerbated the incidence and gravity of dysphagia, resulting in increasing dietary problems. QoL (EORTC) was significantly affected by dysphagia. In particular, the global state of health and QoL were influenced at the end of treatment (p=0.033) and at a later stage (p=0.050). CONCLUSION: The findings of this study suggest that more emphasis should be placed on structured clinical diagnostics, therapy, and rehabilitation of deglutition problems. This means in particular to not only spare the parotids while planning the irradiation, but also to take into consideration the important structures for deglutition, like the retropharyngeal muscles.

IMRT reirradiation with concurrent cetuximab immunotherapy in recurrent head and neck cancer.

PURPOSE: In this retrospective investigation, the outcome and toxicity after reirradiation with concurrent cetuximab immunotherapy of recurrent head and neck cancer (HNC) in patients who had contraindications to platinum-based chemotherapy were analyzed. MATERIALS AND METHODS: Ten patients with locally advanced recurrent HNC were retrospectively evaluated. In 9 cases, histology was squamous cell carcinoma, in one case adenoid cystic carcinoma. External beam radiotherapy was part of the initial treatment in all cases. Reirradiation was carried out using step-and-shoot intensity-modulated radiotherapy (IMRT) with a median dose of 50.4 Gy. Cetuximab was applied as loading dose (400 mg/m(2)) 1 week prior to reirradiation and then weekly concurrently with radiotherapy (250 mg/m(2)). RESULTS: The median overall survival time after initiation of reirradiation was 7 months; the 1-year overall survival (OS) rate was 40%. Local failure was found in 3 patients, resulting in a 1-year local control (LC) rate of 61%. The 1-year locoregional control (LRC) rate was 44%, while the 1-year distant metastasis-free survival (DMFS) was 75%. Acute hematological toxicity was not observed in the group. Severe acute toxicity included one fatal infield arterial bleeding and one flap necrosis. Severe late toxicities were noted in 2 patients: fibrosis of the temporomandibular joint in 1 patient and stenosis of the cervical esophagus in another. CONCLUSIONS: IMRT reirradiation with concurrent cetuximab immunotherapy in recurrent HNC is feasible with acceptable acute toxicity. Further investigations are necessary to determine the clinical role of this therapy concept.

Cystatin C - a fast and reliable biomarker for glomerular filtration rate in head and neck cancer patients.

PURPOSE: Determination of renal function is a prerequisite for planning therapy in cancer patients. Limitations of creatinine as marker for the glomerular filtration rate (GFR) led to the proposal of cystatin C as a more accurate biomarker especially in mild renal insufficiency or in patients with low muscle mass. We compared the accuracy of cystatin C- and creatinine-based equations to estimate GFR in head and neck cancer (HNC) patients receiving platinum-based radiochemotherapy. PATIENTS AND METHODS: The study population consisted of 52 HNC patients (GFR range, 37-105 mL/min/1.73 m(2) complemented by 17 patients with known renal insufficiency (GFR range, 10-60 mL/min/1.73 m(2)). Intraclass correlation coefficients were calculated between the reference method (51)Cr-EDTA clearance and estimated GFR by creatinine clearance and equations based on creatinine (Cockroft-Gault, modification of diet in renal disease (MDRD), Wright) or cystatin C (Larsson, Dade-Behring, Hoek). In addition, sensitivity and specificity to discriminate GFR > 60 mL/min/1.73 m(2) were evaluated by receiver operating characteristic curve (ROC). RESULTS: The highest correlation coefficients were found for the cystatin C-based estimates in comparison with creatinine-based estimates or creatinine clearance, even though Bland-Altman plots revealed GFR overestimation for all equations tested. The cystatin C-based Hoek formula exhibited the highest overall precision and accuracy. GFR of < 60 mL/min/1.73 m(2) was assumed as a cut-off for chemotherapy. ROC analyses revealed the highest AUC to predict a GFR > 60 mL/min/1.73 m(2) for the creatinine-based Wright formula, closely followed by the MDRD formula and cystatin C-based equations of Larsson, Dade-Behring, and Hoek. CONCLUSION: Cystatin C-based GFR estimates showed the overall strongest correlation to the reference method. Thus, we recommend cystatin C for GFR estimation in HNC patients as an alternative method to the estimated creatinine clearance in clinical practice.

