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Background: Personalized treatment is increasingly required for oropharyngeal squamous cell carcinoma (OPSCC) patients due to emerging new cancer subtypes and treatment options. Outcome prediction model can help identify low or high‐risk patients who may be suitable to receive de‐escalation or intensified treatment approaches. Purpose: To develop a deep learning (DL)‐based model for predicting multiple and associated efficacy endpoints in OPSCC patients based on computed tomography (CT). Methods: Two patient cohorts were used in this study: a development cohort consisting of 524 OPSCC patients (70% for training and 30% for independent testing) and an external test cohort of 396 patients. Pre‐treatment CT‐scans with the gross primary tumor volume contours (GTVt) and clinical parameters were available to predict endpoints, including 2‐year local control (LC), regional control (RC), locoregional control (LRC), distant metastasis‐free survival (DMFS), disease‐specific survival (DSS), overall survival (OS), and disease‐free survival (DFS). We proposed DL outcome prediction models with the multi‐label learning (MLL) strategy that integrates the associations of different endpoints based on clinical factors and CT‐scans. Results: The multi‐label learning models outperformed the models that were developed based on a single endpoint for all endpoints especially with high AUCs ≥ 0.80 for 2‐year RC, DMFS, DSS, OS, and DFS in the internal independent test set and for all endpoints except 2‐year LRC in the external test set. Furthermore, with the models developed, patients could be stratified into high and low‐risk groups that were significantly different for all endpoints in the internal test set and for all endpoints except DMFS in the external test set. Conclusion: MLL models demonstrated better discriminative ability for all 2‐year efficacy endpoints than single outcome models in the internal test and for all endpoints except LRC in the external set. [ABSTRACT FROM AUTHOR]

Purpose: Treatment decision-making in advanced-stage laryngeal squamous cell carcinoma (LSCC) is difficult due to the high recurrence rates and the desire to preserve laryngeal functions. New predictive markers for radiosensitivity are needed to facilitate treatment choices. In early stage glottic LSCC treated with primary radiotherapy, expression of hypoxia (HIF-1α and CA-IX) and proliferation (Ki-67) tumour markers showed prognostic value for local control. The objective of this study is to examine the prognostic value of tumour markers for hypoxia and proliferation on locoregional recurrent disease and disease-specific mortality in a well-defined cohort of patients with locally advanced LSCC treated with primary, curatively intended radiotherapy. Methods: In pre-treatment biopsy tissues from a homogeneous cohort of 61 patients with advanced stage (T3–T4, M0) LSCC primarily treated with radiotherapy, expression of HIF-1α, CA-IX and Ki-67 was evaluated with immunohistochemistry. Demographic data (age and sex) and clinical data (T- and N-status) were retrospectively collected from the medical records. Cox regression analysis was performed to assess the relation between marker expression, demographic and clinical data, and locoregional recurrence and disease-specific mortality. Results: Patients with high expression of HIF-1α developed significantly more often a locoregional recurrence (39%) compared to patients with a low expression (21%) (p = 0.002). The expression of CA-IX and Ki-67 showed no association with locoregional recurrent disease. HIF-1α, CA-IX and Ki-67 were not significantly related to disease-specific mortality. Clinical N-status was an independent predictor of recurrent disease (p < 0.001) and disease-specific mortality (p = 0.003). Age, sex and T-status were not related to locoregional recurrent disease or disease-specific mortality. Conclusion: HIF-1α overexpression and the presence of regional lymph node metastases at diagnosis were independent predictors of locoregional recurrent disease after primary treatment with curatively intended radiotherapy in patients with locally advanced LSCC. [ABSTRACT FROM AUTHOR]

Cancers of the head and neck region often present with nodal involvement. There is a long‐standing convention within the community of head and neck radiation oncology to irradiate both sides of the neck electively in almost all cases to include both macroscopic and microscopic disease extension (so called elective nodal volume). International guidelines for the selection and delineation of the elective lymph nodes were published in the early 2000s and were updated recently. However, diagnostic imaging techniques have improved the accuracy and reliability of nodal staging and as a result, small metastases that used to remain undetected and were thus in the past included in the elective nodal volume, will now be included in high‐dose volumes. Furthermore, the elective nodal areas are situated close to the parotid glands, the submandibular glands and the swallowing muscles. Therefore, irradiation of a smaller, more selected volume of the elective nodes could reduce treatment‐related toxicity. Several researchers consider the current bilateral elective neck irradiation strategies an overtreatment and show growing interest in a unilateral nodal irradiation in selected patients. The aim of this article is to give an overview of the current evidence about the indications and benefits of unilateral nodal irradiation and the use of SPECT/CT‐guided nodal irradiation in squamous cell carcinomas of the head and neck. [ABSTRACT FROM AUTHOR]

Background: Chemoradiotherapy (CRT) including three cycles of cisplatin is considered the standard of care for locally advanced head and neck squamous cell carcinoma (LA-HNSCC). However, around one-third of the patients cannot complete cisplatin because of toxicity. Carboplatin plus 5-fluorouracil (carbo-5FU) is another accepted treatment option with a different toxicity profile. We compared tolerability and efficacy of concomitant carbo-5FU and cisplatin. Patients and Methods: We conducted a retrospective analysis of LA-HNSCC patients treated with CRT in two Dutch cancer centers between 2007 and 2016. All patients received intensity-modulated radiotherapy. One center routinely administered carboplatin 300–350 mg/m2 at day 1, 22, and 43 followed by 5FU 600 mg/m2/day for 96 h. The other center used cisplatin 100 mg/m2 at day 1, 22, and 43. The primary endpoint of this study was chemotherapy completion rate. Secondary endpoints included overall survival (OS), disease-free survival (DFS), locoregional control (LRC) and distant metastasis–free interval (DMFS), toxicity, and unplanned admissions. Results: In the carbo-5FU cohort (n = 211), 60.2% of the patients completed chemotherapy vs. 76.7% (p < 0.001) of the patients in the cisplatin cohort (n = 223). Univariate analysis showed a higher risk of death in the carbo-5FU cohort [hazard ratio (HR) 1.53, 95% CI, 1.09–2.14, p = 0.01] with a 3-year OS of 65.4 vs. 76.5% for cisplatin. OS was independently associated with T and N stage and p16 status, but not with chemotherapy regimen (HR 1.08, 95% CI, 0.76–1.55, p = 0.65). Three-year DFS was 70.0% for carbo-5FU vs. 78.6% for cisplatin (HR 1.37, 95% CI, 0.93–2.01, p = 0.05). A similar outcome was observed for both LRC (HR 1.27, 95% CI, 0.74–2.09, p = 0.4) and DMFS (HR 1.08, 95% CI 0.62–1.90, p = 0.77). The risk of discontinuation for chemotherapy-associated toxicity was higher in the carbo-5FU cohort than in the cisplatin cohort (relative risk = 1.69). Conclusion: LA-HNSCC patients treated with concomitant carbo-5FU completed chemotherapy less frequently than patients treated with cisplatin. Treatment regimen was not an independent prognostic factor for OS. [ABSTRACT FROM AUTHOR]

