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Purpose: To evaluate diffusion-weighted imaging (DWI) for assessment of treatment response in head and neck squamous cell carcinoma (HNSCC) three weeks after the end of chemoradiotherapy (CRT)., Methods and Materials: Twenty-nine patients with HNSCC underwent magnetic resonance imaging (MRI) prior to and 3 weeks after CRT, including T(2)-weighted and pre- and postcontrast T(1)-weighted sequences and an echo-planar DWI sequence with six b values (0 to 1,000 s/mm(2)), from which the apparent diffusion coefficient (ADC) was calculated. ADC changes 3 weeks posttreatment compared to baseline (∆ADC) between responding and nonresponding primary lesions and adenopathies were correlated with 2 years locoregional control and compared with a Mann-Whitney test. In a blinded manner, the ∆ADC was compared to conventional MRI 3 weeks post-CRT and the routinely implemented CT, on average 3 months post-CRT, which used size-related and morphological criteria. Positive and negative predictive values (PPV and NPV, respectively) were compared between the ∆ADC and anatomical imaging., Results: The ∆ADC of lesions with later tumor recurrence was significantly lower than lesions with complete remission for both primary lesions (-2.3% ± 0.3% vs. 80% ± 41%; p < 0.0001) and adenopathies (19.9% ± 32% vs. 63% ± 36%; p = 0.003). The ∆ADC showed a PPV of 89% and an NPV of 100% for primary lesions and a PPV of 70% and an NPV of 96% for adenopathies per neck side. DWI improved PPV and NPV compared to anatomical imaging., Conclusion: DWI with the ∆ADC 3 weeks after concluding CRT for HNSCC allows for early assessment of treatment response., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: The study presents the implementation of a novel method for incorporating hypoxia information from PET-CT imaging into treatment planning and estimates the efficiency of various optimization approaches. Its focuses on the feasibility of optimizing treatment plans based on the non-linear conversion of PET hypoxia images into radiosensitivity maps from the uptake properties of the tracers used., Material and Methods: PET hypoxia images of seven head-and-neck cancer patients were used to determine optimal dose distributions needed to counteract the radiation resistance associated with tumor hypoxia assuming various scenarios regarding the evolution of the hypoxic compartment during the treatment. A research planning system for advanced studies has been used to optimize IMRT plans based on hypoxia information from patient PET images. These resulting plans were compared in terms of target coverage for the same fulfilled constraints regarding the organs at risk., Results: The results of a planning study indicated the clinical feasibility of the proposed method for treatment planning based on PET hypoxia. Antihypoxic strategies would lead to small improvements in all the patients, but higher effects are expected for the fraction of patients with hypoxic tumors. For these, individualization of the treatment based on hypoxia PET imaging could lead to improved treatment outcome while creating the premises for limiting the irradiation of the surrounding normal tissues., Conclusions: The proposed approach offers the possibility of improved treatment results as it takes into consideration the heterogeneity and the dynamics of the hypoxic regions. It also provides early identification of the clinical cases that might benefit from dose escalation as well as the cases that could benefit from other counter-hypoxic measures.

Purpose: To review outcome and toxicity of Stage IVa and IVb head-and-neck squamous cell carcinoma patients treated with concomitant chemotherapy and intensity-modulated radiotherapy (IMRT) according to a hybrid fractionation schedule., Methods and Materials: Between 2006 and 2008, 42 patients with Stage IV head-and-neck squamous cell carcinoma were irradiated according to a hybrid fractionation schedule consisting of 20 fractions of 2 Gy (once daily), followed by 20 fractions of 1.6 Gy (twice daily), to a total dose of 72 Gy. Chemotherapy (cisplatinum, 100 mg/m(2)) was administered at the start of Weeks 1 and 4. Treatment outcome and toxicity were retrospectively compared with a previous patient group (n = 55), treated according to the same schedule, but without intensity modulation., Results: Locoregional control (LRC) and overall survival were 81% and 56% after 2 years, respectively. In comparison with the previous cohort, no significant differences were observed regarding either LRC (66%, p = 0.38) or overall survival (73%, p = 0.29). No Grade 4 or 5 toxicity was reported in the IMRT group, either acute or chronic. The use of IMRT significantly reduced the incidence of late Grade 2 or 3 xerostomia (52.9% vs. 90.2%, p < 0.001). No difference was observed regarding late Grade 2 or 3 dysphagia (p = 0.66)., Conclusions: Intensity-modulated chemoradiotherapy does not compromise LRC and significantly reduces late toxicity, especially regarding xerostomia., (Copyright © 2010 Elsevier Inc. All rights reserved.)

