Adaptive radiotherapy for virally mediated head and neck cancer

Purpose: Virally mediated head and neck cancers (VMHNC) often present with nodal involvement, and are generally considered radioresponsive, resulting in the need for plan adaptation during radiotherapy in a subset of patients. We sought to identify a high-risk group based on pre-treatment nodal size to be evaluated in a future prospective adaptive radiotherapy trial. Methodology: Between 2005-2010, 121 patients with virally-mediated, node positive nasopharyngeal or oropharyngeal cancers, receiving definitive radiotherapy were reviewed. Patients were analysed based on maximum size of the dominant node at diagnosis with a view to grouping them in varying risk categories for the need of re-planning. The frequency and timing of the re-planning scans were also evaluated. Results: Sixteen nasopharyngeal and 105 oropharyngeal tumours were reviewed. Twenty-five (21%) patients underwent a re-planning CT at a median of 22 (range, 0-29) fractions with 1 patient requiring re-planning prior to the commencement of treatment. Based on the analysis, patients were subsequently placed into 3 groups defined by pre-treatment nodal size; ≤ 35mm (Group 1), 36-45mm (Group 2), ≥ 46mm (Group 3). Applying these groups to the patient cohort, re-planning CT’s were performed in Group 1- 8/68 (11.8%), Group 2- 4/28 (14.3%), Group 3- 13/25 (52%). Conclusion: In this series, patients with VMHNC and nodal size > 46mm appear to be a high-risk group for the need of plan adaptation during a course of definitive radiotherapy. This finding will now be tested in a prospective adaptive radiotherapy study.

Blood cultures for evaluation of early postoperative fever after femoral neck fracture surgery

PURPOSE. To evaluate the utility of blood cultures in the assessment of early postoperative fever in hip fracture patients with no other indicators of sepsis. METHODS. 101 blood cultures were drawn on postoperative days 0 to 5 to investigate 84 febrile episodes in 31 women and 30 men (mean age, 80 years) whose body temperature measured via the tympanic route was ≥38ºC. Culture results of these 61 patients were divided into culture-positive and culture-negative groups for comparison. RESULTS. Of the 101 blood cultures, only 2 were positive: one was obtained 5 days after dynamic hip screw fixation, and the other 4 days after hemiarthroplasty. Both blood cultures grew coagulase-negative staphylococcal species, which were deemed to be skin contaminants not requiring change of patient management. 44 of these patients were treated with oral or intravenous antibiotics for a period of time. CONCLUSION. The risk of bacteraemia in patients with postoperative fever but no other symptoms of infection is low. Routine procurement of blood cultures in such patients is ineffective and of limited utility.

A systematic review on quality of life among patients at 1 year after treatment for head and neck cancer

Introduction: Although advances in treatment modalities have improved the survival of head and neck (H&N) cancer patients over recent years, survivors’ quality of life (QoL) could be impaired for a number of reasons. The investigation of QoL determinants can inform the design of supportive interventions for this population. Objectives: To examine the QoL of H&N cancer survivors at 1 year after treatment and to identify potential determinants affecting their QoL. Methods: A systematic search of literature was done in December 2011 in five databases: Pubmed, Medline, Scopus, Sciencedirect and CINAHL, using combined search terms ‘head and neck cancer’, ‘quality of life’, ‘health-related quality of life’ and ‘systematic review’. The methodological qualities of selected studies were assessed by two reviewers using predefined criteria. The study characteristics and results were abstracted and summarized. Results: Thirty-seven studies met all inclusion criteria with methodological quality from moderate to high. The global QoL of H&N cancer survivors returned to baseline at 1 year after treatment. Significant improvement showed in emotional functioning while physical functioning, xerostomia, sticky/insufficient saliva, and fatigue were consistently worse at 12 months compared with baseline. Age, cancer sites and stages, social support, smoking, presence of feeding tube are significant QoL determinants at 12 months. Conclusions: Although the global QoL of H&N cancer survivors recover by 12 months after treatment, problems with physical functioning, fatigue, xerostomia and sticky saliva persist. Regular assessment should be carried out to monitor these problems. Further research is required to develop appropriate and effective interventions for this population.