• Radiomic features improve individual lymph node failure prediction. • Clinical parameters, together with radiomic features showed the best performance in predicting nodal failure risk. • Individual nodal failure prediction could lead to treatment individualization in HNC patients. To develop and validate a pre-treatment radiomics-based prediction model to identify pathological lymph nodes (pLNs) at risk of failures after definitive radiotherapy in head and neck squamous cell carcinoma patients. Training and validation cohorts consisted of 165 patients with 558 pLNs and 112 patients with 467 pLNs, respectively. All patients were primarily treated with definitive radiotherapy, with or without systemic treatment. The endpoint was the cumulative incidence of nodal failure. For each pLN, 82 pre-treatment CT radiomic features and 7 clinical features were included in the Cox proportional-hazard analysis. There were 68 and 23 nodal failures in the training and validation cohorts, respectively. Multivariable analysis revealed three clinical features (T-stage, gender and WHO Performance-status) and two radiomic features (Least-axis-length representing nodal size and gray level co-occurrence matrix based - Correlation representing nodal heterogeneity) as independent prognostic factors. The model showed good discrimination with a c-index of 0.80 (0.69–0.91) in the validation cohort, significantly better than models based on clinical features (p < 0.001) or radiomics (p = 0.003) alone. High- and low-risk groups were defined by using thresholds of estimated nodal failure risks at 2-year of 60% and 10%, resulting in positive and negative predictive values of 94.4% and 98.7%, respectively. A pre-treatment prediction model was developed and validated, integrating the quantitative radiomic features of individual lymph nodes with generally used clinical features. Using this prediction model, lymph nodes with a high failure risk can be identified prior to treatment, which might be used to select patients for intensified treatment strategies targeted on individual lymph nodes. [ABSTRACT FROM AUTHOR]

Objectives: Ambiguous results have been reported on the predictive value of the Ki‐67 proliferation index (Ki‐67 PI) regarding local control (LC) and survival after primary radiotherapy (RT) in early‐stage laryngeal squamous cell cancer (LSCC). Small study size, heterogenic inclusion, variations in immunostaining and cut‐off values are attributing factors. Our aim was to elucidate the predictive value of the Ki‐67 PI for LC and disease‐specific survival (DSS) using a well‐defined series of T1‐T2 LSCC, standardised automatic immunostaining and digital image analysis (DIA). Methods: A consecutive and well‐defined cohort of 208 patients with T1‐T2 LSCC treated with primary RT was selected. The Ki‐67 PI was determined using DIA. Mann‐Whitney U‐tests, logistic and Cox regression analyses were performed to assess associations between Ki‐67 PI, clinicopathological variables, LC and DSS. Results: In multivariate Cox regression analysis, poor tumour differentiation (HR 2.20; 95% CI 1.06‐4.59, P =.04) and alcohol use (HR 2.84, 95% CI 1.20‐6.71; P =.02) were independent predictors for LC. Lymph node positivity was an independent predictor for DSS (HR 3.16, 95% CI 1.16‐8.64; P =.03). Ki‐67 PI was not associated with LC (HR 1.59; 95% CI 0.89‐2.81; P =.11) or DSS (HR 0.98; 95% CI 0.57‐1.66; P =.97). In addition, continuous Ki‐67 PI was not associated with LC (HR 2.03; 95% CI 0.37‐11.14, P =.42) or DSS (HR 0.62; 95% CI 0.05‐8.28; P =.72). Conclusion: The Ki‐67 PI was not found to be a predictor for LC or DSS and therefore should not be incorporated in treatment‐related decision‐making for LSCC. [ABSTRACT FROM AUTHOR]

Introduction: Fibroblast growth factor receptor family member proteins (FGFR1-4) have been identified as promising novel therapeutic targets and prognostic markers in a wide spectrum of solid tumors. The present study investigates the expression and prognostic value of four FGFR family member proteins in a large multicenter oral cavity squamous cell carcinoma (OCSCC) and oropharyngeal squamous cell carcinoma (OPSCC) cohort. Methods: Protein expression of FGFR1-4 was determined by immunohistochemistry on tissue microarrays containing 951 formalin-fixed paraffin embedded OCSCC and OPSCC tissues from the University Medical Center Utrecht and University Medical Center Groningen. Protein expression was correlated to overall survival using Cox regression models, and bootstrapping was performed as internal validation. Results: FGFR proteins were highly expressed in 39-64 % of OCSCC and 63-79 % of OPSCC. Seventy-three percent (299/412) of OCSCC and 85 % (305/357) of OPSCC highly co-expressed two or more FGFR family member proteins. FGFR1 protein was more frequently highly expressed in human papillomavirus (HPV)-negative OPSCC than HPV-positive OPSCC (82 vs. 65 %; p = 0.008). Furthermore, protein expression of FGFR family members was not related to overall survival in OCSCC or OPSCC ( p > 0.05). Conclusion: FGFR family members are frequently highly expressed in OCSCC and OPSCC. These FGFR family member proteins are therefore potential targets for novel therapies that are urgently required to improve survival of OCSCC and OPSCC patients. [ABSTRACT FROM AUTHOR]

Background The optimal cumulative dose and timing of cisplatin administration in various concurrent chemoradiotherapy protocols for nonmetastatic head and neck squamous cell carcinoma (HNSCC) has not been determined. Methods The absolute survival benefit at 5 years of concurrent chemoradiotherapy protocols versus radiotherapy alone observed in prospective randomized trials reporting on the use of cisplatin monochemotherapy for nonnasopharyngeal HNSCC was extracted. In the case of nonrandomized studies, the outcome results at 2 years were compared between groups of patients receiving different cumulative cisplatin doses. Results Eleven randomized trials and 7 nonrandomized studies were identified. In 6 definitive radiotherapy phase III trials, a statistically significant association ( p = .027) between cumulative cisplatin dose, independent of the schedule, and overall survival benefit was observed for higher doses. Conclusion Results support the conclusion that the cumulative dose of cisplatin in concurrent chemoradiation protocols for HNSCC has a significant positive correlation with survival. © 2015 Wiley Periodicals, Inc. Head Neck 38: E2151-E2158, 2016 [ABSTRACT FROM AUTHOR]

Background The impact of primary tumor volume (pTV) on local control after definitive radiotherapy (RT) for head and neck squamous cell carcinoma (HNSCC) is unclear. Methods Pertinent literature was reviewed to address the impact of pTV on local control after definitive RT for HNSCC. Results Reproducibility of pTV calculations is probably influenced by interobserver variability and may be reduced by relying on experienced observers. The impact of pTV on local control after definitive RT is probably influenced by primary site. A relatively limited impact of pTV on local control after RT for oropharyngeal squamous cell carcinomas (SCCs) might be attributable to human papillomavirus (HPV) positivity. Conclusion pTV may be a useful parameter to select patients for treatment with definitive RT, particularly for those with laryngeal SCCs. Patients with high-volume primary cancers, in which the probability of local control with a functional larynx is low, are likely better treated with surgery. © 2013 Wiley Periodicals, Inc. Head Neck 36: 1363-1367, 2013 [ABSTRACT FROM AUTHOR]

Post-therapy follow-up for patients with head and neck cancer other than upper aerodigestive tract squamous cell carcinoma should meet several objectives: to detect both local, regional or distant recurrences, to evaluate acute and long-term treatment-related side effects, to guide the rehabilitation process, and to provide psychosocial support when needed. To our knowledge, there are no published reports in the literature dedicated to the follow-up of patients with these tumours. A comprehensive literature search for post-treatment follow-up strategies spanning from 1980 to 2012 was performed on several databases. This review focuses on malignant salivary gland tumors, soft tissue sarcomas, cutaneous squamous cell carcinomas, and sinonasal adenocarcinomas. Given the varying biological behavior and treatment-related factors and based on the literature, different recommendations are made on the follow-up of patients with the above-mentioned tumors. [ABSTRACT FROM AUTHOR]

