Adherence to and uptake of clinical practice guidelines: lessons learned from a clinical practice guideline on chemotherapy concomitant with radiotherapy in head-and-neck cancer.

BACKGROUND: Clinical practice guidelines (cpgs) are systematically developed statements designed to assist practitioners and patients in making decisions about appropriate heath care interventions. Clinical practice guidelines are expensive and time-consuming to create. A cpg on concurrent chemotherapy with radiation therapy (ccrt) was developed in Ontario at a time when treatment approaches for head-and-neck cancer were changing significantly. METHODS: An assessment of treatments and outcomes based on electronic and chart data obtained from a population-based study of 571 patients with oropharynx cancer treated in Ontario (2003-2004) was combined with a review of relevant knowledge transfer (publications and presentations at major meetings) to understand variation in adherence to a cpg. RESULTS: In 9 Ontario cancer treatment centres, ccrt was used for 55% of all patients with oropharyngeal cancer; however, at the centres individually, that proportion ranged from 82% to 39%. Furthermore, there was no agreement on the chemotherapy regimen: 2-4 years later (a period during which newer regimens were emerging), only 4 of 9 centres were following the guideline for most patients. When outcomes of treated patients were compared for centres with "higher" and "lower" use of ccrt, no difference in survival was observed (p = 0.64). CONCLUSIONS: At a time of treatment evolution, the new guideline was controversial, and there are many reasons for the mixed adherence. An estimation of adherence should be included during both development and review of guidelines.

Automatic image-to-world registration based on x-ray projections in cone-beam CT-guided interventions.

Intraoperative imaging offers a means to account for morphological changes occurring during the procedure and resolve geometric uncertainties via integration with a surgical navigation system. Such integration requires registration of the image and world reference frames, conventionally a time consuming, error-prone manual process. This work presents a method of automatic image-to-world registration of intraoperative cone-beam computed tomography (CBCT) and an optical tracking system. Multimodality (MM) markers consisting of an infrared (IR) reflective sphere with a 2 mm tungsten sphere (BB) placed precisely at the center were designed to permit automatic detection in both the image and tracking (world) reference frames. Image localization is performed by intensity thresholding and pattern matching directly in 2D projections acquired in each CBCT scan, with 3D image coordinates computed using backprojection and accounting for C-arm geometric calibration. The IR tracking system localized MM markers in the world reference frame, and the image-to-world registration was computed by rigid point matching of image and tracker point sets. The accuracy and reproducibility of the automatic registration technique were compared to conventional (manual) registration using a variety of marker configurations suitable to neurosurgery (markers fixed to cranium) and head and neck surgery (markers suspended on a subcranial frame). The automatic technique exhibited subvoxel marker localization accuracy (< 0.8 mm) for all marker configurations. The fiducial registration error of the automatic technique was (0.35 +/-0.01) mm, compared to (0.64 +/- 0.07 mm) for the manual technique, indicating improved accuracy and reproducibility. The target registration error (TRE) averaged over all configurations was 1.14 mm for the automatic technique, compared to 1.29 mm for the manual in accuracy, although the difference was not statistically significant (p = 0.3). A statistically significant improvement in precision was observed-specifically, the standard deviation in TRE was 0.2 mm for the automatic technique versus 0.34 mm for the manual technique (p = 0.001). The projection-based automatic registration technique demonstrates accuracy and reproducibility equivalent or superior to the conventional manual technique for both neurosurgical and head and neck marker configurations. Use of this method with C-arm CBCT eliminates the burden of manual registration on surgical workflow by providing automatic registration of surgical tracking in 3D images within approximately 20 s of acquisition, with registration automatically updated with each CBCT scan. The automatic registration method is undergoing integration in ongoing clinical trials of intraoperative CBCT-guided head and neck surgery.

Demons deformable registration for CBCT-guided procedures in the head and neck: convergence and accuracy.