Developing an adaptive radiotherapy technique for virally mediated head and neck cancer

Purpose Virally mediated head and neck cancers (VMHNC) often present with nodal involvement and are highly radioresponsive, meaning that treatment plan adaptation during radiotherapy (RT) in a subset of patients is required. We sought to determine potential risk profiles and a corresponding adaptive treatment strategy for these patients. Methodology 121 patients with virally mediated, node positive nasopharyngeal (Epstein Barr Virus positive) or oropharyngeal (Human Papillomavirus positive) cancers, receiving curative intent RT were reviewed. The type, frequency and timing of adaptive interventions, including source-to-skin distance (SSD) corrections, re-scanning and re-planning, were evaluated. Patients were reviewed based on the maximum size of the dominant node to assess the need for plan adaptation. Results Forty-six patients (38%) required plan adaptation during treatment. The median fraction at which the adaptive intervention occurred was 26 for SSD corrections and 22 for re-planning CTs. A trend toward 3 risk profile groupings was discovered: 1) Low risk with minimal need (< 10%) for adaptive intervention (dominant pre-treatment nodal size of ≤ 35 mm), 2) Intermediate risk with possible need (< 20%) for adaptive intervention (dominant pre-treatment nodal size of 36 mm – 45 mm) and 3) High-risk with increased likelihood (> 50%) for adaptive intervention (dominant pre-treatment nodal size of ≥ 46 mm). Conclusion In this study, patients with VMHNC and a maximum dominant nodal size of > 46 mm were identified at a higher risk of requiring re-planning during a course of definitive RT. Findings will be tested in a future prospective adaptive RT study.

Evaluating the dosimetric effect of treatment-induced changed in virally mediated head and neck cancer patients

Introduction Patients with virally mediated head and neck cancer (VMHNC) often present with advanced nodal disease that is highly radioresponsive as demonstrated by tumour and nodal regression during treatment. The resultant changes may impact on the planned dose distribution and so adversely affect the therapeutic ratio. The aim of this study was to evaluate the dosimetric effect of treatment-induced anatomical changes in VMHNC patients who had undergone a re-plan. Methods Thirteen patients with virally mediated oropharyngeal or nasopharyngeal cancer who presented for definitive radiotherapy between 2005 and 2010 and who had a re-plan generated were investigated. The dosimetric effect of anatomical changes, was quantified by comparing dose volume histograms (DVH) of primary and nodal gross target volumes and organs at risk (OAR), including spinal cord and parotid glands, from the original plan and a comparison plan. Results Eleven 3DCRT and 2 IMRT plans were evaluated. Dose to the spinal cord and brainstem increased by 4.1% and 2.6%, respectively. Mean dose to the parotid glands also increased by 3.5%. In contrast, the dose received by 98% of the primary and nodal gross tumour volumes decreased by 0.15% and 0.3%, respectively when comparing the initial treatment plan to the comparison plan. Conclusion In this study, treatment-induced anatomical changes had the greatest impact on OAR dose with negligible effect on the dose to nodal gross tumour volumes. In the era of intensity modulated radiotherapy (IMRT), accounting for treatment-induced anatomical changes is important as focus is placed on minimising the acute and long-term side effects of treatment.

Expression and prognostic significance of a panel of tissue hypoxia markers in head-and-neck squamous cell carcinomas

Purpose: To investigate the expression pattern of hypoxia-induced proteins identified as being involved in malignant progression of head-and-neck squamous cell carcinoma (HNSCC) and to determine their relationship to tumor pO 2 and prognosis. Methods and Materials: We performed immunohistochemical staining of hypoxia-induced proteins (carbonic anhydrase IX [CA IX], BNIP3L, connective tissue growth factor, osteopontin, ephrin A1, hypoxia inducible gene-2, dihydrofolate reductase, galectin-1, IκB kinase β, and lysyl oxidase) on tumor tissue arrays of 101 HNSCC patients with pretreatment pO 2 measurements. Analysis of variance and Fisher's exact tests were used to evaluate the relationship between marker expression, tumor pO 2, and CA IX staining. Cox proportional hazard model and log-rank tests were used to determine the relationship between markers and prognosis. Results: Osteopontin expression correlated with tumor pO 2 (Eppendorf measurements) (p = 0.04). However, there was a strong correlation between lysyl oxidase, ephrin A1, and galectin-1 and CA IX staining. These markers also predicted for cancer-specific survival and overall survival on univariate analysis. A hypoxia score of 0-5 was assigned to each patient, on the basis of the presence of strong staining for these markers, whereby a higher score signifies increased marker expression. On multivariate analysis, increasing hypoxia score was an independent prognostic factor for cancer-specific survival (p = 0.015) and was borderline significant for overall survival (p = 0.057) when adjusted for other independent predictors of outcomes (hemoglobin and age). Conclusions: We identified a panel of hypoxia-related tissue markers that correlates with treatment outcomes in HNSCC. Validation of these markers will be needed to determine their utility in identifying patients for hypoxia-targeted therapy. © 2007 Elsevier Inc. All rights reserved.