The management of head and neck squamous cell carcinomas does not end with the completion of ablative therapy. The oncologic objectives of post-treatment follow-up are to detect recurrences and second primary tumors; beyond that, follow-up should evaluate acute and chronic treatment-related side effects, guide the rehabilitation process, alleviate functional loss, manage pain, restore nutritional status and assess psychosocial factors. In this structured review, we address the questions of timing and the tools required to achieve a complete and coherent routine surveillance. Several guidelines and consensus statements recommend clinical examination as the cornerstone of follow-up which should be performed for at least 5 years, although there are no data in favor of any one particular follow-up program, and only low-level evidence suggests an improvement in oncologic outcomes by close follow-up. Baseline imaging (computed tomography and magnetic resonance imaging) should be obtained within 2-6 months after definitive therapy if used for treatment response evaluation. Metabolic response, if indicated, should be assessed preferably after 3 months in patients who undergo curative-intent therapy with (chemo)-radiotherapy. Chest computed tomography is more sensitive than plain radiography, if used in follow-up, but the benefit and cost-effectiveness of routine chest computed tomography has not been demonstrated. There are no current data supporting modifications specific to the surveillance plan of patients with human papillomavirus-associated disease. [ABSTRACT FROM AUTHOR]

Although uncommon, cancer of an unknown primary (CUP) metastatic to cervical lymph nodes poses a range of dilemmas relating to optimal treatment. The ideal resolution would be a properly designed prospective randomized trial, but it is unlikely that this will ever be conducted in this group of patients. Accordingly, knowledge gained from retrospective studies and experience from treating patients with known head and neck primary tumors form the basis of therapeutic strategies in CUP. This review provides a critical appraisal of various treatment approaches described in the literature. Emerging treatment options for CUP with metastases to cervical lymph nodes are discussed in view of recent innovations in the field of head and neck oncology and suitable therapeutic strategies for particular clinical scenarios are presented. For pN1 or cN1 disease without extracapsular extension (ECE), selective neck dissection or radiotherapy offer high rates of regional control. For more advanced neck disease, intensive combined treatment is required, either a combination of neck dissection and radiotherapy, or initial (chemo)radiotherapy followed by neck dissection if a complete response is not recorded on imaging. Each of these approaches seems to be equally effective. Use of extensive bilateral neck/mucosal irradiation must be weighed against toxicity, availability of close follow-up with elective neck imaging and guided fine-needle aspiration biopsy (FNAB) when appropriate, the human papillomavirus (HPV) status of the tumor, and particularly against the distribution pattern (oropharynx in the majority of cases) and the emergence rate of hidden primary lesions (<10% after comprehensive workup). The addition of systemic agents is expected to yield similar improvement in outcome as has been observed for known head and neck primary tumors. Head Neck, 2013 [ABSTRACT FROM AUTHOR]

In an era of advanced diagnostics, metastasis to cervical lymph nodes from an occult primary tumor is a rare clinical entity and accounts for approximately 3% of head and neck malignancies. Histologically, two thirds of cases are squamous cell carcinomas (SCCs), with other tissue types less common in the neck. With modern imaging and tissue examinations, a primary tumor initially undetected on physical examination is revealed in >50% of patients and the site of the index primary can be predicted with a high level of probability. In the present review, the range and limitations of diagnostic procedures are summarized and the optimal diagnostic workup is proposed. Initial preferred diagnostic procedures are a fine-needle aspiration biopsy (FNAB) and imaging. This allows directed surgical biopsy (such as tonsillectomy), based on the preliminary findings, and prevents misinterpretation of postsurgical images. When no primary lesion is suggested after imaging and panendoscopy, and for patients without a history of smoking and alcohol abuse, molecular profiling of an FNAB sample for human papillomavirus (HPV) and/or Epstein-Barr virus (EBV) is important. Head Neck, 2013 [ABSTRACT FROM AUTHOR]

Squamous cell carcinoma of the hypopharynx represents a distinct clinical entity. Most patients present with significant comorbidities and advanced-stage disease. The overall survival is relatively poor because of high rates of regional and distant metastasis at presentation or early in the course of the disease. A multidisciplinary approach is crucial in the overall management of these patients to achieve the best results and maintain or improve functional results. Traditionally, operable hypopharyngeal cancer has been treated by total (occasionally partial) laryngectomy and partial or circumferential pharyngectomy, followed by reconstruction and postoperative radiotherapy in most cases. Efforts to preserve speech and swallowing function in the surgical treatment of hypopharyngeal (and laryngeal) cancer have resulted in a declining use of total laryngopharyngectomy and improved reconstructive efforts, including microvascular free tissue transfer. There are many surgical, as well as nonsurgical, options available for organ and function preservation, which report equally effective tumor control and survival. The selection of appropriate treatment is of crucial importance in the achievement of optimal results for these patients. In this article, several aspects of surgical and nonsurgical approaches in the treatment of hypopharyngeal cancer are discussed. Future studies must be carefully designed within clearly defined populations and use uniform terminology and standardized functional assessment and declare appropriate patient or disease endpoints. These studies should focus on improvement of resultsx, without increasing patient morbidity. In this respect, technical improvements in radiotherapy such as intensity-modulated radiotherapy, advances in supportive care, and incorporation of newer systemic agents such as targeted therapy, are relevant developments. © 2010 Wiley Periodicals, Inc. Head Neck, 2012 [ABSTRACT FROM AUTHOR]

Up-front surgery and postoperative radiotherapy constitute a well-recognized treatment concept for locally or regionally advanced squamous cell carcinoma of the head and neck. This 'treatment package' is further intensified with the concomitant application of chemotherapy during irradiation when high-risk features (ie, microscopically involved resection margins, extracapsular extension of the tumor from neck nodes, the presence of soft tissue deposits) are found on histopathologic examination of a resected specimen. With regard to neck disease, however, the demarcation line between low- and higher-risk clinical situations, which would differ with respect to the need for postoperative radiotherapy, is not clear. In an attempt to define the low-risk characteristics of disease in the neck that do not require adjuvant irradiation, we reviewed the available literature reports for any direct or indirect evidence on the value of postoperative radiotherapy in various clinical scenarios. The number of positive lymph nodes found in a dissected tissue specimen that should be used as a 'cut-off' point for introduction of postoperative radiotherapy was evaluated in the context of both primary tumor characteristics and type of neck dissection. © 2010 Wiley Periodicals, Inc. Head Neck, 2012 [ABSTRACT FROM AUTHOR]

Background Squamous cell carcinoma of the nasal vestibule (SCCNV) is an uncommon malignancy. Our purpose is to define the incidence of simultaneous and delayed regional metastasis in SCCNV according to the available literature. Methods Articles discussing SCCNV and addressing the issue of regional lymph node metastases were reviewed. Conclusion SCCNV is an uncommon form of cancer, possibly originating in the mucocutaneous junction. The incidence of lymph node metastasis is variably reported. The data in the literature do not provide a solid basis for recommendations on elective treatment of the neck. Thorough examination of the neck is recommended, preferably with modern imaging techniques. © 2010 Wiley Periodicals, Inc. Head Neck, 2010 [ABSTRACT FROM AUTHOR]

Evidence-based medicine integrates the best available data in decision making, with the goal of minimizing physicians' and patients' subjectivity. In 2006, the American Society of Clinical Oncology edited clinical practice guidelines for the use of larynx preservation strategies. The objective of this review was to evaluate the current levels of evidence for glottic squamous cell carcinoma. Current guidelines for early stage glottic cancer are based on low-level evidence. Conservation surgery (open or transoral) and radiation therapy are all valid options for T1 and selected T2 lesions. For advanced lesions, surgery and combined chemotherapy and radiation are options. High-level evidence favors combined chemotherapy and radiation therapy or altered fractionation radiation therapy as nonsurgical strategies for organ preservation, compared with radiation therapy alone. The optimal combination of chemotherapy, targeted therapy, and radiation therapy remains to be demonstrated, however, and for high-volume tumors, total laryngectomy may still be warranted. © 2011 Wiley Periodicals, Inc. Head Neck, 2011 [ABSTRACT FROM AUTHOR]