PURPOSE: The accuracy and convergence behavior of a variant of the Demons deformable registration algorithm were investigated for use in cone-beam CT (CBCT)-guided procedures of the head and neck. Online use of deformable registration for guidance of therapeutic procedures such as image-guided surgery or radiation therapy places trade-offs on accuracy and computational expense. This work describes a convergence criterion for Demons registration developed to balance these demands; the accuracy of a multiscale Demons implementation using this convergence criterion is quantified in CBCT images of the head and neck. METHODS: Using an open-source "symmetric" Demons registration algorithm, a convergence criterion based on the change in the deformation field between iterations was developed to advance among multiple levels of a multiscale image pyramid in a manner that optimized accuracy and computation time. The convergence criterion was optimized in cadaver studies involving CBCT images acquired using a surgical C-arm prototype modified for 3D intraoperative imaging. CBCT-to-CBCT registration was performed and accuracy was quantified in terms of the normalized cross-correlation (NCC) and target registration error (TRE). The accuracy and robustness of the algorithm were then tested in clinical CBCT images of ten patients undergoing radiation therapy of the head and neck. RESULTS: The cadaver model allowed optimization of the convergence factor and initial measurements of registration accuracy: Demons registration exhibited TRE=(0.8+/-0.3) mm and NCC =0.99 in the cadaveric head compared to TRE=(2.6+/-1.0) mm and NCC=0.93 with rigid registration. Similarly for the patient data, Demons registration gave mean TRE=(1.6+/-0.9) mm compared to rigid registration TRE=(3.6+/-1.9) mm, suggesting registration accuracy at or near the voxel size of the patient images (1 x 1 x 2 mm3). The multiscale implementation based on optimal convergence criteria completed registration in 52 s for the cadaveric head and in an average time of 270 s for the larger FOV patient images. CONCLUSIONS: Appropriate selection of convergence and multiscale parameters in Demons registration was shown to reduce computational expense without sacrificing registration performance. For intraoperative CBCT imaging with deformable registration, the ability to perform accurate registration within the stringent time requirements of the operating environment could offer a useful clinical tool allowing integration of preoperative information while accurately reflecting changes in the patient anatomy. Similarly for CBCT-guided radiation therapy, fast accurate deformable registration could further augment high-precision treatment strategies.

Navigated non-contact fluorescence tomography.

A non-contact approach for diffuse optical tomography (DOT) has been developed for on-demand image updates using surgical navigation technology. A stereoscopic optical tracker provides real-time localization of reflective spheres mounted to a laser diode and near-infrared camera. Standard camera calibration is combined with tracking data to determine the intrinsic camera parameters (focal length, principal point and non-linear lens distortion) and the tracker-to-camera transform. Tracker-to-laser calibration is performed using images of laser beam intersection with a tracked calibration surface. Source and detector positions for a finite-element DOT implementation are projected onto the boundary elements of the tissue mesh by finding ray-triangle intersections. A multi-stage model converts camera counts to surface flux by accounting for lens aperture settings, fluorescence filter transmittance, photodetector quantum efficiency, photon energy, exposure time, readout offset and camera gain. The image-guidance framework was applied to an in-house optical tomography system configured for indocyanine green (ICG) fluorescence. Mean target registration errors for camera and laser calibration were less than 1 mm. Surface flux measurements of total reflectance and fluorescence in Intralipid-based fluorescence phantoms (0-2 µg ml-1) had mean errors of 3.1% and 4.4%, respectively, relative to diffusion theory predictions. Spatially-resolved reflectance measurements in a calibrated optical phantom agreed with theory for radial distances up to 25 mm from the laser source. Inverse fluorescence reconstructions of a sub-surface fluorescence target confirmed the localization accuracy (average target centroid error of 0.44 mm). This translational research system is under investigation for clinical applications in head and neck surgery, including oral cavity tumor resection, lymph node mapping and free-flap perforator assessment.

Intraoperative cone-beam CT spatial priors for diffuse optical fluorescence tomography.

A hybrid system for intraoperative cone-beam CT (CBCT) imaging and continuous-wave fluorescence tomography (FT) has been developed using an image-guidance framework. Intraoperative CBCT images with sub-millimeter spatial resolution are acquired with a flat-panel C-Arm. Tetrahedral meshes are generated from CBCT for finite element method implementation of diffuse optical tomography (NIRFAST). Structural data from CBCT is incorporated directly into the optical reconstruction process using Laplacian-type regularization ('soft spatial priors'). Experiments were performed using an in-house optical system designed for indocyanine green (ICG) fluorescence. A dynamic non-contact geometry was achieved using a stereoscopic optical tracker for real-time localization of a laser diode and CCD camera. Source and detector positions were projected onto the boundary elements of the tissue mesh using algorithms for ray-triangle intersection and camera lens calibration. Simulation studies showed the capabilities of a soft-prior approach, even in the presence of segmentation uncertainties. Experiments with ICG targets embedded in liquid phantoms determined the improvements in the quantification of the fluorophore yield, with errors of 85% and <20% for no priors and spatial priors, respectively. Similar results were observed with the ICG target embedded in ex vivo porcine loin, with errors of 52% and 12%, respectively. A proof-of-principal animal study was performed in a VX2-tumor in vivo rabbit model using liposomal nanoparticles co-encapsulating contrast for CT (iohexol) and fluorescence (ICG) imaging. Fusion of CBCT and FT reconstructions demonstrated concurrent anatomical and functional delineations of contrast enhancement around the periphery of the buccal tumor. These developments motivate future clinical translation of the FT system into an ongoing CBCT-guided head and neck surgery trial.

