P. Clarke

Phase I/II Study of Oncolytic HSVGM-CSF in Combination with Radiotherapy and Cisplatin in Untreated Stage III/IV Squamous Cell Cancer of the Head and Neck

Purpose: This study sought to define the recommended dose of JS1/34.5-/47-/GM-CSF, an oncolytic herpes simplex type-1 virus (HSV-1) encoding human granulocyte-macrophage colony-stimulating factor (GM-CSF), for future studies in combination with chemoradiotherapy in patients with squamous cell cancer of the head and neck (SCCHN). Experimental Design: Patients with stage III/IVA/IVB SCCHN received chemoradiotherapy (70 Gy/35 fractions with concomitant cisplatin 100 mg/m2 on days 1, 22, and 43) and dose-escalating (106, 106, 106, 106 pfu/mL for cohort 1; 106, 107, 107, 107 for cohort 2; 106, 108, 108, 108 for cohort 3) JS1/34.5-/47-/GM-CSF by intratumoral injection on days 1, 22, 43, and 64. Patients underwent neck dissection 6 to 10 weeks later. Primary end points were safety and recommended dose/schedule for future study. Secondary end points included antitumor activity (radiologic, pathologic). Relapse rates and survival were also monitored. Results: Seventeen patients were treated without delays to chemoradiotherapy or dose-limiting toxicity. Fourteen patients (82.3%) showed tumor response by Response Evaluation Criteria in Solid Tumors, and pathologic complete remission was confirmed in 93% of patients at neck dissection. HSV was detected in injected and adjacent uninjected tumors at levels higher than the input dose, indicating viral replication. All patients were seropositive at the end of treatment. No patient developed locoregional recurrence, and disease-specific survival was 82.4% at a median follow-up of 29 months (range, 19-40 months). Conclusions: JS1/34.5-/47-/GM-CSF combined with cisplatin-based chemoradiotherapy is well tolerated in patients with SCCHN. The recommended phase II dose is 106, 108, 108, 108. Locoregional control was achieved in all patients, with a 76.5% relapse-free rate so far. Further study of this approach is warranted in locally advanced SCCHN. Clin Cancer Res; 16(15); 4005–15. ©2010 AACR.

AN EXPLORATORY STUDY INTO THE ROLE OF DYNAMIC CONTRAST-ENHANCED MAGNETIC RESONANCE IMAGING OR PERFUSION COMPUTED TOMOGRAPHY FOR DETECTION OF INTRATUMORAL HYPOXIA IN HEAD-AND-NECK CANCER

PURPOSE Hypoxia in patients with head-and-neck cancer (HNC) is well established and known to cause radiation resistance and treatment failure in the management of HNC. This study examines the role of parameters derived from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and perfusion computed tomography (CT) as surrogate markers of intratumoral hypoxia, defined by using the exogenous marker of hypoxia pimonidazole and the endogenous marker carbonic anhydrase 9 (CA9). METHODS AND MATERIALS Patients with HNC underwent preoperative DCE-MRI, perfusion CT, and pimonidazole infusion. Imaging parameters were correlated with pimonidazole and CA9 staining. The strength of correlations was tested by using a two-tailed Spearmans rank correlation coefficient. RESULTS Twenty-three regions of interest were analyzed from the 7 patients who completed the DCE-MRI studies. A number of statistically significant correlations were seen between DCE-MRI parameters (volume transfer between blood plasma and extracellular extravascular space [EES], volume of EES, rate constant between EES and blood plasma, time at arrival of contrast inflow, time to peak, average gradient, and time to onset) and areas with a pimonidazole score of 4. In the case of CA9 staining, only a weak correlation was shown with wash-in rate. There were no significant correlations between perfusion CT parameters and pimonidazole staining or CA9 expression. CONCLUSION Intratumoral hypoxia in patients with HNC may be predicted by using DCE-MRI; however, perfusion CT requires further investigation.

Validation of the Sydney Swallow Questionnaire (SSQ) in a cohort of head and neck cancer patients.