Summary: This review discusses the role of adjuvant treatment after curative surgery for patients with head and neck squamous cell carcinoma (HNSCC). In general, patients with unfavourable prognostic factors have a high-risk of loco-regional recurrence and subsequent worse survival after surgery alone and are therefore considered proper candidates for adjuvant treatment by either postoperative radiotherapy alone or postoperative chemoradiation. Selection of the most optimal adjuvant treatment strategy should be based on the most important prognostic factors. In this review, the different treatment strategies will be discussed in general. More specifically, we will discuss the role of the interval between surgery and radiotherapy, the overall treatment time of radiation, the selection of target volumes for radiation and the value of adding concomitant chemotherapy to postoperative radiation. [Copyright &y& Elsevier]

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. © 2007 Wiley Periodicals, Inc. Head Neck, 2007 [ABSTRACT FROM AUTHOR]

Abstract: Purpose: To evaluate retrospectively the prognostic significance of lymph node parameters assessed on pretreatment magnetic resonance (MR) images for development of distant metastases in patients with head and neck squamous cell carcinomas. Materials and methods: Pretreatment MR images of 311 patients were retrospectively reviewed for the presence of lymph nodes at specific neck node levels as well as the size and the presence of a number of lymph node characteristics including extranodal spread, central necrosis and number and volume of ipsi- and contralateral nodes. Of these patients, 174 (56%) had MRI-positive nodes (defined as nodes with minimum axial diameter >8 and >4mm for paratracheal level and retropharyngeal nodes). Results: The 2-year distant-metastasis free survival rate (DMFSR) for patients without MRI-positive nodes was 94% compared to 75% for those patients with MRI-positive nodes. In patients with MRI-positive nodes, results of multivariate analysis with the Cox regression model yielded statistical significance for presence of extranodal spread (ENS), detected on MRI, as the only independent prognostic factor associated with the 2-year DMFSR (p =0.002). Based on the analysis, three risk groups regarding the DMFSR could be identified. Low-risk group (DMFSR:94%) consisted of patients without MRI-positive nodes. Intermediate-risk group (DMFSR:81%) consisted of patients with MRI-positive nodes without ENS. High-risk group (DMFSR:59%) consisted of patients with MRI-positive nodes and ENS as shown on MRI (p <0.0001). Statistical separation for different tumor locations showed MRI-determined ENS (larynx: p =0.05; oropharynx: p =0.04; oral cavity: p <0.001), lowjugular/posterior triangle nodes (oropharynx: p =0.02), paratracheal nodes (larynx: p =0.03), and contralateral node volume >5cm3 (larynx: p =0.03; oral cavity: p =0.02) to be significant predictors with regard to DMFSR. Conclusion: Especially patients with on MRI demonstrating extranodal spread and with suspicious nodes at lowjugular/posterior triangle (oropharyngeal cancer) or paratracheal level (laryngeal cancer), or with contralateral enlarged nodes (laryngeal and oral cavity cancer) are at high risk for developing distant metastases and this subset of patients might benefit from supplementary imaging screening (CT-chest, PET-scan). [Copyright &y& Elsevier]

Squamous cell carcinoma may involve the anterior commissure (AC) area of the laryngeal glottis, and can be grouped morphologically into four groups; (1) tumor confined to the AC, (2) tumor involving one cord and the AC, (3) tumor involving the AC and a portion of both vocal cords, and (4) tumor involving a greater part of one cord and crossing over to involve a variable length of the other cord. Some of these patients when evaluated by imaging, either CT and/or MRI, may demonstrate thyroid cartilage erosion or involvement, thereby upstaging a T1a, T1b into a T3 or a T4 glottic cancer. The majority of patients treated by radiotherapy have only been staged clinically, and hence a failure or recurrence rate of 15%. In patients treated surgically by endoscopic or external surgery, the local recurrence rates are similar at 15%. Therefore, future reporting of patients treated with AC involvement should be staged radiologically, to include CT or MRI, and documentation of the treatment results be reported in subgroups, according to whether there is no cartilage involvement, inner-table cartilage erosion, or through-and-through cartilage invasion. Should endoscopic cordectomy be used, then the type of surgery performed should be based on the classification as suggested by the European Laryngological Society. The use of the above recommendations would allow for more meaningful results to be reported and for cause specific analysis of failure of treatment techniques applied. [ABSTRACT FROM AUTHOR]

Abstract: 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 46Gy was applied to elective areas with a boost up to 60Gy 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. [Copyright &y& Elsevier]

Purpose: To evaluate the results of primary radiotherapy (RT) for squamous cell carcinoma of the nasal vestibule.Methods and materials: A total of 56 patients with Stage T1 and T2 tumors (Wang classification) were treated with external beam RT (EBRT) with or without a boost using endocavitary brachytherapy. Of these, 32 were treated with EBRT and an additional boost with intermediate-dose-rate brachytherapy, 15 with EBRT and a boost with high-dose-rate brachytherapy, and 9 with EBRT alone.Results: The local control rate at 2 years was 80%. Most cases could be successfully salvaged with surgery, resulting in an ultimate local control rate of 95%. No statistically significant differences were noted among the different treatment approaches. Of the 56 patients, 12% developed lymph node metastases.Conclusion: Primary RT is an adequate treatment for Stage T1 and T2 squamous cell carcinoma of the nasal vestibule with excellent cosmetic results. The radiation technique used depends on the primary tumor extension and the experience of the treating radiation oncologist. In the case of N0 disease, elective treatment of the regional lymph nodes is not recommended. [Copyright &y& Elsevier]

Patients with squamous cell carcinoma of the oropharynx are generally treated with (chemo) radiation. Patients with oropharyngeal cancer have better survival than patients with squamous cell carcinoma of other head and neck subsites, especially when related to human papillomavirus. However, radiotherapy results in a substantial percentage of survivors suffering from significant treatment-related side-effects. Late radiation-induced side-effects are mostly irreversible and may even be progressive, and particularly xerostomia and dysphagia affect health-related quality of life. As the risk of radiation-induced side-effects highly depends on dose to healthy normal tissues, prevention of radiation-induced xerostomia and dysphagia and subsequent improvement of health-relatedquality of life can be obtained by applying proton therapy, which offers the opportunity to reduce the dose to both the salivary glands and anatomic structures involved in swallowing. This review describes the results of the first cohort studies demonstrating that proton therapy results in lower dose levels in multiple organs at risk, which translates into reduced acute toxicity (i.e. up to 3 months after radiotherapy), while preserving tumour control. Next to reducing mucositis, tube feeding, xerostomia and distortion of the sense of taste, protons can improve general well-being by decreasing fatigue and nausea. Proton therapy results in decreased rates of tube feeding dependency and severe weight loss up to 1 year after radiotherapy, and may decrease the risk of radionecrosis of the mandible. Also, the model-based approach for selecting patients for proton therapy in the Netherlands is described in this review and future perspectives are discussed. [ABSTRACT FROM AUTHOR]

• Older patients may experience delayed treatment and adverse events due to frailty. • Treatment delay can result in tumor progression and inferior outcome. • Delay was a significant predictor for recurrence in surgically treated patients. • Delayed treatment initiation was not associated with short-term adverse events. As a result of rapid tumor growth in head and neck squamous cell carcinoma (HNSCC), delay in treatment initiation can result in tumor progression and inferior outcome. Especially older and frail patients are prone to develop adverse events. The aim of this study was to assess the effect of delay on development of adverse events and recurrence in older HNSCC patients. This cohort study with prospectively collected data included all newly diagnosed, curatively treated HNSCC patients (≥60 years) between 2015 and 2017. Time-to-treatment interval and geriatric domains were assessed. Adverse events were defined as postoperative complications (Clavien-Dindo classification) and acute radiation-induced toxicity (Common Terminology Criteria of Adverse Events). Multivariable regression models were performed, using adverse events and recurrence as outcome variables. A total of 245 patients were included. Median time-to-treatment was 26 days for surgery patients and 40 days for radiotherapy patients (p < 0.001). Delayed treatment initiation was not associated with postoperative complications or acute radiation-induced toxicity. Delay was significantly associated with recurrence risk within two years after treatment initiation in a model adjusted for stage and tumor location in patients treated with initial surgery (HR:4.1, 95%CI:1.2–14.0, p = 0.024). For patients treated with radiotherapy, delay was not significantly associated with recurrence risk. Delayed treatment initiation was independently associated with increased recurrence risk in patients treated with initial surgery. Delay was not associated with short-term adverse events. These findings highlight the importance of establishing fast-track care pathways to minimize delays and improve especially long-term outcome. [ABSTRACT FROM AUTHOR]