Geometric calibration of a mobile C-arm for intraoperative cone-beam CT.

A geometric calibration method that determines a complete description of source-detector geometry was adapted to a mobile C-arm for cone-beam computed tomography (CBCT). The non-iterative calibration algorithm calculates a unique solution for the positions of the source (X(s), Y(s), Z(s)), detector (X(d), Y(d), Z(d)), piercing point (U(o), V(o)), and detector rotation angles (phi, theta, eta) based on projections of a phantom consisting of two plane-parallel circles of ball bearings encased in a cylindrical acrylic tube. The prototype C-arm system was based on a Siemens PowerMobil modified to provide flat-panel CBCT for image-guided interventions. The magnitude of geometric nonidealities in the source-detector orbit was measured, and the short-term (approximately 4 h) and long-term (approximately 6 months) reproducibility of the calibration was evaluated. The C-arm exhibits large geometric nonidealities due to mechanical flex, with maximum departures from the average semicircular orbit of deltaU(o) = 15.8 mm and deltaV(o) = 9.8 mm (for the piercing point), deltaX and deltaY = 6-8 mm and deltaZ = 1 mm (for the source and detector), and deltaphi approximately 2.9 degrees, deltatheta approximately 1.9 degrees, and delta eta approximately 0.8 degrees (for the detector tilt/rotation). Despite such significant departures from a semicircular orbit, these system parameters were found to be reproducible, and therefore correctable by geometric calibration. Short-term reproducibility was < 0.16 mm (subpixel) for the piercing point coordinates, < 0.25 mm for the source-detector X and Y, < 0.035 mm for the source-detector Z, and < 0.02 degrees for the detector angles. Long-term reproducibility was similarly high, demonstrated by image quality and spatial resolution measurements over a period of 6 months. For example, the full-width at half-maximum (FWHM) in axial images of a thin steel wire increased slightly as a function of the time (delta) between calibration and image acquisition: FWHM=0.62, 0.63, 0.66, 0.71, and 0.72 mm at delta = 0 s, 1 h, 1 day, 1 month, and 6 months, respectively. For ongoing clinical trials in CBCT-guided surgery at our institution, geometric calibration is conducted monthly to provide sufficient three-dimensional (3D) image quality while managing time and workflow considerations of the calibration and quality assurance process. The sensitivity of 3D image quality to each of the system parameters was investigated, as was the tolerance to systematic and random errors in the geometric parameters, showing the most sensitive parameters to be the piercing point coordinates (U(o), V(o)) and in-plane positions of the source (X(s), Y(s)) and detector (X(d), Y(d)). Errors in the out-of-plane position of the source (Z(s)) and detector (Z(d)) and the detector angles (phi, theta, eta) were shown to have subtler effects on 3D image quality.

Emergency department visits and unplanned hospitalizations in the treatment period for head and neck cancer patients treated with curative intent: A population-based analysis.

BACKGROUND: Mucosal head and neck squamous cell cancers are often managed with multimodality treatment which can be associated with significant toxicity. The objective of this study was to assess emergency department visits and unplanned hospitalizations for these patients during and immediately after their treatment. METHODS: A cohort of patients treated for head and neck squamous cell carcinoma was developed using administrative data. Emergency department visits and hospitalizations in the 90-day post-treatment period was determined. If a second treatment was initiated prior to the completion of 90 days, the attributable risk period was changed to the second treatment. RESULTS: Cohort of 3898 patients (1312 larynx/hypopharynx; 2586 oral cavity/oropharynx) from 2008 to 2012. The number of unplanned hospitalizations or ED visits (per 100 patient days) were 0.69 for surgery, 0.78 for surgery followed by concurrent chemoradiotherapy (CCRT), 0.55 for surgery followed by radiotherapy, 0.86 for CCRT, and 0.50 for radiation. Patients receiving CCRT had a statistically higher likelihood of treatment period events. The larynx/hypopharynx cancer subsite, higher comorbidity and more advanced stage of disease were all independent predictors of events. CONCLUSIONS: Patients undergoing treatment for head and neck cancer have significant unplanned hospitalizations and visits to the emergency department in the treatment period. Rates are higher in patients receiving CCRT. Quality improvement interventions should be used to improve these rates.

Image quality and localization accuracy in C-arm tomosynthesis-guided head and neck surgery.

