Neuroendocrine neoplasms of the middle ear: Unpredictable tumor behavior and tendency for recurrence.

BACKGROUND: Middle ear adenomatous neuroendocrine tumors (MEANTs) are rare temporal bone tumors. This study evaluates its clinical behavior and therapy outcome. METHOD: Retrospective case review in a tertiary referral center evaluating histopathology, immunohistochemistry, treatment, and outcome. RESULTS: Nine patients were diagnosed with MEANT. One patient presented with locally invasive tumor and underwent extensive en-bloc tumor resection with adjuvant radiotherapy. Seven of eight patients with locally non-aggressive tumor confined to the tympanomastoid space underwent tumor resection. Two patients were disease-free, five presented recurrence, even after apparent successful surgery. All tumors showed neuroendocrine features. Histopathology and immunohistochemistry did not yield prognostic tumor characteristics. CONCLUSION: MEANTs are rare tumors with uncertain biological behavior and subsequent unpredictable clinical course. The preferred treatment is complete surgical tumor resection. They have a high tendency for recurrence, irrespective of negative intermediary surgery. As of yet, there are no prognostic biomarkers, including histopathology and immunohistochemistry.

The QUANTEC criteria for parotid gland dose and their efficacy to prevent moderate to severe patient-rated xerostomia.

BACKGROUND: Recently, the Quantitative Analysis of Normal Tissue Effect in the Clinic (QUANTEC) Group defined dose-volume constraints for the parotid glands to avoid severe xerostomia. The aim of this study was to determine if application of these QUANTEC criteria also protected against moderate-to-severe patient-rated xerostomia. MATERIAL AND METHODS: The study population consisted of 307 head and neck cancer patients treated with primary (chemo)radiotherapy, either with 3D-CRT (56%) or with IMRT (44%). All patients participated in a standard follow-up program in which radiation-induced toxicity and quality of life were prospectively assessed. Patients who met the QUANTEC criteria were classified as low risk and otherwise as high risk. RESULTS: In total, 41% of the patients (treated with 3D-CRT and IMRT) were classified as low risk patients. In the group treated with 3D-CRT and IMRT, it was possible to meet the QUANTEC criteria in 47% and 32% of the patients, respectively. Sparing the parotid glands with IMRT was considerably more difficult in patients with lymph node metastases and in patients with nasopharyngeal and oropharyngeal tumours. Low risk patients reported significantly less moderate-to-severe xerostomia than high risk patients. However, the predicted risk of elderly patients and patients with pre-existing minor patient-rated xerostomia at baseline was > 20%, even when the QUANTEC criteria were met. CONCLUSIONS: Significantly lower rates of radiation-induced patient-rated xerostomia were found among low risk patients treated according to the QUANTEC criteria, but these criteria do not completely protect against xerostomia. Particularly in elderly patients and patients already suffering from minor xerostomia at baseline, the QUANTEC criteria do not sufficiently protect against persistent, moderate-to-severe patient-rated xerostomia.

NTCP models for patient-rated xerostomia and sticky saliva after treatment with intensity modulated radiotherapy for head and neck cancer: the role of dosimetric and clinical factors.

PURPOSE: The purpose of this multicentre prospective study was to develop multivariable logistic regression models to make valid predictions about the risk of moderate-to-severe patient-rated xerostomia (XER(M6)) and sticky saliva 6 months (STIC(M6)) after primary treatment with intensity modulated radiotherapy (IMRT) with or without chemotherapy for head and neck cancer (HNC). METHODS AND MATERIALS: The study population was composed of 178 consecutive HNC patients treated with IMRT. All patients were included in a standard follow up programme in which acute and late side effects and quality of life were prospectively assessed, prior to, during and after treatment. The primary endpoints were XER(M6) and STIC(M6) as assessed by the EORTC QLQ-H&N35 after completing IMRT. Organs at risk (OARs) potentially involved in salivary function were delineated on planning-CT, including the parotid, submandibular and sublingual glands and the minor glands in the soft palate, cheeks and lips. Patients with moderate-to-severe xerostomia or sticky saliva, respectively, at baseline were excluded. The optimal number of variables for a multivariate logistic regression model was determined using a bootstrapping method. RESULTS: Eventually, 51.6% of the cases suffered from XER(M6). The multivariate analysis showed that the mean contralateral parotid gland dose and baseline xerostomia (none vs. a bit) were the most important predictors for XER(M6). For the multivariate NTCP model, the area under the receiver operating curve (AUC) was 0.68 (95% CI 0.60-0.76) and the discrimination slope was 0.10, respectively. Calibration was good with a calibration slope of 1.0. At 6 months after IMRT, 35.6% of the cases reported STIC(M6). The mean contralateral submandibular gland dose, the mean sublingual dose and the mean dose to the minor salivary glands located in the soft palate were most predictive for STIC(M6). For this model, the AUC was 0.70 (95% CI 0.61-0.78) and the discrimination slope was 0.12. Calibration was good with a calibration slope of 1.0. CONCLUSIONS: The multivariable NTCP models presented in this paper can be used to predict patient-rated xerostomia and sticky saliva. The dose volume parameters included in the models can be used to further optimise IMRT treatment.

