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La radiothérapie hypofractionnée du carcinome épidermoïde du larynx glottique, de stade précoce, est une option de traitement prometteuse. Celle-ci peut être divisée en radiothérapie avec hypofractionnement modérée (jusque 2,5 Gy par fraction), hypofractionnement plus intense (entre 2,5 et 4,5 Gy par fraction) et radiothérapie stéréotaxique (au-delà de 4,5 Gy par fraction). La plupart des études évaluant l'hypofractionnement modéré montrent un taux de contrôle local entre 85 et 95 %. La toxicité aiguë laryngée est plus sévère que celle du traitement classique, mais uniquement pour les cancers de grades 1 et 2, sans différence significative rapportée pour la toxicité sévère. La radiothérapie stéréotaxique est également une entité émergente, mais certains auteurs ont rapporté une toxicité non négligeable. Il n'existe pas aujourd'hui, de directives standardisées pour le traitement et le schéma de prise en charge. Nous avons réalisé une revue systématique de la littérature des essais prospectifs et rétrospectifs publiés, afin d'évaluer l'efficacité, la toxicité, et de discuter des orientations futures. Hypofractionated radiotherapy of early-stage squamous cell carcinoma of the glottic larynx is a promising treatment option. This can be divided into radiotherapy with moderate hypofractionation (up to 2.5 Gy per fraction), more intense hypofractionation (between 2.5 and 4.5 Gy per fraction) and stereotactic radiotherapy (above 4.5 Gy per fraction). Most studies evaluating moderate hypofractionation show a local control rate between 85 and 95%. Acute laryngeal toxicity is superior to conventional treatment, but only for grades 1 and 2, with no significant difference reported for severe toxicity. Stereotactic radiotherapy in this pathology is also an emerging entity, but some authors have reported significant toxicity. There are currently no standardized guidelines for treatment and management regimen. We conducted a systemic review of published prospective and retrospective trials to evaluate efficacy, toxicity, and discuss future directions. [ABSTRACT FROM AUTHOR]

We aimed to investigate possible causes of leukoplakia and squamous cell carcinoma. We particularly sought to characterize the effect of smoking history because leukoplakia has been observed in nonsmokers. We retrospectively identified patients with a diagnosis of leukoplakia who were treated at Mayo Clinic (Jacksonville, Florida), in the Department of Otorhinolaryngology, from 1/1/2006 through 8/31/2019. Each patient was age- and sex-matched (1:2 ratio) to control patients without leukoplakia. Information about possible risk factors, chief symptoms, and social history with smoking and alcohol use was obtained from health records. Nine risk factors were analyzed independently with multivariate analysis. Continuous risk factors were compared between cases and controls with the Wilcoxon rank sum test; categorical variables were compared with the χ2 test. The final cohort consisted of 72 patients with leukoplakia (mean [SD] age, 66 [11] years; 61 men [85%]) and 144 age- and sex-matched controls. Compared with the control group, significantly more cases were current smokers (26% vs. 5%) and fewer were never-smokers. (17% vs. 51%) (P < 0.001). Cases also had a significantly longer duration of smoking history compared with controls (median, 30 vs. 0 years; P < 0.001). Alcohol consumption was not significantly different between cases and controls (53% vs. 54%; P > 0.99). When assessing never-smokers and those who had not smoked for more than 25 years, a history of smoking (P = 0.002) and the number of years smoked (P = 0.002) were significantly different for cases and controls. Most vocal fold leukoplakia lesions have a low risk of malignancy. It is important to evaluate the characteristics of the lesion and assess the patient's risk factors. Follow-up is a key factor in patient management, but for patients with recurrent leukoplakia, the duration and frequency of surveillance is still controversial and varies among medical centers. Future prospective studies with advanced analyses are warranted because they may strengthen the ability to identify clinical factors that influence the development of squamous cell carcinoma. [ABSTRACT FROM AUTHOR]

For early-stage glottic cancers, intensity-modulated radiation therapy (IMRT) has been shown to have comparable local control to 3D-conformal radiotherapy with the advantage of decreased dose to the carotid arteries. The planning target volume (PTV) for early glottic cancers typically includes the entire larynx, plus a 3 to 5 mm uniform margin. The air cavity within the larynx creates a challenge for the inverse optimization process as the software attempts to "build up" dose within the air. This unnecessary attempt at dose build-up in air can lead to hot spots within the rest of the PTV and surrounding soft tissue. We hypothesized that removal of the air from the PTV would decrease hot spots and allow for a more homogeneous plan while still maintaining adequate coverage of the PTV. We analyzed 20 consecutive patients with early-stage glottic cancer, T1-2N0, who received IMRT at our institution from April 2015 to December 2016. Each patient received 63 to 65.25 Gy in 2.25 Gy per fraction. Two plans were created for each case: one in which the PTV included the laryngeal air cavity and one in which the air cavity was subtracted from the PTV to create a new PTV-air structure. Dosimetric variables were collected for PTV-air structure from both IMRT plans, including V100%, D98% D2%, and D0.2%. Dosimetric variables for spinal cord and the carotid arteries were also recorded. Homogeneity index (HI) defined as D98/D2 was calculated. Two-sided t-tests were used to compare dosimetric variables. The median PTV volume was 69.9 cc (standard deviation [SD] ± 28.7 cc) and the median air cavity volume removed was 11.0 cc (SD ± 3.4 cc). A 2-sided t-test revealed a statistically significant decrease in max dose (112.7% vs 108.8%, p value = 0.0002) and improvement of HI (0.93 vs 0.91, p value = 0.0023) for the PTV air in the IMRT plan optimized for PTV air, which had air excluded, compared to the IMRT plan optimized for PTV with air included. There was no significant worsening of PTV-air coverage or significant increase in doses to the organs at risk (OARs). The removal of the air cavity from the PTV for early-stage glottic cancers does not compromise PTV coverage or sparing of OARs and can result in a more homogeneous IMRT plan. A more homogeneous plan has the potential to reduce treatment morbidity, although further study is warranted to investigate the clinical impact of air cavity removal from the PTV. [ABSTRACT FROM AUTHOR]