Summary: The aim of the study was to investigate the possible impact of comorbidity on survival of patients undergoing composite resection and microvascular reconstruction for oral/oropharyngeal cancer. Patient, tumour and treatment data were recorded. Comorbidity was graded by the Adult Comorbidity Evaluation (ACE-27) test. Survival and statistics were calculated. Comorbidity score ACE-27 grade ⩾2 was present in 47% of patients, for ACE-27 grade 3 this was 13%. The median follow-up was 50 (3–87) months. Thirty-eight patients died, 32 developed a recurrence. Comorbidity score ACE-27 grade 3 turned out to be a clear predictor for overall survival (p &#60;0.05). For ACE-27 grade 3 (n =13) 5-years survival was 29%, for ACE-27 grade ⩽2 (n =87) this was 64%. No multivariate influences on the effects of comorbidity were found. Improved knowledge of the effect of comorbidity on survival may lead to better patient selection and counselling for major surgery and microvascular reconstruction. [Copyright &y& Elsevier]

• The season of radiotherapy delivery (fall/winter versus spring/summer) was queried. • Season of treatment does not influence either PFS or LRF in head and neck cancer. • No impact was seen even in Northern countries where differences are expected to be greater. A single institution retrospective study suggested that head and neck squamous cell cancer (HNSCC) patients receiving radiotherapy (RT) during "dark" season (fall/winter) may have better outcomes than those treated during "light" season (spring/summer), possibly secondary to seasonal variations in cell cycle progression. We investigated the impact of season of RT in two large, multi-institutional, prospective datasets of randomized trials. Individual patient data from the MACH-NC and MARCH meta-analyses were analyzed. Dark season was defined as mid-radiotherapy date during fall or winter and light the reverse, using equinoxes to separate the two periods. Primary endpoint was progression-free survival (PFS) and secondary endpoint was locoregional failure (LRF). The effect of season was estimated with a Cox model stratified by trial and adjusted on sex, tumor site, stage, and treatment. Planned sensitivity analyses were performed on patients treated around solstices, who received "complete radiotherapy", patients treated with concomitant radio-chemotherapy and on trials performed in Northern countries. 11320 patients from 33 trials of MARCH and 6276 patients from 29 trials of MACH-NC were included. RT during dark season had no benefit on PFS in the MARCH (hazard ratio[HR]: 1.01 [95%CI 0.97;1.05],p=0.72) or MACH-NC dataset (HR:1.00 [95%CI 0.94;1.06],p=1.0. No difference in LRF was observed in the MARCH (HR:1.00 [95%CI 0.94;1.06,p=0.95) or MACH-NC dataset (HR:0.99 [95%CI 0.91; 1.07],p=0.77). Sensitivity analyses showed similar results. Season of RT had no impact on PFS or LRF in two large databases of HNSCC. [ABSTRACT FROM AUTHOR]

Purpose: To externally validate the previously published pre-treatment prediction models for lymph nodes failure after definitive radiotherapy in head and neck squamous cell carcinoma (HNSCC) patients.Materials and Methods: This external validation cohort consisted of 143 node positive HNSCC patients treated between July 2007 and June 2016 by curative radiotherapy with or without either cisplatin or cetuximab. Imaging and pathology reports during follow-up were analyzed to indicate persisting or recurring nodes. The previously established clinical, radiomic and combined models were validated on this cohort by assessing the concordance index (c-index) and model calibration.Results: Overall 113 patients with 374 pLNs were suitable for final analysis. There were 20 (5.3%) nodal failures from 15 patients after a median follow-up of 36.1 months. Baseline characteristics and radiomic features were comparable to the training cohort. Both the radiomic model (Least-axis-length of lymph node (LALLN) and correlation of gray level co-occurrence matrix (Corre-GLCM)) and the combined model (T stage, gender, WHO performance score, LALLN and Corre-GLCM) showed good agreement between predicted and observed nodal control probabilities. The radiomic (c-index: 0.71; 95% confidence interval (CI): 0.59-0.84) and combined (c-index: 0.71; 95% CI: 0.59-0.82) models performed better than the clinical model (c-index: 0.57; 95% CI: 0.47-0.68) on this cohort, with a significant difference between the combined and clinical models (z-score test: p = 0.005).Conclusion: The combined model including clinical and radiomic features was externally validated and proved useful to predict nodal failures and could be helpful to guide treatment choices before and after curative radiation treatment for node positive HNSCC patients. [ABSTRACT FROM AUTHOR]

• RCT compared 2 palliative radiation schemes in HNSCC in terms of efficacy & toxicity. • 50 Gy/16 fr. vs. 36 Gy/6 fr. did not show significantly better oncologic outcomes. • 50 Gy/16 fr. was associated with more acute grade 3 mucositis. • No meaningful differences in quality of life scores were found. • Trial closed early because of slow accrual. Conclusion need be interpreted cautionly. No randomized controlled trials (RCT) have yet identified the optimal palliative radiotherapy scheme in patients with incurable head and neck squamous cell carcinoma (HNSCC). We conducted RCT to compare two radiation schemes in terms of efficacy, toxicity and quality-of-life (QoL). Patients with locally-advanced HNSCC who were ineligible for radical treatment and those with limited metastatic disease were randomly assigned in 1:1 ratio to arm 1 (36 Gy in 6 fractions, twice a week) or arm 2 (50 Gy in 16 fractions, four times a week). The trial was discontinued early because of slow accrual (34 patients enrolled). Objective response rates were 38.9% and 57.1% for arm 1 and 2 respectively (p = 0.476). The median time to loco-regional progression was not reached. The loco-regional control rates at 1 year was 57.4% and 69.3% in arm 1 and 2 (p = 0.450, HR = 0.56, 95%CI 0.12–2.58). One-year overall survival was 33.3% and 57.1%, with medians of 35.4 and 59.5 weeks, respectively (p = 0.215, HR = 0.55, 95%CI 0.21–1.43). Acute grade ≥3 toxicity was lower in arm 1 (16.7% versus 57.1%, p = 0.027), with the largest difference in grade 3 mucositis (5.6% versus 42.9%, p = 0.027). However, no significant deterioration in any of the patient-reported QoL-scales was found. No solid conclusion could be made on this incomplete study which is closed early. Long-course radiotherapy did not show significantly better oncologic outcomes, but was associated with more acute grade 3 mucositis. No meaningful differences in QoL-scores were found. Therefore, the shorter schedule might be carefully advocated. However, this recommendation should be interpreted with great caution because of the inadequate statistical power. [ABSTRACT FROM AUTHOR]