Concomitant weekly cisplatin and radiotherapy for head and neck cancer.

OBJECTIVE: The most common chemoradiotherapy regimen is high-dose (100 mg/m(2)) three-weekly cisplatin with concomitant radiotherapy; however, this protocol is associated with acute and late toxicities. Here, we reviewed the dose intensity and toxicity for concomitant weekly cisplatin and radiotherapy in patients with head and neck cancer. METHODS: Fifty-three patients with untreated head and neck cancer were enrolled and evaluated at our institution from April 2006 to April 2010. Weekly cisplatin (40 mg/m(2)) was given on weeks 1, 2, 3, 5, 6 and 7 with radiotherapy, which comprised a standard dose of 70 Gy delivered in 35 daily fractions over 7 weeks. RESULTS: Fifty-one patients (96.2%) received the full dose of radiotherapy, while the course was disrupted by adverse events in two. Over the course of the chemotherapy, 31 patients (58.5%) received more than 200 mg/m(2) cisplatin. The toxicity was manageable in all except one patient, who died of sepsis after completing treatment. The 2-year overall survival rate and local progression-free rate for all patients were 93.7% and 88.0%, respectively. The primary site showed a complete response in 52 patients (98.1%) and a partial response in 1 patient (1.9%). The primary disease was well controlled by chemoradiotherapy in 47 patients (88.7%). CONCLUSIONS: Weekly cisplatin could be easier to manage than three-weekly cisplatin, because patients can be monitored more regularly for toxicity allowing the schedule to be altered if required. This regimen appears to be a suitable alternative to three-weekly high-dose cisplatin with concomitant radiotherapy.

[Treatment related swallowing dysfunction and the potentialities of IMRT]. / Schluckstörungen nach Kopf-Hals-Tumortherapie und die Möglichkeiten der IMRT.

Altered fractionated radiotherapy and concurrent chemoradiation could improve local control and survival for patients with locally advanced head and neck cancer. However, intensified treatment seems to increase late toxicity. Late swallowing dysfunction is common and has a large impact on quality of life and can get life-threatening character. Recent studies could show interrelations between the radiation dose to certain anatomical structures involved in the swallowing process and the risk of swallowing dysfunction. Important structures seem to be the pharyngeal constrictors and the supraglottic and glottic larynx. Further prospective clinical validations using standardized diagnostic protocols for dysphagia are necessary to establish dose constraints to anatomical structures involved in swallowing.

New multileaf collimator with a leaf width of 5 mm improves plan quality compared to 10 mm in step-and-shoot IMRT of HNC using integrated boost procedure.

PURPOSE: To investigate whether a new multileaf collimator with a leaf width of 5 mm (MLC-5) over the entire field size of 40 x 40 cm(2) improves plan quality compared to a leaf width of 10 mm (MLC-10) in intensity-modulated radiotherapy (IMRT) with integrated boost for head and neck cancer. PATIENTS AND METHODS: A plan comparison was performed for ten patients with head and neck cancer. For each patient, seven plans were calculated: one plan with MLC-10 and nine beams, four plans with MLC-5 and nine beams (with different intensity levels and two-dimensional median filter sizes [2D-MFS]), and one seven-beam plan with MLC-5 and MLC-10, respectively. Isocenter, beam angles and planning constraints were not changed. Mean values of common plan parameters over all ten patients were estimated, and plan groups of MLC-5 and MLC-10 with nine and seven beams were compared. RESULTS: The use of MLC-5 led to a significantly higher conformity index and an improvement of the 90% coverage of PTV1 (planning target volume) and PTV2 compared with MLC-10. This was noted in the nine- and seven-beam plans. Within the nine-beam group with MLC-5, a reduction of the segment number by up to 25% at reduced intensity levels and for increased 2D-MFS did not markedly worsen plan quality. Interestingly, a seven-beam IMRT with MLC-5 was inferior to a nine-beam IMRT with MLC-5, but superior to a nine-beam IMRT with MLC-10. CONCLUSION: The use of an MLC-5 has significant advantages over an MLC-10 with respect to target coverage and protection of normal tissues in step-and-shoot IMRT of head and neck cancer.

