Sandra Nuyts

Head and Neck Squamous Cell Carcinoma: Value of Diffusion-weighted MR Imaging for Nodal Staging

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.

Radiation-induced xerostomia in patients with head and neck cancer: a literature review.

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. Cancer 2006.

Dose Painting in Radiotherapy for Head and Neck Squamous Cell Carcinoma: Value of Repeated Functional Imaging with 18F-FDG PET, 18F-Fluoromisonidazole PET, Diffusion-Weighted MRI, and Dynamic Contrast-Enhanced MRI

The purpose of this work was to evaluate the potential of functional imaging with 18F-FDG PET, 18F-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 (18F-FDG and 18F-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 18F-fluoromisonidazole ratio (T/Bmax) on the baseline 18F-fluoromisonidazole scan (P = 0.04), with the size of the initial hypoxic volume (P = 0.04), and with T/Bmax on the 18F-fluoromisonidazole scan during treatment (P = 0.02). All locoregional recurrences were within the 18F-FDG–avid regions on baseline 18F-FDG PET; 3 recurrences mapped outside the hypoxic volume on baseline 18F-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 mm2/s, P = 0.01) and at 3 wk after treatment (0.0014 vs. 0.0018 mm2/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 18F-FDG PET and 18F-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.

The influence of xerostomia after radiotherapy on quality of life : Results of a questionnaire in head and neck cancer

IntroductionXerostomia 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 materialsA 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.ResultsThe 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.ConclusionsXerostomia 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.

Dysphagia After Chemoradiotherapy for Head-and-Neck Squamous Cell Carcinoma: Dose–Effect Relationships for the Swallowing Structures

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.

Evidence-based organ-sparing radiotherapy in head and neck cancer

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.

The prognostic value of the hypoxia markers CA IX and GLUT 1 and the cytokines VEGF and IL 6 in head and neck squamous cell carcinoma treated by radiotherapy ± chemotherapy

BackgroundSeveral parameters of the tumor microenvironment, such as hypoxia, inflammation and angiogenesis, play a critical role in tumor aggressiveness and treatment response. A major question remains if these markers can be used to stratify patients to certain treatment protocols.The purpose of this study was to investigate the inter-relationship and the prognostic significance of several biological and clinicopathological parameters in patients with head and neck squamous cell carcinoma (HNSCC) treated by radiotherapy ± chemotherapy.MethodsWe used two subgroups of a retrospective series for which CT-determined tumoral perfusion correlated with local control. In the first subgroup (n = 67), immunohistochemistry for carbonic anhydrase IX (CA IX) and glucose transporter-1 (GLUT-1) was performed on the pretreatment tumor biopsy. In the second subgroup (n = 34), enzyme linked immunosorbent assay (ELISA) was used to determine pretreatment levels of the cytokines vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6) in serum. Correlation was investigated between tumoral perfusion and each of these biological markers, as well as between the markers mutually. The prognostic value of these microenvironmental parameters was also evaluated.ResultsFor CA IX and GLUT-1, the combined assessment of patients with both markers expressed above the median showed an independent correlation with local control (p = 0.02) and disease-free survival (p = 0.04) with a trend for regional control (p = 0.06).In the second subgroup, IL-6 pretreatment serum level above the median was the only independent predictor of local control (p = 0.009), disease-free survival (p = 0.02) and overall survival (p = 0.005).ConclusionTo our knowledge, we are the first to report a link in HNSCC between IL-6 pretreatment serum levels and radioresistance in vivo. This link is supported by the strong prognostic association of pretreatment IL-6 with local control, known to be the most important parameter to judge radiotherapy responses.Furthermore, the combined assessment of CA IX and GLUT-1 correlated independently with prognosis. This is a valuable indication that a combined approach is important in the investigation of prognostic markers.