In the head and neck, squamous cell carcinoma is one of the most common tumour types. Currently, the primary imaging modalities for initial locoregional staging are computed tomography and-to a lesser extent-magnetic resonance imaging, whilst [(18)F]fluorodeoxyglucose (FDG) positron emission tomography has additional value in the detection of subcentimetric metastatic lymph nodes and of tumour recurrence after chemoradiotherapy (CRT). However, dependency on the morphological and size-related criteria of anatomical imaging and the limited spatial resolution and FDG avidity of inflammation in metabolic imaging may reduce diagnostic accuracy in the head and neck. Diffusion-weighted magnetic resonance imaging (DWI) is a noninvasive imaging technique that measures the differences in water mobility in different tissue microstructures. Water mobility is likely influenced by cell size, density, and cellular membrane integrity and is quantified by means of the apparent diffusion coefficient. As such, the technique is able to differentiate tumoural tissue from normal tissue, inflammatory tissue and necrosis. In this article, we examine the use of DWI in head and neck cancer, focussing on technique optimization and image interpretation. Afterwards, the value of DWI will be outlined for clinical questions regarding nodal staging, lesion characterization, differentiation of post-CRT tumour recurrence from necrosis and inflammation, and predictive imaging towards treatment outcome. The possible consequences of adding DWI towards therapeutic management are outlined.

With the association of concurrent chemotherapy, the widespread implementation of altered fractionation schedules and the use of more conformal radiotherapy techniques, the locoregional management of patients with squamous cell carcinoma of the head and neck region (HNSCC) has greatly improved over the last decades. However, associated toxicity has reached the limits of acceptability. If we want to further improve the therapeutic index of HNSCC we will need to target the tumor more accurately while sparing the surrounding organs at risk as much as possible. Therefore, accurate detection and delineation of tumor areas is essential, and diffusion-weighted MRI (DW-MRI) might help us in this task. DW-MRI can characterize tissues and generate image contrast based on differences in water mobility. Thus, while conventional imaging techniques such as computed tomography and MRI depict anatomical structures, functional imaging techniques such as DW-MRI provide us with a deeper insight in the tumor's underlying biological activity and microstructural characteristics. In this article, we aim to bundle the current experience on DW-MRI in HNSCC and elaborate on its potential value and drawbacks at different time points before, during and after radiotherapy.

Purpose: To evaluate late brachial plexopathy after primary chemoradiotherapy for locally advanced head and neck squamous cell carcinoma., Patients and Methods: Consecutive 43 disease-free patients were evaluated by a specifically developed 26-item questionnaire. Retrospectively, the brachial plexus was delineated and the dose-volume histograms were calculated., Results: After a median follow-up of 24 months, no radiation-induced brachial plexopathy was reported in these 43 patients., Conclusion: No radiation-induced brachial plexopathy was seen in the patient group, although 72.1% of the brachial plexuses received doses > 60 Gy. These findings should prompt further prospective studies and also stress the importance of trying to keep the doses to the brachial plexus as low as possible while covering the target volumes well.