Treatment of locally advanced carcinomas of head and neck with intensity-modulated radiation therapy (IMRT) in combination with cetuximab and chemotherapy: the REACH protocol.

BACKGROUND: Primary treatment of carcinoma of the oro-/hypopharynx or larynx may consist of combined platinum-containing chemoradiotherapy. In order to improve clinical outcome (i.e. local control/overall survival), combined therapy is intensified by the addition of the EGFR inhibitor cetuximab (Erbitux®). Radiation therapy (RT) is carried out as intensity-modulated RT (IMRT) to avoid higher grade acute and late toxicity by sparing of surrounding normal tissues. METHODS/DESIGN: The REACH study is a prospective phase II study combining chemoradiotherapy with carboplatin/5-Fluorouracil (5-FU) and the monoclonal epidermal growth factor-receptor (EGFR) antibody cetuximab (Erbitux®) as intensity-modulated radiation therapy in patients with locally advanced squamous-cell carcinomas of oropharynx, hypopharynx or larynx.Patients receive weekly chemotherapy infusions in the 1st and 5th week of RT. Additionally, cetuximab is administered weekly throughout the treatment course. IMRT is delivered as in a classical concomitant boost concept (bid from fraction 16) to a total dose of 69,9 Gy. DISCUSSION: Primary endpoint of the trial is local-regional control (LRC). Disease-free survival, progression-free survival, overall survival, toxicity, proteomic and genomic analyses are secondary endpoints. The aim is to explore the efficacy as well as the safety and feasibility of this combined radioimmunchemotherapy in order to improve the outcome of patients with advanced head and neck cancer. TRIAL REGISTRATION: ISRCTN87356938.

Role of narrow-band imaging and high-definition television in the surveillance of head and neck squamous cell cancer after chemo- and/or radiotherapy.

Narrow-band imaging (NBI) is an endoscopic technique enhancing mucosal vasculature and better identifying superficial carcinomas due to their neo-angiogenic pattern. NBI accuracy is increased by combination with a high-definition television (HDTV) camera. The aim of this report was to evaluate the diagnostic improvement of NBI +/- HDTV in the evaluation of head and neck squamous cell cancer (HNSCC) previously treated by chemo-radiotherapy (CHT-RT) or RT. A total of 390 patients affected by HNSCC were prospectively evaluated by NBI and white light (WL) endoscopy +/- HDTV between April 2007 and April 2009 at a single academic institution. Among them, we focused on 59 (15%) patients who received CHT-RT or RT as part of their treatment. Of 59 patients, 13 (22%) showed adjunctive preoperative NBI findings when compared to the standard WL examination. These findings were always confirmed by intraoperative HDTV NBI, while only eight (62%) were visible with HDTV WL. Of 13 lesions, 12 received histopathologic confirmation (from carcinoma in situ to invasive carcinoma). The sensitivity of flexible NBI, HDTV WL, and HDTV NBI was 100, 66 and 100%, respectively. The specificity was 98, 100, and 98%. The positive predictive value was 92, 100, and 92%. The negative predictive value was 100, 94, and 100%. The accuracy was 98, 91, and 98%. NBI +/- HDTV after CHT-RT or RT was of value in detecting tumor persistence (n = 2), early recurrences (n = 6), and metachronous tumors (n = 4). By contrast, only 1 of 59 (2%) patients was found to be false positive.