• Sarcopenia is relevant for head and neck cancer patients treated with radiotherapy. • Sarcopenia is an independent adverse prognostic factor for survival outcomes. • For oropharyngeal cancer, survival is more defined by p16 status than by sarcopenia. • Sarcopenia is associated with late radiation-induced toxicities. Sarcopenia is emerging as an adverse prognostic factor for survival and complication risk in cancer patients. This study aims to determine the impact of sarcopenia on survival and late toxicity in a large cohort of head and neck squamous cell carcinoma (HNSCC) patients treated with definitive (chemo)radiotherapy ((C)RT). HNSCC patients treated with definitive (C)RT from January 2007 to June 2016 were included. Sarcopenia was assessed from radiation planning computed tomography (CT) scans using skeletal muscles at level C3. The impact of sarcopenia on overall survival (OS) and disease-free survival (DFS) was evaluated using the Kaplan–Meier method. Multivariable association models were developed to assess the impact of sarcopenia on late toxicity. The study population was composed of 750 HNSCC patients. Cut-off values for sarcopenia were set at SMI < 42.4 cm2/m2 (men) and <30.6 cm2/m2 (women) corresponding lowest gender specific quartile. Sarcopenic patients had significantly poorer survival rates, especially those with lower performance status and locally advanced disease. In oropharyngeal cancer patients, survival was more determined by p16 status than by sarcopenia. In multivariable analysis, sarcopenia was associated with worse OS (HR 0.72, p = 0.012) and DFS (HR 0.67, p = 0.001). In multivariable association models, sarcopenia was associated with physician-rated xerostomia six months after treatment (OR 1.65, p = 0.027) and physician-rated dysphagia six and twelve months after treatment (OR 2.02, p = 0.012 and 2.51, p = 0.003, respectively). Sarcopenia in HNSCC patients receiving definitive (C)RT is an independent prognostic factor for worse survival outcomes and is associated with physician-rated toxicity. [ABSTRACT FROM AUTHOR]

Objectives: To identify predictive factors for the presence of viable tumor and outcome in head and neck cancer patients who undergo therapeutic salvage neck dissections.Materials and Methods: Retrospective analysis of 76 salvage neck dissections after radiotherapy alone (n = 22), radiotherapy in combination with carboplatin/5-fluorouracil (n = 42) or with cetuximab (n = 12).Results: Viable tumor was detected in 41% of all neck dissections. Univariate analysis revealed initial treatment with radiotherapy without systemic therapy (OR 6.93, 95%CI: 2.28-21.07, p < .001), increased lymph node size after initial treatment compared to pretreatment CT scan (OR 20.48, 95%CI: 2.46-170.73, p = .005), more extensive neck dissections (OR 8.40, 95%CI: 2.94-23.98, p < .001), and human papillomavirus negative cancer (OR 4.22, 95%CI: 1.10-16.22, p = .036) as predictors of viable tumor. Patients with decreased or stable, but persistently enlarged lymph node size after chemoradiation had a significantly lower chance of viable tumor (OR 0.15, 95%CI: 0.05-0.41, p < .001). Disease-specific 5-year survival was 34% in case of viable tumor, and 78% when no viable tumor was found (p < .001).Conclusions: Viable tumor in salvage neck dissections is associated with reduced survival. Radiotherapy alone, human papillomavirus negative cancer and increase in lymph node size, are associated with viable tumor in salvage neck dissections. In case of decreased or stable lymph node size after chemoradiation, watchful waiting could be considered. [ABSTRACT FROM AUTHOR]

Background: The Meta-Analysis of Radiotherapy in squamous cell Carcinomas of Head and neck (MARCH) showed that altered fractionation radiotherapy is associated with improved overall and progression-free survival compared with conventional radiotherapy, with hyperfractionated radiotherapy showing the greatest benefit. This update aims to confirm and explain the superiority of hyperfractionated radiotherapy over other altered fractionation radiotherapy regimens and to assess the benefit of altered fractionation within the context of concomitant chemotherapy with the inclusion of new trials.Methods: For this updated meta-analysis, we searched bibliography databases, trials registries, and meeting proceedings for published or unpublished randomised trials done between Jan 1, 2009, and July 15, 2015, comparing primary or postoperative conventional fractionation radiotherapy versus altered fractionation radiotherapy (comparison 1) or conventional fractionation radiotherapy plus concomitant chemotherapy versus altered fractionation radiotherapy alone (comparison 2). Eligible trials had to start randomisation on or after Jan 1, 1970, and completed accrual before Dec 31, 2010; had to have been randomised in a way that precluded prior knowledge of treatment assignment; and had to include patients with non-metastatic squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx undergoing first-line curative treatment. Trials including a non-conventional radiotherapy control group, investigating hypofractionated radiotherapy, or including mostly nasopharyngeal carcinomas were excluded. Trials were grouped in three types of altered fractionation: hyperfractionated, moderately accelerated, and very accelerated. Individual patient data were collected and combined with a fixed-effects model based on the intention-to-treat principle. The primary endpoint was overall survival.Findings: Comparison 1 (conventional fractionation radiotherapy vs altered fractionation radiotherapy) included 33 trials and 11 423 patients. Altered fractionation radiotherapy was associated with a significant benefit on overall survival (hazard ratio [HR] 0·94, 95% CI 0·90-0·98; p=0·0033), with an absolute difference at 5 years of 3·1% (95% CI 1·3-4·9) and at 10 years of 1·2% (-0·8 to 3·2). We found a significant interaction (p=0·051) between type of fractionation and treatment effect, the overall survival benefit being restricted to the hyperfractionated group (HR 0·83, 0·74-0·92), with absolute differences at 5 years of 8·1% (3·4 to 12·8) and at 10 years of 3·9% (-0·6 to 8·4). Comparison 2 (conventional fractionation radiotherapy plus concomitant chemotherapy versus altered fractionation radiotherapy alone) included five trials and 986 patients. Overall survival was significantly worse with altered fractionation radiotherapy compared with concomitant chemoradiotherapy (HR 1·22, 1·05-1·42; p=0·0098), with absolute differences at 5 years of -5·8% (-11·9 to 0·3) and at 10 years of -5·1% (-13·0 to 2·8).Interpretation: This update confirms, with more patients and a longer follow-up than the first version of MARCH, that hyperfractionated radiotherapy is, along with concomitant chemoradiotherapy, a standard of care for the treatment of locally advanced head and neck squamous cell cancers. The comparison between hyperfractionated radiotherapy and concomitant chemoradiotherapy remains to be specifically tested.Funding: Institut National du Cancer; and Ligue Nationale Contre le Cancer. [ABSTRACT FROM AUTHOR]

Purpose: We sought to assess the effect of age on overall survival (OS), cancer-specific survival (CSS), and non-cancer-related death (NCRD) in elderly (aged ≥70 years) head and neck squamous cell carcinoma (HNSCC) patients treated with definitive radiation therapy. The results were compared with those of younger patients, and the most important prognostic factors for survival endpoints were determined. Treatments may be better justified based on identification of the main differences in survival between young and elderly patients.Methods and Materials: Data were analyzed from all consecutive HNSCC patients treated with definitive radiation therapy (66-70 Gy) in our department between April 2007 and December 2014. A total of 674 patients, including 168 elderly patients (24.9%), were included in the study. Multivariate association models were constructed to assess the effect of age on survival endpoints. Multivariate analysis was performed to identify potential prognostic factors for survival in elderly patients.Results: A total of 674 consecutive patients, including 168 elderly patients, were analyzed. The 5-year OS and NCRD rates were significantly worse for elderly patients than for young patients: 45.5% versus 58.2% (P=.007) and 39.0% versus 20.7% (P<.001), respectively. In the multivariate association analysis on the relationship between age and OS, lymph node involvement and worse World Health Organization (WHO) performance status were identified as significant confounders. Multivariate association analysis between age and NCRD identified Union for International Cancer Control stage as a significant confounder. After correction for confounders, the effect of age on OS and NCRD increased. Worse WHO performance status, lymph node involvement, and specific tumor site were independent prognostic factors for OS and CSS in the elderly patient group. Of the elderly patients, 80 (47%) died during follow-up; 45% of these deaths were ascribed to the index tumor. For elderly patients, radiation therapy combined with systemic forms of treatment was significantly associated with adverse NCRD rate (hazard ratio, 8.02; 95% confidence interval, 2.36-27.2; P=.001) after we performed a multivariate association analysis.Conclusions: Elderly HNSCC patients have worse survival outcomes than young HNSCC patients. Age is an independent prognostic factor for OS, mainly due to an increase in non-cancer-related mortality and comorbid diseases. The differences in CSS between young and elderly patients are negligible. [ABSTRACT FROM AUTHOR]