The image quality and localization accuracy for C-arm tomosynthesis and cone-beam computed tomography (CBCT) guidance of head and neck surgery were investigated. A continuum in image acquisition was explored, ranging from a single exposure (radiograph) to multiple projections acquired over a limited arc (tomosynthesis) to a full semicircular trajectory (CBCT). Experiments were performed using a prototype mobile C-arm modified to perform 3D image acquisition (a modified Siemens PowerMobil). The tradeoffs in image quality associated with the extent of the source-detector arc (theta(tot)), the number of projection views, and the total imaging dose were evaluated in phantom and cadaver studies. Surgical localization performance was evaluated using three cadaver heads imaged as a function of theta(tot). Six localization tasks were considered, ranging from high-contrast feature identification (e.g., tip of a K-wire pointer) to more challenging soft-tissue delineation (e.g., junction of the hard and soft palate). Five head and neck surgeons and one radiologist participated as observers. For each localization task, the 3D coordinates of landmarks pinpointed by each observer were analyzed as a function of theta(tot). For all tomosynthesis angles, image quality was highest in the coronal plane, whereas sagittal and axial planes exhibited a substantial decrease in spatial resolution associated with out-of-plane blur and distortion. Tasks involving complex, lower-contrast features demonstrated steeper degradation with smaller tomosynthetic arc. Localization accuracy in the coronal plane was correspondingly high, maintained to < 3 mm down to theta(tot) approximately 30 degrees, whereas sagittal and axial localization degraded rapidly below theta(tot) approximately 60 degrees. Similarly, localization precision was better than approximately 1 mm within the coronal plane, compared to approximately 2-3 mm out-of-plane for tomosynthesis angles below theta(tot) approximately 45 degrees. An overall 3D localization accuracy of approximately 2.5 mm was achieved with theta(tot) approximately 90 degrees for most tasks. The high in-plane spatial resolution, short scanning time, and low radiation dose characteristic of tomosynthesis may enable the surgeon to collect near real-time images throughout the procedure with minimal interference to surgical workflow. Therefore, tomosynthesis could provide a useful addition to the image-guided surgery arsenal, providing on-demand, high quality image updates, complemented by CBCT at critical milestones in the surgical procedure.

Intraoperative cone-beam CT for guidance of head and neck surgery: Assessment of dose and image quality using a C-arm prototype.

Cone-beam computed tomography (CBCT) with a flat-panel detector represents a promising modality for intraoperative imaging in interventional procedures, demonstrating sub-mm three-dimensional (3D) spatial resolution and soft-tissue visibility. Measurements of patient dose and in-room exposure for CBCT-guided head and neck surgery are reported, and the 3D imaging performance as a function of dose and other acquisition/reconstruction parameters is investigated. Measurements were performed on a mobile isocentric C-arm (Siemens PowerMobil) modified in collaboration with Siemens Medical Solutions (Erlangen, Germany) to provide flat-panel CBCT. Imaging dose was measured in a custom-built 16 cm cylindrical head phantom at four positions (isocenter, anterior, posterior, and lateral) as a function of kVp (80-120 kVp) and C-arm trajectory ("tube-under" and "tube-over" half-rotation orbits). At 100 kVp, for example ("tube-under" orbit), the imaging dose was 0.059 (isocenter), 0.022 (anterior), 0.10 (posterior), and 0.056 (lateral) mGy/ mAs, with scans at approximately 50 and approximately 170 mAs typical for visualization of bony and soft-tissue structures, respectively. Dose to radiosensitive structures (viz., the eyes and thyroid) were considered in particular: significant dose sparing to the eyes (a factor of 5) was achieved using a "tube-under" (rather than "tube-over") half-rotation orbit; a thyroid shield (0.5 mm Pb-equivalent) gave moderate reduction in thyroid dose due to x-ray scatter outside the primary field of view. In-room exposure was measured at positions around the operating table and up to 2 m from isocenter. A typical CBCT scan (10 mGy to isocenter) gave in-air exposure ranging from 29 mR (0.26 mSv) at 35 cm from isocenter, to <0.5 mR (<0.005 mSv) at 2 m from isocenter. Three-dimensional (3D) image quality was assessed in CBCT reconstructions of an anthropomorphic head phantom containing contrast-detail spheres (11-103 HU; 1.6-12.7 mm) and a natural human skeleton. The contrast-to-noise ratio (CNR) was evaluated across a broad range of dose (0.6-23.3 mGy). CNR increased as the square root of dose, with excellent visualization of bony and soft-tissue structures achieved at approximately 3 mGy (0.10 mSv) and approximately 10 mGy (0.35 mSv), respectively. The prototype C-arm demonstrates CBCT image quality sufficient for guidance of head and neck procedures based on soft-tissue and bony anatomy at dose levels low enough for repeat intraoperative imaging, with total dose over the course of the procedure comparable to or less than the effective dose of a typical (2 mSv) diagnostic CT of the head.