Objective: To evaluate diffusion-weighted (DWI) magnetic resonance imaging (MRI) for treatment prediction during chemoradiotherapy (CRT) of head and neck squamous cell carcinoma (HNC)., Methods: Thirty patients with HNC underwent echo-planar DWI and anatomical MRI before and 2 and 4 weeks into CRT. Patient follow-up lasted 2 years post-CRT. Tumour ADC (DeltaADC) and volume changes (DeltaV) between baseline, and 2 and 4 weeks' follow-up were compared for lesions with recurrence versus complete remission (CR) using a Mann-Whitney U test. The predictive value of the DeltaADC and DeltaV for locoregional control (LRC) was examined with the Kaplan-Meier method. The study was approved by the local ethics committee. All patients gave written informed consent., Results: The DeltaADC in primary tumours and nodal metastases, 2 and 4 weeks after the start of CRT, was significantly lower in lesions with post-CRT recurrence than in lesions with CR (DeltaADC(2 weeks) and DeltaADC(4 weeks) for primary tumours, relative to nodal metastases: p < 0.0001). The DeltaV only showed a significant difference for primary tumours at 2 weeks (DeltaV(2 weeks): p = 0.03). The DeltaADC correlated significantly with 2-year LRC (p < 0.001); the DeltaV did not (p > 0.05)., Conclusion: DWI during CRT for HNC allows more accurate response prediction than anatomical imaging, correlating significantly with 2-year LRC.

Dysphagia is a very common complaint of head and neck cancer patients and can exist before, during, and after chemoradiotherapy. It leads to nutritional deficiency, weight loss, and prolonged unnatural feeding and also has a major potential risk for aspiration. This has a significant negative impact on the patient's entire quality of life. Because treatment of dysphagia in this setting is rarely effective, prevention is paramount. Several strategies have been developed to reduce dysphagia. These include swallowing exercises, treatment modification techniques such as intensity-modulated radiotherapy, selective delineation of elective nodes, reducing xerostomia by parotid-sparing radiotherapy, and adding of radioprotectors. However, more research is needed to further decrease the incidence of dysphagia and improve quality of life.

Purpose: To evaluate the use of diffusion-weighted magnetic resonance imaging (DW-MRI) for nodal staging and its impact on radiotherapy (RT) planning., Methods and Materials: Twenty-two patients with locally advanced head and neck squamous cell carcinoma underwent contrast-enhanced computed tomography (CT), as well as MRI (with routine and DW sequences) prior to neck dissection. After topographic correlation, lymph nodes were evaluated microscopically with prekeratin immunostaining. Pathology results were correlated with imaging findings and an RT planning study was performed for these surgically treated patients. One set of target volumes was based on conventional imaging only, and another set was based on the corresponding DW-MRI images. A third reference set was contoured based solely on pathology results., Results: A sensitivity of 89% and a specificity of 97% per lymph node were found for DW-MRI. Nodal staging agreement between imaging and pathology was significantly stronger for DW-MRI (kappa = 0.97; 95% confidence interval [CI], 0.84-1.00) than for conventional imaging (kappa = 0.56; 95% CI, 0.16-0.96; p = 0.019, by McNemar's test). For both imaging modalities, the absolute differences between RT volumes and those obtained by pathology were calculated. Using an exact paired Wilcoxon test, the observed difference was significantly larger for conventional imaging than for DW-MRI for nodal gross tumor volume (p = 0.0013), as well as for nodal clinical target volume (p = 0.0415) delineation., Conclusions: These results suggest that DW-MRI is superior to conventional imaging for preradiotherapy nodal staging of head and neck squamous cell carcinoma, and provides a potential impact on organsparing and tumor control., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Intensification of radiotherapy treatment for locally advanced head and neck cancer by use of altered fractionation schedules or concomitant chemotherapy has resulted in substantially improved locoregional control and survival. However, these improvements have come at the cost of increased acute, and late, toxic effects. The application of technological advances, such as intensity-modulated radiotherapy, is expected to further improve the therapeutic index of radiotherapy for head and neck cancer, by limiting toxicity and possibly by increasing locoregional control. However, the organ-sparing potential of such highly conformal radiotherapy techniques relies heavily on the appropriate selection and accurate delineation of the crucial organs at risk, with the application of rigorous dose constraints during planning. Because xerostomia and dysphagia are the main causes of decreased quality of life after radiotherapy for head and neck cancer, the prevention of these two complications will form the focus of this review., (Copyright (c) 2010 Elsevier Ltd. All rights reserved.)