Intensity-Modulated Radiotherapy for Sinonasal Cancer: Improved Outcome Compared to Conventional Radiotherapy

PURPOSE To evaluate clinical outcome and toxicity of postoperative intensity-modulated radiotherapy (IMRT) for malignancies of the nasal cavity and paranasal sinuses. METHODS AND MATERIALS Between 2003 and 2008, 40 patients with cancer of the paranasal sinuses (n = 34) or nasal cavity (n = 6) received postoperative IMRT to a dose of 60 Gy (n = 21) or 66 Gy (n = 19). Treatment outcome and toxicity were retrospectively compared with that of a previous patient group (n = 41) who were also postoperatively treated to the same doses but with three-dimensional conformal radiotherapy without intensity modulation, from 1992 to 2002. RESULTS Median follow-up was 30 months (range, 4-74 months). Two-year local control, overall survival, and disease-free survival were 76%, 89%, and 72%, respectively. Compared to the three-dimensional conformal radiotherapy treatment, IMRT resulted in significantly improved disease-free survival (60% vs. 72%; p = 0.02). No grade 3 or 4 toxicity was reported in the IMRT group, either acute or chronic. The use of IMRT significantly reduced the incidence of acute as well as late side effects, especially regarding skin toxicity, mucositis, xerostomia, and dry-eye syndrome. CONCLUSIONS Postoperative IMRT for sinonasal cancer significantly improves disease-free survival and reduces acute as well as late toxicity. Consequently, IMRT should be considered the standard treatment modality for malignancies of the nasal cavity and paranasal sinuses.

Panitumumab plus radiotherapy versus chemoradiotherapy in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck (CONCERT-2): a randomised, controlled, open-label phase 2 trial.

BACKGROUND We aimed to compare panitumumab, a fully human monoclonal antibody against EGFR, plus radiotherapy with chemoradiotherapy in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck. METHODS In this international, open-label, randomised, controlled, phase 2 trial, we recruited patients with locally advanced squamous-cell carcinoma of the head and neck from 22 sites in eight countries worldwide. Patients aged 18 years and older with stage III, IVa, or IVb, previously untreated, measurable (≥ 10 mm for at least one dimension), locally advanced squamous-cell carcinoma of the head and neck (non-nasopharygeal) and an Eastern Cooperative Oncology Group performance status of 0-1 were randomly assigned (2:3) by an independent vendor to open-label chemoradiotherapy (two cycles of cisplatin 100 mg/m(2) during radiotherapy) or to radiotherapy plus panitumumab (three cycles of panitumumab 9 mg/kg every 3 weeks administered with radiotherapy) using a stratified randomisation with a block size of five. All patients received 70-72 Gy to gross tumour and 54 Gy to areas of subclinical disease with accelerated fractionation radiotherapy. The primary endpoint was local-regional control at 2 years, analysed in all randomly assigned patients who received at least one dose of their assigned protocol-specific treatment (chemotherapy, radiation, or panitumumab). The trial is closed and this is the final analysis. This study is registered with ClinicalTrials.gov, number NCT00547157. FINDINGS Between Nov 30, 2007, and Nov 16, 2009, 152 patients were enrolled, and 151 received treatment (61 in the chemoradiotherapy group and 90 in the radiotherapy plus panitumumab group). Local-regional control at 2 years was 61% (95% CI 47-72) in the chemoradiotherapy group and 51% (40-62) in the radiotherapy plus panitumumab group. The most frequent grade 3-4 adverse events were mucosal inflammation (25 [40%] of 62 patients in the chemoradiotherapy group vs 37 [42%] of 89 patients in the radiotherapy plus panitumumab group), dysphagia (20 [32%] vs 36 [40%]), and radiation skin injury (seven [11%] vs 21 [24%]). Serious adverse events were reported in 25 (40%) of 62 patients in the chemoradiotherapy group and in 30 (34%) of 89 patients in the radiotherapy plus panitumumab group. INTERPRETATION Panitumumab cannot replace cisplatin in the combined treatment with radiotherapy for unresected stage III-IVb squamous-cell carcinoma of the head and neck, and the role of EGFR inhibition in locally advanced squamous-cell carcinoma of the head and neck needs to be reassessed. FUNDING Amgen.

Diffusion-weighted magnetic resonance imaging early after chemoradiotherapy to monitor treatment response in head-and-neck squamous cell carcinoma.

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.