Explaining socioeconomic status effects in laryngeal cancer.

INTRODUCTION: People with lower socioeconomic status (SES) experience shorter survival times after a cancer diagnosis for many disease sites. We determined whether area-level SES was associated with the outcomes: cause-specific survival and local-regional failure in laryngeal cancer in Ontario, Canada. When we found an association we sought explanations that might be related to access to care including age, sex, rural residence, tumor stage, lymph node status, use of diagnostic imaging, treatment type, percentage of prescribed radiotherapy delivered, number of radiotherapy interruption days, treatment waiting time, and treating cancer center. MATERIALS AND METHODS: The study population consisted of 661 glottic and 495 supraglottic stage-stratified randomly-sampled patients identified using the Ontario Cancer Registry. Area-level SES quintiles were assigned using adjusted median household income from the Canadian Census. Other data were collected from patient charts. Explanations for SES effects were determined by measuring whether the effect moved toward the null value by at least 10% when an access indicator was added to a the model. RESULTS: Socioeconomic status was not related to either outcome for those with supraglottic cancer, but an association was present in glottic cancer. With the highest socioeconomic status quintile as the referent group, the relative risks for patients in the lowest socioeconomic quintile were 2.75 (95% CI 1.48, 5.12) for cause-specific survival and 1.90 (95% CI 1.24, 2.93) for local-regional failure. Disease stage as measured by T-category explained between 3% and 23% of these socioeconomic effects. None of the other access indicators met our 10% change criterion. CONCLUSION: We question why people in lower socioeconomic quintiles were not diagnosed earlier in the disease progression. Having ruled out several variables that may be related to access to care, additional biologic and social variables should be examined to further understand socioeconomic status effects.

Nasopharyngeal brush biopsies and detection of nasopharyngeal cancer in a high-risk population.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is an important tumor in many countries. Ethnic and regional factors strongly influence disease risk. NPC is usually diagnosed late in disease development, and 10-year survival rates are as low as 10%. Epstein-Barr virus (EBV), a possibly causative agent, is present in all cells of essentially all undifferentiated NPCs. We wished to determine the following: 1) whether an ambulatory nasopharyngeal brush biopsy could provide sufficient tumor cell DNA for the detection of EBV and 2) whether the detection of EBV in this locale reflects the presence of tumor cells or simply EBV carrier status. METHODS: We collected nasopharyngeal tissue via ambulatory brush biopsies from 21 patients with newly diagnosed NPC and from 157 subjects with other otolaryngologic complaints. The majority of study subjects were from high-risk populations. Sample DNA was analyzed for the presence of EBV genomic sequences by use of the polymerase chain reaction (PCR). RESULTS: Ninety-six percent of samples yielded sufficient DNA for PCR amplification. Nineteen of 21 patients with NPC brushed positive for EBV DNA, while all but two (1.3%) of 149 informative control subjects were negative for EBV (two-sided P<.0001). One of the EBV-positive control subjects had an EBV-positive inverted sinonasal papilloma; the other EBV-positive control subject exhibited no overt clinical disease. CONCLUSION: Demonstration of EBV DNA in nasopharyngeal brush biopsy specimens detects NPC with a sensitivity of at least 90% (95% confidence interval = 89.63%-91.32%) and a specificity of approximately 99% (95% confidence interval = 98.64%-98.68%). This technique merits further testing as a possible ambulatory screening strategy in high-risk populations.

Correlation between clinical and MRI assessment of depth of invasion in oral tongue squamous cell carcinoma.