Impact of late treatment-related toxicity on quality of life among patients with head and neck cancer treated with radiotherapy.

PURPOSE: To investigate the impact of treatment-related toxicity on health-related quality of life (HRQoL) among patients with head and neck squamous cell carcinoma treated with radiotherapy either alone or in combination with chemotherapy or surgery. PATIENTS AND METHODS: The study sample was composed of 425 disease-free patients. Toxicity was scored according to the European Organisation for Research and Treatment of Cancer (EORTC)/Radiation Therapy Oncology Group (RTOG) late radiation-induced morbidity scoring system. HRQoL was assessed using the EORTC Quality of Life Questionnaire C30. These assessments took place at 6, 12, 18, and 24 months after completion of radiotherapy. The analysis was performed using a multivariate analysis of variance. RESULTS: Of the six RTOG scales investigated, two significantly affected self-reported HRQoL, salivary gland (RTOG(xerostomia)) and esophagus/pharynx (RTOG(swallowing)). Although RTOG(xerostomia) was reported most frequently, HRQoL was most affected by RTOG(swallowing), particularly in the first 18 months after completion of radiotherapy. CONCLUSION: Late radiation-induced toxicity, particularly RTOG(swallowing) and RTOG(xerostomia), has a significant impact on the more general dimensions of HRQoL. These findings suggest that the development of new radiation-induced delivery techniques should not only focus on reduction of the dose to the salivary glands, but also on anatomic structures that are involved in swallowing.

External validation of a risk group defined by recursive partitioning analysis in patients with head and neck carcinoma treated with surgery and postoperative radiotherapy.

BACKGROUND: Several clinical trials have proved that concurrent chemoradiotherapy is more efficacious than radiotherapy alone among high-risk patients with head and neck squamous cell carcinoma (HNSCC) who undergo surgery. A risk-group classification defined according to a recursive partitioning analysis (RPA) for these patients has been recently proposed. The objective of the present study was to carry out an external validation of this RPA-derived classification system. METHODS: A retrospective study of 442 HNSCC patients treated with surgery and postoperative radiotherapy was conducted. The external validity of the RPA-derived classification system was assessed, and its ability to stage patients and to predict locoregional control of the disease was compared with the TNM system. RESULTS: The RPA-derived classification system succeeded in obtaining a monotonic prognosis gradient in locoregional control of the disease with increasing stage, and achieved greater differences in survival between stages than the TNM and pTNM classifications. Besides, the RPA method had a better homogeneity of the categories included in each stage, and in the heterogeneity between stages. CONCLUSIONS: The RPA-derived classification system allowed for the clear definition of prognostic groups in surgically treated HNSCC patients, improving the prognostic capacity of the TNM and pTNM classifications. The RPA-derived classification system is a useful tool in the definition of patients who, given a poor prognosis, should be considered candidates to adjuvant chemoradiotherapy.

A phase II study of primary reirradiation in squamous cell carcinoma of head and neck.

BACKGROUND AND PURPOSE: In this prospective study, the effect of a second course of primary radiotherapy on locoregional control, survival and toxicity was investigated, in patients who underwent a second course of high dose irradiation for second primary or locoregional recurrent squamous cell head and neck carcinoma (HNSCC) in a previously irradiated area. PATIENTS AND METHODS: A total of 34 patients with second primary (n=26) or locoregional recurrent (n=8) tumours were treated with a second course of high dose radiotherapy. Patients were selected for re-irradiation in case of inoperable and/or unresectable tumours. In most cases, the target volume for re-irradiation was confined to the gross tumour volume (GTV). No elective radiotherapy was applied in the former high-dose area. A total dose of 46 Gy was applied to elective areas with a boost up to 60 Gy with conventional fractionation. The median follow-up period was 32 months. RESULTS: The locoregional control rate after 2 years was 27%. The 3-year overall survival was 22%. The most frequently reported acute side-effect was acute mucositis resulting in swallowing complaints. Pharyngeal and oesophageal late morbidity was also the most important late side-effect. In general, acute and late radiation-induced morbidity remained within acceptable limits. CONCLUSIONS: In conclusion, primary re-irradiation appears to be feasible in terms of acute and late radiation-induced toxicity. To improve outcome in terms locoregional control and survival, future studies should be focussed on optimising radiation schedules and the addition of concomitant chemotherapy.

Risk-group definition by recursive partitioning analysis of patients with squamous cell head and neck carcinoma treated with surgery and postoperative radiotherapy.