Objectives: To compare cumulative cisplatin dose and toxicity between patients who received 3-weekly versus weekly cisplatin during adjuvant radiotherapy for high-risk head and neck squamous cell carcinoma (HNSCC).Materials and Methods: Consecutive HNSCC patients with involved resection margins and/or extra-capsular extension in two tertiary cancer centers with different institutional practices were identified. Cumulative cisplatin dose was calculated and information on toxicity reviewed and compared between patients who received 3-weekly versus weekly cisplatin.Results: Of 270 high risk patients, 60 received 3-weekly 100mg/m(2) and 48 received weekly 50mg/m(2) cisplatin during adjuvant radiotherapy (60-66Gy in 30-33 fractions). Fourteen patients received other chemotherapy schedules and 148 received no chemotherapy. Mean cumulative cisplatin dose was 199.4mg/m(2) (standard error (SE) 5.4) in 3-weekly versus 239.8mg/m(2) (SE 11.0, P=0.001) in weekly treated patients. Cumulative cisplatin ⩾200mg/m(2) was given to 67.7% of patients in the 3-weekly cohort and 85.2% (P=0.039) in the weekly cohort. The rate of feeding tube dependency 6months after treatment, osteoradionecrosis, neutropenic fever, and persistent renal function decline were not statistically different.Conclusions: About one half of high-risk HNSCC patients are not eligible for cisplatin during postoperative radiotherapy. Patients treated with weekly 50mg/m(2) cisplatin received a higher cumulative dose with comparable toxicity as patients who received 3-weekly 100mg/m(2) cisplatin. Efficacy and applicability to the frequently used weekly 40mg/m(2) schedule remains to be evaluated. [ABSTRACT FROM AUTHOR]

Introduction To define the optimal time point for the integration of hypoxia 18 F-FAZA-PET/CT information into radiotherapy treatment planning to benefit from hypoxia modification or dose escalation treatment. Therefore, we performed a prospective cohort study, using serial hypoxic imaging ( 18 F-FAZA-PET/CT) prior to and at several time-points during (chemo)radiotherapy (CHRT) in six head and neck squamous cell (HNSCC) and six non-small cell lung cancer (NSCLC) patients. Methods The spatio-temporal dynamics of tumor hypoxia and fractional hypoxic volumes (FHV) were evaluated using a voxel-by-voxel analysis based on a 18 F-FAZA-T/B ratio of 1.4 at four time points in HNSCC patients, at baseline (FAZA-BL), at week one (FAZA-W1), two (FAZA-W2), and four (FAZA-W4) during CHRT and at three time points in NSCLC patients (baseline; W2, W4). Results Ten out of twelve patients showed a substantial pre-treatment tumor hypoxia representing a FHV ⩾ 1.4 assessed by 18 F-FAZA-PET/CT. The median FHV was 38% (FAZA-BL), 15% (FAZA-W1), 17% (FAZA-W2) and 1.5% (FAZA-W4) in HNSCC patients, and 34% (FAZA-BL), 26% (FAZA-W2) and 26% (FAZA-W4) in NSCLC patients, respectively. Stable tumor hypoxia was observed in three HNSCC patients and two NSCLC patients at FAZA-W2. In three HNSCC patients and two NSCLC patients FHVs declined to non-detectable hypoxia levels at FAZA-W4 during CHRT, while two NSCLC patients, showed increasing FHVs. Conclusion Our results indicate that, instead of using the FAZA-BL scan as the basis for the dose escalation, FAZA-W2 of CHRT is most suitable and might provide a more reliable basis for the integration of 18 F-FAZA-PET/CT information into radiotherapy treatment planning for hypoxia-directed dose escalation strategies. [ABSTRACT FROM AUTHOR]

Purpose To assess the prevalence of EGFRvIII, a specific variant of EGFR (epidermal growth factor receptor), in 3 well-defined cohorts of head and neck squamous cell carcinoma (HNSCC). Methods and Materials Immunohistochemistry for the specific detection of EGFRvIII using the L8A4 antibody was optimized on formalin-fixed, paraffin-embedded tissue using glioblastoma tissue. It was compared with EGFR and EGFRvIII RNA expression using a specific reverse transcription–polymerase chain reaction also optimized for formalin-fixed, paraffin-embedded tissue. Tissue microarrays including 531 HNSCCs of various stages with complete clinicopathologic and follow-up data were tested for the presence of EGFRvIII. Results None of the 531 cases showed EGFRvIII protein expression. Using an immunohistochemistry protocol reported by others revealed cytoplasmic staining in 8% of cases. Reverse transcription–polymerase chain reaction for the EGFRvIII transcript of the 28 highest cytoplasmic staining cases, as well as 69 negative cases, did not show expression in any of the tested cases, suggesting aspecific staining by a nonoptimal protocol. Conclusions The EGFRvIII mutation is not present in HNSCC. Therefore, EGFRvIII does not influence treatment response in HNSCC and is not a usable clinical prognostic marker. [ABSTRACT FROM AUTHOR]

Human papilloma virus (HPV) is a well-established causative factor in a subset of squamous cell carcinomas of the head and neck (HNSCC). Although HPV can be detected in various anatomical subsites, HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) is the most common HPV-related malignancy of the head and neck, and its worldwide incidence is constantly rising. Patients with OPSCC are generally younger, have less co-morbidities and generally have better prognosis due to different biological mechanisms of carcinogenesis. These facts have generated hypotheses on potential treatment modifications, aiming to minimize treatment-related toxicities without compromising therapy efficacy. Numerous randomized clinical trials have been designed to verify this strategy and increasingly real-world evidence data from retrospective, observational studies is becoming available. Until now, the data do not support any modification in contemporary treatment protocols. In this narrative review, we outline recent data provided by both randomized controlled trials and real-world evidence of HPV-positive OPSCC in terms of clinical value. We critically analyze the potential value and drawbacks of the available data and highlight future research directions. This article was written by members and invitees of the International Head and Neck Scientific Group.(www.IHNSG.com). [ABSTRACT FROM AUTHOR]

Summary: Distant metastases from head and neck squamous cell carcinoma (HNSCC), though rare at initial presentation, remain an important manifestation of cancer recurrence and mortality. Although generally considered incurable with a dismal prognosis despite palliative therapy, highly selected patients with distant metastases may have a long term survival benefit from aggressive surgery or radiotherapy. Advances in systemic treatments also may improve patient survival. This article reviews the current state of management of HNSCC patients with distant metastases. [ABSTRACT FROM AUTHOR]

Purpose: We recently reported on the identification of the Fas-associated death domain (FADD) as a possible driver of the chromosome 11q13 amplicon and the association between increased FADD expression and disease-specific survival in advanced-stage laryngeal carcinoma. The aim of this study was to examine whether expression of FADD and its Ser194-phosphorylated isoform (pFADD) predicts local control in patients with early-stage glottic carcinoma primarily treated with radiotherapy only. Methods and Materials: Immunohistochemical staining for FADD and pFADD was performed on pretreatment biopsy specimens of 92 patients with T1–T2 glottic squamous cell carcinoma primarily treated with radiotherapy between 1996 and 2005. Cox regression analysis was used to correlate expression levels with local control. Results: High levels of pFADD were associated with significantly better local control (hazard ratio, 2.40; 95% confidence interval, 1.04–5.55; p = 0.040). FADD overexpression showed a trend toward better local control (hazard ratio, 3.656; 95% confidence interval, 0.853–15.663; p = 0.081). Multivariate Cox regression analysis showed that high pFADD expression was the best predictor of local control after radiotherapy. Conclusions: This study showed that expression of phosphorylated FADD is a new prognostic biomarker for better local control after radiotherapy in patients with early-stage glottic carcinomas. [Copyright &y& Elsevier]