BACKGROUND: Neck metastasis is the most important prognostic factor in oral cavity squamous cell carcinomas (SCC). Apart from the T- stage, depth of invasion has been used as a highly predictable factor for microscopic neck metastasis, despite the controversy on the exact depth cut off point. Depth of invasion can be determined clinically and radio logically. However, there is no standard tool to determine depth of invasion preoperatively. Although MRI is used widely to stage the head and neck disease, its utility in depth evaluation has not formally been assessed. OBJECTIVE: To compare preoperative clinical and radiological depth evaluation in oral tongue SCC using the standard pathological depth. To compare clinical and radiological accuracy between superficial (<5 mm) vs. deep invaded tumor (≥5 mm) METHODS: This prospective study used consecutive biopsy-proven oral tongue invasive SCC that presented to the University health network (UHN), Toronto. Clinical examination, radiological scan and appropriate staging were determined preoperatively. Standard pathology reports postoperatively were reviewed to determine the depth of invasion from the tumor specimen. RESULTS: 72 tumour samples were available for analysis and 53 patients were included. For all tumors, both clinical depth (r = 0.779; p < 0.001) and radiographic depth (r =0.907; p <0.001) correlated well with pathological depth, with radiographic depth correlating slightly better. Clinical depth also correlated well with radiographic depth (r = 0.731; p < 0.001). By contrast, for superficial tumors (less than 5 mm on pathological measurement) neither clinical (r = 0.333, p = 0.34) nor radiographic examination (r = - 0.211; p = 0.56) correlated with pathological depth of invasion. CONCLUSION: This is the first study evaluating the clinical assessment of tumor thickness in comparison to radiographic interpretation in oral cavity cancer. There are strong correlations between pathological, radiological, and clinical measurements in deep tumors (≥5 mm). In superficial tumors (<5 mm), clinical and radiological examination had low correlation with pathological thickness.

Investigation of C-arm cone-beam CT-guided surgery of the frontal recess.

OBJECTIVE/HYPOTHESIS: A cone-beam CT (CBCT) imaging system based on a mobile C-arm (Siemens PowerMobil) incorporating a high-performance flat-panel detector (Varian PaxScan) has been developed in our laboratory. We hypothesize that intraoperative C-arm CBCT provides image quality and guidance performance sufficient to assist surgical approach to the frontal recess. STUDY DESIGN: A preclinical prospective study was conducted using six cadaver heads to assess the performance characteristics and the potential clinical utility of this imaging system. METHODS: The mobile C-arm was employed for intraoperative CBCT guidance of the endoscopic approach to twelve frontal recesses. RESULTS: The imaging system is capable of sub-mm 3D spatial resolution with bone and soft-tissue visibility and a field of view sufficient for guidance of head and neck surgery. The system can generate intraoperative, volumetric CT images rapidly with an acceptably low radiation exposure to the patient and with image quality sufficient for most surgical tasks. Moreover, the system is portable and compatible with the surgical setup, providing excellent access to the patient. Finally, the accuracy of the system is not bound to a registration process. CONCLUSIONS: The ability to create updated images as surgery progresses introduces the concept of 'near-real-time' CT guidance for head and neck surgery. We found that the use of CBCT increased surgical confidence in accessing the frontal recess, resolved ambiguities with anatomical variations, and provided valuable teaching information to surgeons in training in both preoperative planning and correlation between tri-planar CT scans and intraoperative endoscopic findings.

Glottic cancer in Ontario, Canada and the SEER areas of the United States. Do different management philosophies produce different outcome profiles?

We compared the management and outcome of glottic cancer in Ontario, Canada to that in the Surveillance, Epidemiology and End Results (SEER) Program areas in the United States to determine whether the greater use of primary radiotherapy with surgery reserved for salvage in Ontario was associated with similar survival and better larynx retention rates than the U.S. approach where primary surgery is used more often. Electronic, clinical and hospital data were linked to cancer registry data and supplemented by chart review where necessary. Initial treatment and survival in patients diagnosed in the SEER areas from 1988 through 1994 were compared to patients from Ontario diagnosed from 1982 through 1995. Actuarial laryngectomy rates were compared for patients over 65 at diagnosis in the two regions. Analyses were conducted over all cases and stratified by disease stage. In localized disease (T1 or T2), conservative treatment was the most common initial treatment in both regions, although total laryngectomy was used more often in SEER than Ontario (6.2% vs. 0.2%, respectively, P <.001). In advanced disease (T3 or T4), total laryngectomy was more commonly used as initial treatment in SEER (62.9% vs. 21.0% in Ontario, P < or =.001). Over all cases, the relative survival rate was 80% in Ontario at 5 years compared to 78% in SEER (P =.33). In localized disease, the relative survival rates were 4 to 5% higher in Ontario from the second year on, while in advanced disease 2 to 3% higher rates in SEER did not approach statistical significance. Actuarial laryngectomy rates at 3 years differed between the two regions, with a 4% higher rate in SEER (P =.01). In localized disease, 12.6% of Ontario patients had a laryngectomy by 3 years postdiagnosis compared to 17.9% in SEER (P =.05). In advanced disease, the rates were 63.3% and 79.2%, respectively (P =.07). There are large differences in the management of glottic cancer between the SEER areas of the U.S. and Ontario and no evidence that a policy emphasizing radiotherapy with surgery reserved for salvage is associated with worse survival. Ultimate laryngectomy rates are lower in Ontario for localized disease and may be lower for advanced disease. Conservation treatment should be used for localized disease while the treatment decision in advanced disease may be especially sensitive to patient values for voice retention versus initial cure.