BACKGROUND: The objective of this study was to define different prognostic groups with regard to locoregional control (LRC) derived from recursive partitioning analysis (RPA). METHODS: Eight hundred one patients with squamous cell head and neck carcinoma underwent with primary surgery and received postoperative radiotherapy. For the definition of prognostic groups, the method of classification and regression trees was performed, including a large number of well known prognostic factors. RESULTS: The final model was composed of six prognostic factors for LRC, resulting in seven terminal nodes. RPA Class I (intermediate risk) consisted of 381 patients who had no N3 lymph nodes, free surgical margins (> 5 mm), and no extranodal spread (ENS). RPA Class II (high risk) consisted of 189 patients who had 1 positive lymph node with ENS or had T1, T2, or T4 tumors with close or positive surgical margins. RPA Class III (very high risk) consisted of 231 patients who had a N3 neck, > or = 2 positive lymph nodes with ENS, or a T3 tumor with close or positive surgical margins. The 5-year LRC rate was 88%, 73% and 58%, in RPA Class I, II, and III, respectively (P < 0.0001). The hazard ratio (HR) relative to RPA Class I was 2.3 (95% confidence interval [95%CI], 1.5-3.6) for RPA Class II and 4.2 (95%CI, 2.8-6.1) for RPA Class III. CONCLUSIONS: The RPA classification scheme studied allowed for the clear definition of three prognostic groups with regard to LRC and OS. These groups may be useful in the design of future prospective, randomized studies investigating new treatment modalities.

Cervical necrotizing fasciitis with thoracic extension after total laryngectomy.

Cervical necrotizing fasciitis (CNF) with thoracic extension is rare. It has never been reported in laryngectomized patients. A case of fatal CNF in a laryngectomized patient equipped with a voice prosthesis is presented. Diagnosis and treatment are discussed. CNF with thoracic extension was diagnosed on clinical picture, computed tomography (CT) and biopsies were taken just above the tracheostoma. Antibiotic treatment was started and extensive debridement of the affected tissues performed. A minor extension to the left pleura was considered irresectable. Irradical debridement and the impossibility of administering hyperbaric oxygen therapy caused death within two day after presentation. CNF is a rare disease and to our knowledge, has never been reported after total laryngectomy. This case emphasizes the need for early antibiotic treatment and radical surgical resection of the affected tissues.

Involvement of cell cycle control in bleomycin-induced mutagen sensitivity.

Bleomycin-induced chromosomal instability, generally referred to as mutagen sensitivity, is associated with an increased risk for the development of environmentally related cancer including head and neck squamous cell carcinoma and lung cancer. On average, the cultured lymphocytes of patients with these types of cancer show an increased number of chromatid breaks per cell after bleomycin exposure in the late S or G2 phase of the cell cycle as compared to lymphocytes from control persons. The aim of the present study was to investigate whether cell cycle regulation is involved in mutagen sensitivity. We determined cell cycle arrest after bleomycin-induced DNA damage in 21 lymphoblastoid cell lines that varied in mutagen sensitivity score. An ataxia telangiectasia (AT) cell line was included for comparison. Using a cut-off point of 0.70 breaks per cell, eight cell lines were classified as insensitive and 13 cell lines showed the hypersensitive phenotype. Compared to insensitive cell lines, bleomycin-treated hypersensitive cells remained at a relatively high level of DNA synthesis, as measured by thymidine incorporation, and showed a decreased accumulation of cells in G2 and M phase, as measured by flow cytometry. AT cells showed an extremely high mutagen sensitivity score, a high level of DNA synthesis, and a strong G2 block. In conclusion, mutagen sensitivity is associated with "damage-resistant growth," which is indicative of impaired cell cycle arrest. By which specific pathway(s) this checkpoint defect is explained has yet to be elucidated; however, it is probably distinct from the checkpoint defect in AT cells. Environ. Mol. Mutagen. 40:79-84, 2002.

Wait-and-see policy for the N0 neck in early-stage oral and oropharyngeal squamous cell carcinoma using ultrasonography-guided cytology: is there a role for identification of the sentinel node?

BACKGROUND: Management of the N0 neck in patients with head and neck squamous cell carcinoma (SCC) remains controversial. We describe the outcome of patients who underwent transoral tumor excision and a wait-and-see policy for the neck staged N0 by ultrasonography-guided cytology (USgFNAC). Because selection of lymph nodes for USgFNAC is currently based on size criteria, we investigated the additional value of sentinel node (SN) identification. METHODS: The outcome of 161 patients with T1-T2 oral/oropharyngeal SCC was determined. In a subgroup of 39 patients the SN was identified and aspirated in addition. RESULTS: SN identification and aspiration was possible in 38 of 39 patients but without decreasing the false-negative rate of USgFNAC. During follow-up (12-99 months) 34 of 161 (21%) patients developed lymph node metastases. After therapeutic neck dissection and postoperative radiotherapy, 27 of 34 (79%) could be salvaged (88% regional control). CONCLUSIONS: Wait-and-see seems justified in case of negative USgFNAC. Strict follow-up with USgFNAC is required. SN identification and aspiration is feasible but did not improve lymph node selection.