Genome stability pathways in head and neck cancers

Genomic instability underlies the transformation of host cells toward malignancy, promotes development of invasion and metastasis and shapes the response of established cancer to treatment. In this review, we discuss recent advances in our understanding of genomic stability in squamous cell carcinoma of the head and neck (HNSCC), with an emphasis on DNA repair pathways. HNSCC is characterized by distinct profiles in genome stability between similarly staged cancers that are reflected in risk, treatment response and outcomes. Defective DNA repair generates chromosomal derangement that can cause subsequent alterations in gene expression, and is a hallmark of progression toward carcinoma. Variable functionality of an increasing spectrum of repair gene polymorphisms is associated with increased cancer risk, while aetiological factors such as human papillomavirus, tobacco and alcohol induce significantly different behaviour in induced malignancy, underpinned by differences in genomic stability. Targeted inhibition of signalling receptors has proven to be a clinically-validated therapy, and protein expression of other DNA repair and signalling molecules associated with cancer behaviour could potentially provide a more refined clinical model for prognosis and treatment prediction. Development and expansion of current genomic stability models is furthering our understanding of HNSCC pathophysiology and uncovering new, promising treatment strategies. © 2013 Glenn Jenkins et al.

Weekly cisplatin concurrently with radiotherapy in head and neck squamous cell cancer : a retrospective analysis of a tertiary institute experience

Radiotherapy combined with three weekly 100 mg/m2 of cisplatin is the accepted standard of care in head and neck squamous cell carcinoma. However, this regimen is associated with severe toxicities with devastating effects on patients. Alternative protocols like weekly 40 mg/m2 have been used in an attempt to reduce toxicities. The main objective of the present study is to identify the dose intensities and toxicities of weekly cisplatin in patients treated in a tertiary centre over a 12 month period. Included patients had squamous cell carcinoma arising in the oral cavity, oropharynx, larynx, or hypopharynx. Patients were excluded if they had nasopharyngeal squamous cell carcinoma, distant metastasis or if they had prior treatment for head and neck cancer excluding neck dissection. During the study period, 52 patients met the inclusion criteria and their data were retrospectively obtained from the patients' database of St James hospital, Dublin. The median age of the study cohort was 54 years (range 33-73). Of the patients, 40 (76.9 %) were male and 12 (20.1 %) were female. The primary tumour sites were as follows: oral cavity and oropharynx in 38 (73 %), larynx in 10 (19 %), and hypopharynx in 4 (8 %). In total, 33 (63.5 %) patients had stage IV disease, while 19 (36.5 %) had stage III disease. Treatment was definitive in 35 (67 %) patients and adjuvant in 17 (35 %). Full-dose radiotherapy was achieved in 50 (96 %) patients. Only 22 (42.3 %) patients completed the intended six cycles of chemotherapy. Cumulative dose of 200 mg/m2 or more was reached in 37 (71 %) patients. The acute adverse effects included grades 3 and 4 mucositis, which occurred in 22 (43.3 %) and 6 patients (12 %), respectively. Grade 3 and 4 neutropenia occurred in six (11.5 %) and three (5.7 %) patients, respectively. The only other haematological toxicity was grade 3 anaemia in 20 (38.4 %) patients. There was no grade 3 or 4 renal toxicity among the study cohort, although grade 2 was observed in six (11.5 %) patients. Death occurred in one patient due to neutropenic septicaemia. In conclusion, weekly cisplatin is associated with moderate to severe toxicities and might lead to suboptimal chemotherapy delivery. More prospective clinical studies are required to determine the optimal chemoradiation regimen in head and neck squamous cell carcinoma.