Purpose: The purpose was to evaluate the contralateral nodal control (CLNC) in postoperative patients with oral and oropharyngeal cancer treated with ipsilateral irradiation of the neck and primary site. Late radiation-induced morbidity was also evaluated. Methods and Materials: The study included 123 patients with well-lateralized squamous cell carcinomas treated with surgery and unilateral postoperative irradiation. Most patients had tumors of the gingiva (41%) or buccal mucosa (21%). The majority of patients underwent surgery of the ipsilateral neck (n = 102 [83%]). The N classification was N0 in 73 cases (59%), N1 or N2a in 23 (19%), and N2b in 27 cases (22%). Results: Contralateral metastases developed in 7 patients (6%). The 5-year actuarial CLNC was 92%. The number of lymph node metastases was the only significant prognostic factor with regard to CLNC. The 5-year CLNC was 99% in N0 cases, 88% in N1 or N2a cases, and 73% in N2b cases (p = 0.008). Borderline significance (p = 0.06) was found for extranodal spread. Successful salvage could be performed in 71% of patients with contralateral metastases. The prevalence of Grade 2 or higher xerostomia was 2.6% at 5 years. Conclusions: Selected patients with oral or oropharyngeal carcinoma treated with primary surgery and postoperative ipsilateral radiotherapy have a very high CLNC with a high probability of successful salvage in case of contralateral metastases. However, bilateral irradiation should be applied in case of multiple lymph node metastases in the ipsilateral neck, particularly in the presence of extranodal spread. The incidence of radiation-induced morbidity is considerably lower as observed after bilateral irradiation. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to compare intensity-modulated radiation therapy (IMRT) and three-dimensional conventional radiotherapy (3D-CRT) with regard to patient-rated xerostomia, Radiation Therapy Oncology Group (RTOG) acute and late xerostomia and health-related quality of life (HRQoL) among patients with head and neck squamous cell carcinoma (HNSCC). Methods and Materials: Included were 241 patients with HNSCC treated with bilateral irradiation ± chemotherapy. Since 2000, all patients treated with HNSCC were included in a program, which prospectively assessed acute and late morbidity according to the RTOG and HRQoL on a routine basis at regular intervals. Before October 2004, all patients were treated with 3D-CRT (N = 150). After clinical implementation in October 2004, 91 patients received IMRT. In this study, the differences regarding RTOG toxicity, xerostomia, and other items of HRQoL were analyzed. Results: The use of IMRT resulted in a significant reduction of the mean dose of the parotid glands (27 Gy vs. 43 Gy (p < 0.001). During radiation, Grade 2 RTOG xerostomia was significantly less with IMRT than with 3D-CRT. At 6 months, the prevalence of patient-rated moderate to severe xerostomia and Grade 2 or higher RTOG xerostomia was significantly lower after IMRT versus 3D-CRT. Treatment with IMRT also had a positive effect on several general and head and neck cancer–specific HRQoL dimensions. Conclusions: IMRT results in a significant reduction of patient- and observer-rated xerostomia, as well as other head and neck symptoms, compared with standard 3D-CRT. These differences translate into a significant improvement of the more general dimensions of HRQoL. [Copyright &y& Elsevier]

Purpose: To validate the recursive partitioning analysis (RPA) classification system for squamous cell head and neck cancer as recently reported by the VU University Medical Center. Methods and Materials: In eight Dutch head and neck cancer centers, data necessary to classify patients according to the RPA system were retrospectively collected from the charts of a group of 780 patients treated between 1989 and 2003. The patients in this validation group were classified according to the RPA classification system. For each endpoint, the 5-year values and hazard ratios were calculated and compared with the results of the VU University Medical Center. The RPA classification system was considered valid if the hazard ratio of the validation population was within the 95% confidence interval of the VU University Medical Center study population. Results: The locoregional control rate was 82%, 75%, and 63% at 5 years for those with class I, II, and III, respectively (p < 0.0001). The hazard ratio for the locoregional control rate relative to class I was 1.44 (95% confidence interval, 0.97–2.16) for class II and 2.37 (95% confidence interval, 1.57–3.57) for class III. Similar results were found for the distant metastasis, overall survival, and disease-free survival rates. Conclusion: The RPA classification system for head and neck squamous cell carcinoma in the postoperative setting, which was originally designed at one center, proved to be valid in a multicenter setting among patients included in a national multicenter study. This validated RPA classification scheme can be used to assess standard treatment strategies for head and neck squamous cell carcinoma in the postoperative setting, as well as in the design of future prospective studies. [Copyright &y& Elsevier]

Purpose: The aim of this study was to investigate the prognostic significance of epidermal growth factor (EGFr) expression in oral cavity squamous cell carcinoma (OCSCC) treated with curative surgery and postoperative radiotherapy. Methods and Materials: This retrospective study included 165 OCSCC patients. The expression of EGFr was assessed on paraffin-embedded tissue of the primary tumor by immunohistochemistry using a monoclonal antibody directed against EGFr. Intensity of the EGFr expression was scored by two authors blinded for the clinical outcome. Results: In the univariate analysis, locoregional control at 3 years (LRC) in the EGFr-negative cases was 69% compared with 77% in the EGFr-positive cases (p = 0.22). In the multivariate analysis for local control, a significant interaction was found between EGFr and overall treatment time of radiation (OTT). After stratification for EGFr expression, the OTT was of no importance in the EGFr-negative cases, whereas a significant difference in LRC was found in the EGFr-positive cases, in which the LRC after 3 years was 69% and 94% in case of an OTT of 0–42 days and >42 days, respectively (p = 0.009; hazard ratio = 3.42; 95% confidence interval, 1.28–8.96). No significant association was found between EGFr expression and overall survival. Conclusions: In the present study, no association was found between EGFr expression and outcome regarding locoregional control and overall survival. However, the results of the present study suggest that patients with squamous cell carcinoma of the oral cavity with high EGFr expression benefit more from a reduction of the overall treatment time of postoperative radiation than those with low EGFr expression. [Copyright &y& Elsevier]

Summary: The objective of this study was to investigate the prognostic significance of the hemoglobin (Hb) levels at different timepoints in locally advanced squamous cell carcinoma of the head and neck (SCCHN). Included were 111 patients. The hemoglobin levels were assessed before surgery (PreS-Hb), between surgery and radiotherapy (HbAAC), before postoperative radiotherapy (PreRT-Hb) and at the end of radiotherapy (EndRT-Hb). HbAAC takes into account the duration of anemia during the interval between surgery and radiotherapy. Higher HbAAC corresponds with lower Hb levels. Five year locoregional control (LRC) among patients with HbAAC⩾median was 72% and significantly worse as compared to the 88% in case of HbAAC < median (p =0.0097). Multivariate analysis for LRC showed that the HbAAC was a prognostic factor. Overall survival (OS) after 3 years was 77% in case of HbAAC < median and 34% in case of HbAAC⩾median (p <0.0002). Multivariate analysis for OS showed that the PreS-Hb and HbAAC were prognostic factors. Hb level between surgery and radiotherapy is an important prognostic factor for both LRC and OS among patients with SCCHN treated with surgery and postoperative radiotherapy. [Copyright &y& Elsevier]