Impairment of swallowing function is a common multidimensional symptom complex seen in 50-75% of head and neck cancer (HNC) survivors. Although there are a number of validated swallowing-specific questionnaires, much of their focus is on the evaluation of swallowing-related quality of life (QOL) rather than swallowing as a specific function. The aim of this study was to validate the Sydney Swallow Questionnaire (SSQ) as a swallowing-specific instrument in HNC patients. Fifty-four consecutive patients in follow-up for oral and oropharyngeal cancer completed the SSQ and MD Anderson Dysphagia Inventory (MDADI). Thirty-one patients completed both questionnaires again four weeks later to address test-retest reliability. Internal consistency and test-retest reliability was assessed using Cronbachs alpha and Spearmans correlation coefficient, respectively. Construct validity (including group validity) and criterion validity were determined using Spearmans correlation coefficient and Mann-Whitney U-test. Internal consistency, test-retest reliability, construct validity, group validity and criterion validity of the SSQ was found to be significant (P<0.01). We were able to demonstrate the reliability and validity of the SSQ in HNC patients. The SSQ is a precise, reliable and valid tool for assessing swallow in this patient group.

Evaluation of speech outcomes following treatment of oral and oropharyngeal cancers

Oral and oropharyngeal cancers are amongst the commonest cancers worldwide and present a major health problem. Owing to their critical anatomical location and complex physiologic functions, the treatment of oral and oropharyngeal cancers often affects important functions, including speech. The importance of speech in a patients life can not be overemphasized, as its loss is often associated with severe functional and psychosocial problems and a poor quality of life. A thorough understanding of the speech problems that are faced by these patients and their timely management is the key to providing a better functional quality of life, which must be one of the major goals of modern oncologic practice. This review summarises key methods of evaluation and outcome of speech functions in the literature on oral and oropharyngeal cancer published between January 2000 and December 2008. Speech has been generally overlooked and poorly investigated in this group of patients. This review is an attempt to fill this gap by conducting the first speech-specific review for oral and oropharyngeal cancer patients. We have proposed guidelines for better understanding and management of speech problems faced by these patients in their day-to-day life.

Surgical voice restoration after total laryngectomy: an overview.

Total laryngectomy is potentially a debilitative surgery resulting in compromise of some of the most basic functions of life including speech and swallowing. This may have a profound adverse effect on the patients physical, functional, and emotional health, and may result in a decreased quality of life (QOL). Until the 1980s, total laryngectomy was regarded as a dreadful, but often, life-saving procedure for which there was little alternative, and was used as a last resort. At that time survival at any cost in terms of QOL was paramount and many laryngectomies were forced into an isolated life as a mute and dysphasic recluse. Most attempts at voice restoration produced inconsistent results and often techniques were laborious, expensive, and ineffective, particularly when carried out as a salvage procedure after failed radiotherapy. Progress in voice rehabilitation, following total laryngectomy, over the last 30 years, has made an enormous difference in the whole concept of the management of laryngeal cancers. Currently there are several options available for these patients, namely, esophageal speech, artificial larynx, and tracheoesophageal speech. The choice of speech rehabilitation varies from patient to patient, but tracheoesophageal voice has become the preferred method. This article provides a brief account of surgical voice restoration after total laryngectomy. Special emphasis has been given to the surgical technique, special considerations, complications, and the prevention / treatment of tracheoesophageal voice restoration.

Quality of Life following Total Laryngectomy: Assessment Using the UW-QOL Scale

Objectives: To determine the quality of life (QOL) in patients using valved speech following total laryngectomy with a validated patient self-report scale. Study Design: Cross-sectional cohort study. Patients: 63 patients following total laryngectomy using valved speech. Intervention: University of Washington Quality of Life (UW-QOL) questionnaire. Main Outcome Measures: Patient perception of the QOL over the last 7 days following total laryngectomy in response to specific questions and correlated with sociodemographic and treatment factors. Results: Responses were received from 44 males and 11 females (response rate: 87.3%) with a median age of 66 years (range: 40–84). The mean (SD) composite score of the QOL in our series of patients with total laryngectomy was 81.3 (10.9). As regards the overall QOL, 80% of our patients cited it as very good (45.5%) to good (34.5%). Patients identified speech, appearance, and activity as the most important issues following total laryngectomy. Only age and pharyngo-oesophageal segment closure were significant predictors of QOL scores (Student t test, p < 0.05) and not other demographic and treatment variables. Conclusions: The composite score and overall QOL were high in our series of total laryngectomy patients and this possibly reflects adequate multidisciplinary management. We strongly urge the use of prospective longitudinal studies that will adequately identify any QOL changes over time. Although the UW-QOL questionnaire is a simple and brief scale, it has limitations that can curtail its effective use in laryngectomy patients and we advise supplementing it with the use of domain-specific questionnaires.