Purpose: To evaluate late dysphagia after chemoradiotherapy for locally advanced head-and-neck squamous cell carcinoma, and to examine its correlation with clinical and dosimetric parameters., Methods and Materials: Consecutive patients, treated with radiotherapy (70-72 Gy) and concomitant chemotherapy (cisplatinum 100 mg/m(2) every 3 weeks) between 2004 and 2007, were examined. Swallowing was evaluated by four quality-of-life questionnaires: EORTC C30 and H&N35, the Performance Status Scale of List, and the MD Anderson Dysphagia Inventory. Clinical and dosimetric parameters were correlated with late dysphagia., Results: A total of 53 disease-free patients were evaluated; mean follow-up was 20.4 months (range, 6-45 months). The volume of the middle pharyngeal constrictor muscle receiving > or =50 Gy (p = 0.04), the mean dose to this structure (p = 0.02) and to the supraglottic larynx (p = 0.04) were significantly associated with late swallowing problems at univariate analysis, along with tumor localization (p = 0.008), T-classification (p = 0.02), and pretreatment swallowing problems (p = 0.01). Only this last factor significantly correlated with late dysphagia at multivariate analysis., Conclusion: These findings motivate further efforts to reduce the dose to the swallowing structures, especially to the pharyngeal constrictor muscles and the larynx. However, clinical parameters are also important and should be included in future prospective trials.

Unlabelled: The purpose of this work was to evaluate the potential of functional imaging with (18)F-FDG PET, (18)F-fluoromisonidazole PET, diffusion-weighted MRI, and dynamic contrast-enhanced MRI to provide an appropriate and reliable biologic target for dose painting in radiotherapy for head and neck squamous cell carcinoma (HNSCC)., Methods: Fifteen patients with locally advanced HNSCC, treated with concomitant chemoradiotherapy, were prospectively enrolled in a bioimaging protocol. Sequential PET ((18)F-FDG and (18)F-fluoromisonidazole) and MRI (T1, T2, dynamic enhanced, and diffusion-weighted sequences) were performed before, during, and after radiotherapy., Results: Median follow-up was 30.7 mo (range, 6.3-56.3 mo); in 7 patients, disease recurred. Disease-free survival correlated negatively with the maximum tissue-to-blood (18)F-fluoromisonidazole ratio (T/B(max)) on the baseline (18)F-fluoromisonidazole scan (P = 0.04), with the size of the initial hypoxic volume (P = 0.04), and with T/B(max) on the (18)F-fluoromisonidazole scan during treatment (P = 0.02). All locoregional recurrences were within the (18)F-FDG-avid regions on baseline (18)F-FDG PET; 3 recurrences mapped outside the hypoxic volume on baseline (18)F-fluoromisonidazole PET. Lesions (primary tumor and lymph nodes) where a locoregional recurrence developed during follow-up had significantly lower apparent diffusion coefficients on diffusion-weighted MRI during week 4 of radiotherapy (0.0013 vs. 0.0018 mm(2)/s, P = 0.01) and at 3 wk after treatment (0.0014 vs. 0.0018 mm(2)/s, P = 0.01) and a significantly higher initial slope on baseline dynamic enhanced MRI (26.2 vs. 17.5/s, P = 0.03) than did lesions that remained controlled., Conclusion: These results confirm the added value of (18)F-FDG PET and (18)F-fluoromisonidazole PET for radiotherapy planning of HNSCC and suggest the potential of diffusion-weighted and dynamic enhanced MRI for dose painting and early response assessment.