A simple method for EPID-based in vivo dosimetry for radiotherapy treatments of head-and-neck cancers

This study used a homogeneous water-equivalent model of an electronic portal imaging device (EPID), contoured as a structure in a radiotherapy treatment plan, to produce reference dose images for comparison with in vivo EPID dosimetry images. Head and neck treatments were chosen as the focus of this study, due to the heterogeneous anatomies involved and the consequent difficulty of rapidly obtaining reliable reference dose images by other means. A phantom approximating the size and heterogeneity of a typical neck, with a maximum radiological thickness of 8.5 cm, was constructed for use in this study. This phantom was CT scanned and a simple treatment including five square test fields and one off-axis IMRT field was planned. In order to allow the treatment planning system to calculate dose in a model EPID positioned a distance downstream from the phantom to achieve a source-to-detector distance (SDD) of 150 cm, the CT images were padded with air and the phantom’s “body” contour was extended to encompass the EPID contour. Comparison of dose images obtained from treatment planning calculations and experimental irradiations showed good agreement, with more than 90% of points in all fields passing a gamma evaluation, at γ (3%, 3mm )Similar agreement was achieved when the phantom was over-written with air in the treatment plan and removed from the experimental beam, suggesting that water EPID model at 150 cm SDD is capable of providing accurate reference images for comparison with clinical IMRT treatment images, for patient anatomies with radiological thicknesses ranging from 0 up to approximately 9 cm. This methodology therefore has the potential to be used for in vivo dosimetry during treatments to tissues in the neck as well as the oral and nasal cavities, in the head-and-neck region.

Interaction of psychosocial risk factors explain increased neck problems among female office workers

This study investigated the relationship between psychosocial risk factors and (1) neck symptoms and (2) neck pain and disability as measured by the neck disability index (NDI). Female office workers employed in local private and public organizations were invited to participate, with 333 completing a questionnaire. Data were collected on various risk factors including age, negative affectivity, history of previous neck trauma, physical work environment, and task demands. Sixty-one percent of the sample reported neck symptoms lasting greater than 8 days in the last 12 months. The mean NDI of the sample was 15.5 out of 100, indicating mild neck pain and disability. In a hierarchical multivariate logistic regression, low supervisor support was the only psychosocial risk factor identified with the presence of neck symptoms. Similarly, low supervisor support was the only factor associated with the score on the NDI. These associations remained after adjustment for potential confounders of age, negative affectivity, and physical risk factors. The interaction of job demands, decision authority, and supervisor support was significantly associated with the NDI in the final model and this association increased when those with previous trauma were excluded. Interestingly, and somewhat contrary to initial expectations, as job demands increased, high decision authority had an increasing effect on the NDI when supervisor support was low.

Quantitative sensory measures distinguish office workers with varying levels of neck pain and disability

This study was undertaken to investigate any relationship between sensory features and neck pain in female office workers using quantitative sensory measures to better understand neck pain in this group. Office workers who used a visual display monitor for more than four hours per day with varying levels of neck pain and disability were eligible for inclusion. There were 85 participants categorized according to their scores on the neck disability index (NDI): 33 with no pain (NDI < 8); 38 with mild levels of pain and disability (NDI 9–29); 14 with moderate levels of pain (NDI ⩾ 30). A fourth group of women without neck pain (n = 22) who did not work formed the control group. Measures included: thermal pain thresholds over the posterior cervical spine; pressure pain thresholds over the posterior neck, trapezius, levator scapulae and tibialis anterior muscles, and the median nerve trunk; sensitivity to vibrotactile stimulus over areas of the hand innervated by the median, ulnar and radial nerves; sympathetic vasoconstrictor response. All tests were conducted bilaterally. ANCOVA models were used to determine group differences between the means for each sensory measure. Office workers with greater self-reported neck pain demonstrated hyperalgesia to thermal stimuli over the neck, hyperalgesia to pressure stimulation over several sites tested; hypoaesthesia to vibration stimulation but no changes in the sympathetic vasoconstrictor response. There is evidence of multiple peripheral nerve dysfunction with widespread sensitivity most likely due to altered central nociceptive processing initiated and sustained by nociceptive input from the periphery.

Alterations in cervical muscle activity in functional and stressful tasks in female office workers with neck pain

This study determined differences between computer workers with varying levels of neck pain in terms of work stressors, employee strain, electromyography (EMG) amplitude and heart rate response to various tasks. Participants included 85 workers (33, no pain; 38, mild pain; 14, moderate pain) and 22 non-working controls. Work stressors evaluated were job demands, decision authority, and social support. Heart rate was recorded during three tasks: copy-typing, typing with superimposed stress and a colour word task. Measures included electromyography signals from the sternocleidomastoid (SCM), anterior scalene (AS), cervical extensor (CE) and upper trapezius (UT) muscles bilaterally. Results showed no difference between groups in work stressors or employee strain measures. Workers with and without pain had higher measured levels of EMG amplitude in SCM, AS and CE muscles during the tasks than controls (all P < 0.02). In workers with neck pain, the UT had difficulty in switching off on completion of tasks compared with controls and workers without pain. There was an increase in heart rate, perceived tension and pain and decrease in accuracy for all groups during the stressful tasks with symptomatic workers producing more typing errors than controls and workers without pain. These findings suggest an altered muscle recruitment pattern in the neck flexor and extensor muscles. Whether this is a consequence or source of the musculoskeletal disorder cannot be determined from this study. It is possible that workers currently without symptoms may be at risk of developing a musculoskeletal disorder.