Oncogenes in head and neck cancer.

Primary head and neck squamous cell carcinomas from 58 patients were analyzed for the presence of alterations in the K-ras, raf, and erb-B oncogenes. Analysis of 17 fresh tumor specimens using sequence analysis of target sequences amplified by the polymerase chain reaction showed no evidence of mutations in the K-ras oncogene. Thirty fresh tumor specimens were analyzed for the presence of raf gene activation using Southern blot analysis. Under these conditions, no mutations in the c-raf oncogene were detected. In this study, 6 (13%) of the 47 tumors studied displayed epidermal growth factor receptor (EGFR) gene amplification and/or gene rearrangement. Overexpression of the erb-B gene was observed in 18 (67%) of the 27 head and neck tumors studied. Those patients expressing high levels of EGFR or showing EGFR amplification had tumors that were clinically more advanced. These data suggest that amplification and over-expression of the EGFR gene may be a useful diagnostic and prognostic marker in head and neck squamous cell carcinomas.

Botulinum toxin for essential tremor of the voice with multiple anatomical sites of tremor: a crossover design study of unilateral versus bilateral injection.

OBJECTIVES/HYPOTHESIS: To evaluate the relative efficacy of unilateral and bilateral injections of botulinum toxin injection (BOTOX) in the treatment of essential tremor of the voice (ETV). STUDY DESIGN: Prospective open-label crossover study. METHODS: Patients referred to the Neurolaryngology Clinic at Toronto General Hospital with a diagnosis of ETV were eligible for the study. Patients were sequentially assigned to receive BOTOX as either a bilateral 2.5-U or a unilateral 15-U electromyography-guided injection, followed by the alternative injection 16 to 18 weeks later. Acoustic, aerodynamic, and nasopharyngoscopic data were collected approximately 2, 6, 10, and 16 weeks after each injection. Patients were asked to provide a perceptual evaluation of BOTOX effects at the conclusion of the study. RESULTS: Three of 10 patients demonstrated an objective reduction in tremor severity with bilateral injection, and 2 of 9 with unilateral injection. However, 8 of 10 patients wished to be re-injected at the conclusion of the study. A reduction in vocal effort appeared to be coincident with reduction in laryngeal airway resistance after BOTOX injection. CONCLUSIONS: Using objective acoustic measures, only a small proportion of patients achieved benefit from BOTOX injection for ETV. However, a majority of patients in our study benefited from a subjective reduction in vocal effort that may have been attributable to reduced laryngeal airway resistance.

Effects of botulinum toxin type A injections on aerodynamic measures of spasmodic dysphonia.

The effects of botulinum toxin type A (BOTOX) injections on aerodynamic measures of phonation were examined in 30 patients with adductor spasmodic dysphonia. Patients received bilateral injections of 2.5 U of botulinum toxin type A in each thyroarytenoid muscle. Measures of air pressure, average airflow, coefficient of variation (CV) of airflow, and laryngeal resistance were obtained before the injections and at 2 and 10 weeks after the injections. These measures were also obtained from 12 normal subjects. Compared with normal subjects, the spasmodic dysphonia patients had significantly higher preinjection values for air pressure, CV of airflow, and laryngeal resistance. At 2 and 10 weeks after the botulinum toxin type A injections, the spasmodic dysphonia patients showed a significant increase in the average airflow values and a significant decrease in the CV of airflow values and the laryngeal resistance values. At 10 weeks after the injections, the values for the three measures began to approach the preinjection values. It is concluded that these aerodynamic measures of phonation can provide useful measures of treatment outcome in adductor spasmodic dysphonia.

Effects of medialization laryngoplasty on airway resistance: a pilot study.

OBJECTIVE: To investigate the effects of medialization laryngoplasty on laryngeal airway resistance at various clinically relevant flow rates. STUDY DESIGN: This study was conducted using a total of 13 laboratory experiments. Two of the experiments were used to validate the cadaveric model employed. Eleven experiments were used to quantify airway resistance relative to increasing medialization laryngoplasty stent size. METHODS: With autopsy consent the authors obtained 13 consecutive and anatomically complete larynges for experimentation. A thyrotomy window measuring 8 x 6 mm was made on the left side of the thyroid cartilage. A #4 laryngeal mask was secured to the pharyngeal airway with sutures. Eleven experiments were conducted at the same flow rates using increasingly larger stents from 1 mm to 11 mm in size. Using the Bernoulli equation, the pressure measured at the proximal end of the laryngeal mask is representative of the pressure drop across the airway. The experimental model was validated in two experiments using flow rates between 5 and 50 L/min and stents measured at 5, 10, 15, and 20 mm. RESULTS: Average results from the 11 experiments indicate that at increasing levels of medialization, from 0 to 11 mm, there is essentially the same pressure drop across the larynx at a given flow rate. CONCLUSION: At physiologic airflow rates in a cadaveric model, medialization laryngoplasty implants of 11 mm or less seem to have no obvious effect on airway resistance.