Purpose: To evaluate diffusion-weighted (DW) magnetic resonance (MR) imaging, as compared with turbo spin-echo MR imaging, for the detection of nodal metastases in head and neck squamous cell carcinoma (HNSCC)., Materials and Methods: The study was approved by the ethics committee, and patients gave written informed consent. Before undergoing surgery, 33 consecutive patients underwent 1.5-T MR imaging, including DW imaging performed with a wide range of b values (0-1000 sec/mm(2)). The apparent diffusion coefficients (ADCs) of lymph nodes 4 mm or greater in short-axis diameter depicted on images obtained with b values of 0 and 1000 sec/mm(2) were calculated. After topographic correlation, the lymph nodes were evaluated microscopically with prekeratin immunostaining. The optimal ADC thresholds for discriminating between metastatic and benign lymph nodes were determined. The sensitivity, specificity, and accuracy of DW imaging were calculated separately-on per-lymph-node and per-neck-level bases-for all lymph nodes and for supracentimeter and subcentimeter lymph nodes and were compared with corresponding turbo spin-echo MR imaging values., Results: Correlation of histopathologic and radiologic findings was possible for 301 lymph nodes. The ADC derived from the signal intensity averaged across images obtained with b values of 0 and 1000 sec/mm(2) (ADC(b0-1000)) was 1.19 x 10(-3) mm(2)/sec +/- 0.22 (standard deviation) for benign lymph nodes and 0.85 x 10(-3) mm(2)/sec +/- 0.27 for malignant lymph nodes (P < .0001). With an optimal ADC(b0-1000) threshold of 0.94 x 10(-3) mm(2)/sec, 84% sensitivity, 94% specificity, and 91% accuracy for differentiation of malignant versus benign status of each lymph node and 94% sensitivity, 97% specificity, and 97% accuracy for differentiation at each neck level were achieved. Compared with turbo spin-echo imaging, DW imaging had higher sensitivity (76% vs 7%) but slightly lower specificity (94.0% vs 99.5%) for detection of subcentimeter nodal metastases., Conclusion: DW imaging performed with ADC(b0-1000) values had higher accuracy than turbo spin-echo MR imaging in nodal staging, providing added value in the detection of subcentimeter nodal metastases.

Purpose: To evaluate the feasibility and efficacy of a hyperfractionated accelerated radiotherapy (RT) schedule combined with concomitant chemotherapy (Cx) in patients with locally advanced head-and-neck squamous cell carcinoma., Methods and Materials: Between 2004 and 2007, a total of 90 patients with locoregionally advanced head-and-neck squamous cell carcinoma underwent irradiation according to a hybrid fractionation schedule consisting of 20 fractions of 2 Gy (once daily) followed by 20 fractions of 1.6 Gy (twice daily) to a total dose of 72 Gy. Concomitant Cx (cisplatinum 100 mg/m(2)) was administered at the start of Weeks 1 and 4. Treatment outcome and toxicity were retrospectively compared with a previous patient group (n = 73) treated with the same schedule, but without concomitant Cx, between 2001 and 2004., Results: The locoregional control (LRC) rate was 70% after 2 years. Two-year overall and 2-year disease-free survival rates were 74% and 60%, respectively. In comparison with the RT-only group, an improvement of 15% in both LRC (p = 0.03) and overall survival (p = 0.09) was observed. All patients were treated to full radiation dose according to protocol, although the Cx schedule had to be adjusted in 12 patients. No acute Grade 4 or 5 toxicity was seen, but incidences of Grade 3 acute mucositis (74.5% vs. 50.7%; p = 0.002) and dysphagia (82.2% vs. 47.9%; p < 0.001) were significantly higher in the chemoradiotherapy group compared with patients treated with RT alone., Conclusion: With this chemoradiotherapy regimen, excellent LRC and survival rates were achieved, with acceptable acute toxicity.

Introduction: Xerostomia is a common complication of radiotherapy for head and neck cancer because irreparable damage is caused to the salivary glands if they are included in the radiation fields. The aim of the study was to evaluate the degree of xerostomia in survivors of head and neck cancer and to determine its impact on quality of life., Methods and Materials: A xerostomia questionnaire consisting of three parts (xerostomia score, quality of life survey, and visual analogue scale) was completed by 75 head and neck cancer patients, more than 6 months after radiotherapy and without evidence of disease., Results: The majority of patients (93%) suffered from a dry mouth, and 65% had moderate to severe xerostomia (grade 2 to 3). Both dysphagia (65%) and taste loss (63%) were common, although oral pain was less frequent (33%). The emotional impact of xerostomia was significant, causing worry (64%), tension (61%), or feelings of depression (44%). Furthermore, patients reported problems with talking to (60%) or eating with (54%) other people and to feel restricted in amount and type of food (65%). Quality of life was influenced by T classification, clinical stage, a higher radiation dose or the use of concomitant chemotherapy, but was independent of the interval since the end of radiotherapy., Conclusions: Xerostomia after radiotherapy for head and neck cancer is extremely common and significantly affects quality of life. No recuperation is seen over time, and the use of concomitant chemotherapy significantly increases the oral complications of radiation. These results warrant the continuing efforts put into the development of salivary gland-sparing radiotherapy techniques and effective treatments of radiation-induced xerostomia.