Validation of a voice prosthesis questionnaire to assess valved speech and its related issues in patients following total laryngectomy

Objectives:  To establish the reliability and validity of a new self‐administered questionnaire to assess valved speech and its related issues in patients who have undergone a total laryngectomy operation.

Quality of life outcome measures following partial glossectomy: Assessment using the UW-QOL scale

BACKGROUND The consequences of a diagnosis of head and neck cancer and the impact of treatment have a clear and direct influence on well-being and associated quality of life (QOL) in these patients. AIMS To determine the QOL in head and neck cancer patients following a partial glossectomy operation. DESIGN AND SETTING Cross-sectional cohort study; Head and Neck Oncology Unit, tertiary referral center. MATERIALS AND METHODS 38 patients with partial glossectomy were assessed with the University of Washington head and neck quality of life (UW-QOL) scale, version 4. STATISTICAL ANALYSIS Statistical analysis was performed using the Statistical Package for Social Sciences 10.0 (SPSS Inc, Chicago version III). Information from the scale was correlated using the Mann Whitney test. A P value less than/equal to 0.05 was considered as significant. RESULTS The mean (sd) composite score of the QOL in our series was 73.6 (16.1). The majority (71.8%) quoted their QOL as good or very good. Swallowing (n = 16, 47.1%), speech (n = 15, 44.1%) and saliva (n = 15, 44.1%) were most commonly cited issues over the last 7 days. On the other hand, the groups with reconstruction, neck dissection, complications and radiotherapy demonstrated a significant reduction of quality of life scores (Mann Whitney test, P < 0.005). CONCLUSION The composite score and overall QOL as assessed using the UW-QOL scale (version 4) were modestly high in our series of partial glossectomy patients. Swallowing, speech, and saliva are regarded as the most important issues. Stage of the disease, neck dissection, reconstruction, complications, radiotherapy and time since operation were seen to significantly affect domain scores.

Multidimensional assessment of female tracheoesophageal prosthetic speech

Objective:  The objective of this study was to undertake a multidimensional assessment of female tracheoesophageal prosthetic speech.

Prospective, longitudinal electroglottographic study of voice recovery following accelerated hypofractionated radiotherapy for T1/T2 larynx cancer

BACKGROUND AND PURPOSE To measure voice outcomes following accelerated hypofractionated radiotherapy for larynx cancer. MATERIALS AND METHODS Twenty-five patients with T1/T2 glottic cancer underwent serial electroglottographic and acoustic analysis (sustained vowel/i/ and connected speech) before radiotherapy and 1, 6 and 12 months post-treatment. Twenty-five normal subjects served as a reference control population. RESULTS Pre-treatment measures were significantly worse for larynx cancer patients. Median jitter (0.23% vs 0.97%, p=0.001) and shimmer (0.62dB vs 0.98dB, p=0.05) and differences in data ranges reflected greater frequency and amplitude perturbation in the larynx cancer patients. Pre-treatment Mean Phonation Time (MPT) was significantly reduced (21s vs 14.8s, p=0.002) in larynx cancer patients. There was a trend towards improvement of jitter, shimmer and normalized noise energy at 12 months post-treatment. MPT improved but remained significantly worse than for normal subjects (21s vs 16.4s, p=0.013). Average fundamental frequency resembled normal subjects, including improvement of the measured range (91.4-244.6Hz in controls vs 100-201Hz in post-treatment larynx cancer patients). CONCLUSIONS This non-invasive technique effectively measures post-treatment vocal function in larynx cancer patients. This study demonstrated improvement of many key parameters that influence voice function over 12 months after radiotherapy.