A matched control study of treatment outcome in young patients with squamous cell carcinoma of the head and neck.

OBJECTIVES/HYPOTHESIS: To determine if there is a difference in overall survival, cause-specific survival, and relapse-free rate between young patients (<40 years of age) with head and neck squamous cell carcinoma (HNSCC) and older patients (>40 years of age). STUDY DESIGN: A matched control study describing the outcome of 185 previously untreated HNSCC patients less than 40 years of age treated at the Princess Margaret Hospital, Toronto, Ontario, Canada, between 1958 and 1992. The young patient group was compared with a control group of older patients (> 40 years of age) which was selected randomly from an entire cohort of patients (n = 10,072) and matched for site, sex, and date of presentation. METHODS: The medical records were reviewed and data abstracted for demographic information, tobacco and alcohol use, family history, primary site, clinical stage, primary treatment, histology, the occurrence of residual or recurrent disease, salvage treatment, development of subsequent primaries, survival, and the eventual cause of death. The patient's TNM stage was reclassified according to American Joint Cancer Committee/Union Internationale Contre le Cancer (AJCC/UICC) 1992 criteria on the basis of the initial clinical description and staging investigations. A multivariate regression analysis was performed. To assess the importance of age as a prognostic factor for survival, the Cox proportion hazard model was used. Smoking status was also tested in the stratified Cox proportional hazard model. RESULTS: Tumor stage and treatment modalities were comparable in both groups. The 5-year, cause-specific survival in both groups was not statistically different (72% vs. 68%, P = .91). The young patient group had a significantly better 5-year overall survival compared with the older patient group (68% vs. 49%, P = .0011). Older patients developed more subsequent primary neoplasms than the younger patient population (18% vs. 8%, P = .005). There were significantly more females, an increased incidence of oral or oropharyngeal cancer, and fewer smokers in the young patient group. Smoking, however, had an important impact on outcome with all but one patient who developed a second primary in the upper aerodigestive tract having smoked. Multivariate analysis showed that only disease stage and cancer site were significant prognostic factors for survival. CONCLUSIONS: Young patients with HNSCC do not have a worse prognosis than a matched older patient group in this case-controlled study (power > 0.75 for a minimal detectable difference of 10% disease-free survival between the two groups).

The free vascularized flap and the flap plate options: comparative results of reconstruction of lateral mandibular defects.

OBJECTIVES/HYPOTHESIS: Reconstruction of the mandible and oral cavity after segmental resection is a challenging surgical problem. Although osteocutaneous free flaps are generally accepted to be optimal for reconstruction of anterior defects, the need for bony reconstruction for a pure lateral mandibular defect remains controversial. STUDY DESIGN: A retrospective study. METHODS: A retrospective comparative study of short- and long-term outcomes of three different reconstruction techniques for lateral defects was performed. In total, 57 patients were included, of whom 27 had a plate and pedicled pectoralis major myocutaneous flap (PMMF group), 16 had a plate and free radial forearm flap (FRFF group), and 14 had an osteocutaneous free flap. Functionality, flap failure, and complications were scored. RESULTS: Plates had to be removed in 7 of the 27 patients in the PMMF group and 2 of the 16 in the FRFF group; none of the 14 osteocutaneous free flaps failed. The difference was of borderline statistical significance (P = .055). Longterm functional outcome revealed no statistically significant difference in oral deglutition (P = .76) or in facial contour (P = .36). Oral continence was significantly better in patients in the FRFF group (88%) as compared with the PMMF group (52%) or the osteocutaneous free flap group (43%) (P = .02). On the other hand, the results for speech favored the osteocutaneous free flap group; 13 of 14 patients (92.9%) had a normal score compared with 12 of 16 patients (75%) in the FRFF group and 17 of 27 (63%) in the PMMF group. However, this represented a borderline statistically significant result (P = .06). CONCLUSIONS: For lateral mandibular defects, the osteocutaneous free flap is reliable and durable in the long term. However, in a selected group of patients either of the two flap-plate options is a viable reconstructive option.