Background: Our aim was to determine feasibility and efficacy of a hybrid radiotherapy schedule in locally advanced head and neck cancer., Methods: Seventy-three patients with locally advanced head and neck cancer were irradiated according to a hybrid accelerated schedule consisting of 20 fractions of 2 Gy (once daily), followed by 20 fractions of 1.6 Gy (twice daily), to a total dose of 72 Gy., Results: Locoregional control was 55% after 2 years. Overall survival was 59%, disease-specific survival was 63%, and disease-free survival was 46%. Acute toxicity was prospectively scored in all 73 patients: the most frequent toxicities were mucositis (50.7%, grade 3), dysphagia (47.9%, grade 3), and dermatitis (34.5%, grade 3). All patients were treated to full dose, without treatment interruption., Conclusion: With this regimen, acceptable locoregional control and survival rates are achieved. Toxicity was well manageable, suggesting that a combination of this schedule with concomitant chemotherapy is possible and could lead to further improvement in the treatment of locally advanced head and neck cancer.

Purpose: To investigate the value of diffusion weighted magnetic resonance imaging (DW-MRI) in differentiating persistent or recurrent head and neck squamous cell carcinoma (HNSCC) from nontumoral postradiotherapeutic alterations., Methods and Materials: In 26 patients with suspicion of persistent or recurrent HNSCC, MRI of the head and neck was performed, including routine turbo spin-echo (TSE) sequences and an additional echo-planar DW-MRI sequence, using a large range of b-values (0-1000 s/mm(2)). Apparent diffusion coefficient (ADC) maps were calculated. In the suspect areas at the primary site and in the suspect lymph nodes, signal intensity was measured on the native b0 and b1000 images and ADC values were calculated for these tissues. The same was done for surrounding irradiated normal tissue. Imaging results were correlated to histopathology., Results: Signal intensity on native b0 images was significantly lower for HNSCC than for nontumoral postradiotherapeutic tissue (p < 0.0001), resulting in a sensitivity of 66.2%, specificity of 60.8%, and accuracy of 62.4%. Signal intensity on native b1000 images was significantly higher for HNSCC than for nontumoral tissue (p < 0.0001), resulting in a sensitivity of 71.6%, specificity of 71.3%, and accuracy of 71.4%. ADC values were significantly lower for HNSCC than for nontumoral tissue (p < 0.0001), resulting in a sensitivity of 94.6%, specificity of 95.9%, and accuracy of 95.5%. When compared with computed tomography, TSE-MRI and fluorodeoxyglucose-positron emission tomography, DW-MRI yielded fewer false-positive results in persistent primary site abnormalities and in persistent adenopathies, and aided in the detection of subcentimetric nodal metastases., Conclusions: Diffusion weighted-MRI accurately differentiates persistent or recurrent HNSCC from nontumoral tissue changes after (chemo)radiotherapy.

A dry mouth or xerostomia is one of the most common complications during and after radiotherapy for head and neck cancer, because irreparable damage is caused to the salivary glands, which are included in the radiation fields. Xerostomia not only significantly impairs the quality of life of potentially cured cancer patients, it may also lead to severe and long-term oral disorders. Because management of xerostomia is rarely effective, prevention is paramount. Several strategies have been developed to avoid radiation-induced salivary dysfunction without compromising definitive oncologic treatment. These include salivary gland-sparing radiation techniques, such as 3-dimensional conformal or intensity-modulated radiotherapy, concomitant cytoprotectants, and surgical salivary gland transfer. However, these preventive approaches are not applicable to all patients, and comprehensive scientific research that incorporates new biological insights is warranted to optimize the therapeutic index of radiotherapy for head and neck cancer., ((c) 2006 American Cancer Society.)