Neck movement and muscle activity characteristics in female office workers with neck pain

Study Design Cross-sectional study. Objective To explore aspects of cervical musculoskeletal function in female office workers with neck pain. Summary of Background Data Evidence of physical characteristics that differentiate computer workers with and without neck pain is sparse. Patients with chronic neck pain demonstrate reduced motion and altered patterns of muscle control in the cervical flexor and upper trapezius (UT) muscles during specific tasks. Understanding cervical musculoskeletal function in office workers will better direct intervention and prevention strategies. Methods Measures included neck range of motion; superficial neck flexor muscle activity during a clinical test, the craniocerivcal flexion test; and a motor task, a unilateral muscle coordination task, to assess the activity of both the anterior and posterior neck muscles. Office workers with and without neck pain were formed into 3 groups based on their scores on the Neck Disability Index. Nonworking women without neck pain formed the control group. Surface electromyographic activity was recorded bilaterally from the sternocleidomastoid, anterior scalene (AS), cervical extensor (CE) and UT muscles. Results Workers with neck pain had reduced rotation range and increased activity of the superficial cervical flexors during the craniocervical flexion test. During the coordination task, workers with pain demonstrated greater activity in the CE muscles bilaterally. On completion of the task, the UT and dominant CE and AS muscles demonstrated an inability to relax in workers with pain. In general, there was a linear relationship between the workers’ self-reported levels of pain and disability and the movement and muscle changes. Conclusion These results are consistent with those found in other cervical musculoskeletal disorders and may represent an altered muscle recruitment strategy to stabilize the head and neck. An exercise program including motor reeducation may assist in the management of neck pain in office workers.

Associations between individual and workplace risk factors for self-reported neck pain and disability among female office workers

A cross-sectional survey of female office workers (n=333) was undertaken to determine the level of neck pain and disability (Neck Disability Index—NDI) and to explore the relationship between individual and workplace risk factors with the NDI score and the presence of pain. Workers reported nil (32%), mild (53%), moderate (14%) and severe (1%) neck pain. There were more risk factors associated with the NDI score than the presence of neck pain. The presence of neck pain was associated with a history of neck trauma (OR: 4.8), using a graduated lens (OR: 4.6), and negative affectivity (OR: 2.7) in the multiple regression model. Factors associated with higher NDI score were using the computer mouse for more than 6 h per day, higher negative affectivity, older age and an uncomfortable workstation. These results suggest that measuring the level of neck pain and disability rather than just the presence of neck pain provides more specific directives for the prevention and management of this disorder.

Contribution of individual, workplace, psychosocial and physiological factors to neck pain in female office workers

This study investigated the relative contribution of individual, workplace, psychosocial and physiological features associated with neck pain in female office workers towards developing appropriate intervention programs. Workers without disability (Neck Disability Index (NDI) score≤8, n=33); workers with neck pain and disability (NDI≥9/100, n=52) and 22 controls (women who did not work and without neck pain) participated in this study. Two logistic regression models were constructed to test the association between various measures in (1) workers with and without disability, and (2) workers without disability and controls. Measures included those found to be significantly associated with higher NDI in our previous studies: psychosocial domains; individual factors; task demands; quantitative sensory measures and measures of motor function. In the final model, higher score on negative affectivity scale (OR=4.47), greater activity in the neck flexors during cranio-cervical flexion (OR=1.44), cold hyperalgesia (OR=1.27) and longer duration of symptoms (OR=1.19) remained significantly associated with neck pain in workers. Workers without disability and controls could only be differentiated by greater muscle activity in the cervical flexors and extensors during a typing task. No psychosocial domains remained in either regression model. These results suggest that impairments in the sensory and motor system should be considered in any assessment of the office worker with neck pain and may have stronger influences on the presenting symptoms than workplace and psychosocial features.