Objectives: The impact of positive tumor margin status and other clinicopathological factors on prognosis in early stage glottic squamous cell carcinoma (SCC) treated with transoral laser microsurgery (TLM) remains unclear. This study examined overall survival (OS) rates of patients with positive tumor margin status compared to negative tumor margin status after TLM in clinical T1-2 glottic SCC.Materials and Methods: The National Cancer Data Base (NCDB) was queried for patients who underwent resection of T1-2 glottic SCC by TLM. Patients were treated from 2004 to 2013. Overall survival was assessed with Kaplan-Meier curve analysis, and univariate and multivariate Cox proportional hazards analysis. Differences in clinicopathologic factors between positive and negative margin groups were compared using Pearson Chi-squared analysis.Results: Of 747 patients meeting inclusion criteria, 598 (80.1%) had negative margins. Median follow-up time was 48.0 months. Unadjusted 5-year OS for positive margins (80.0%) was lower compared to that of negative tumor margins (82.9%), but this was not statistically significant (P = 0.265). This persisted after multivariate analysis (P = 0.960). When tumors were stratified by T stage (647 T1, 100 T2), unadjusted 5-year OS based on margin status remained statistically insignificant for both T1 (P = 0.933) and T2 tumors (P = 0.350).Conclusion: Positive margins did not negatively impact overall survival among patients with TLM-treated early-stage glottic cancer. This finding might be useful clinically in deciding treatment modality for early stage glottic SCC. [ABSTRACT FROM AUTHOR]

Objectives: To perform a systematic review of 1762 patients to comprehensively assess the benefit of altered-fractionation radiotherapy (ART) in early stage glottic carcinoma (ESGC).Materials and Methods: Studies were identified in PubMed and EMBASE. Inclusion criteria were: (1) diagnosis of squamous cell ESGC (Tis, T1, T2); (2) ART versus conventionally-fractionationated radiotherapy (CRT); and (3) provision of number of local recurrence events and total numbers per fractionation arm. The random-effects model was fitted to estimate the pooled hazard ratio (HR). Subgroup sensitivity analyses were performed based on ART strategy (hypo- versus hyperfractionation), treatment-day reductions, machine type, tumor stage, and anterior commissure involvement.Results: Eleven studies met inclusion criteria: 4 randomized controlled trials (RCTs) and 7 two-arm retrospective studies. ART was associated with 38% fewer (HR 0.62; 95% CI: 0.46-0.82, p = 0.0009) and 60% fewer (HR 0.40; 95% CI: 0.24-0.66, p = 0.0003) local failure events in pooled analyses of the RCTs and retrospective studies, respectively. Both hyperfractionation (HR 0.65; 95% CI: 0.43-0.97, p = 0.03) and hypofractionation (HR 0.55; 95% CI: 0.33-0.91, p = 0.02) strategies were superior to CRT. The benefit persisted for all treatment- and tumor-related parameters, including anterior commissure involvement, with the exception of a pooled analysis of studies with predominantly T2 (<50% T1) cases (HR 0.60, 95% CI: 0.30-1.20, p = 0.15).Conclusion: Both hypofractionation and hyperfractionation improve local control in ESGC, including T1 tumors and for anterior commissure involvement. However, this benefit may not persist for T2 tumors, for which alternative strategies should be considered. [ABSTRACT FROM AUTHOR]

Summary Objectives The aim of this study was to investigate long-term voice outcomes and voice-related quality of life (QOL) for early glottic cancer treated with radiotherapy. Study Design Long-term exploratory follow-up study of a prospective patient cohort comparing outcomes at a mean of 11 years postradiotherapy with the original 1-year posttreatment results. Method Eight patients completed voice tasks for auditory perception and acoustic and aerodynamic measures. Patient-reported voice-related QOL (VR-QOL) and voice quality were measured. Changes in outcomes over time were analysed using repeated-measures linear mixed models. Results Acoustic and aerodynamic outcomes remained stable from 1 year postradiotherapy to long-term follow-up, with only jitter mildly increasing from 1.9% at 1 year posttreatment to 2.8% (difference = 1.0%, 95% confidence interval [CI] = 0.1–1.9). Perceptually, voice remained relatively stable with only phonation breaks slightly increasing within the normal range, from 1.1 to 1.7 (difference = 0.6, 95% CI = 0.3–0.9) and breathy quality increasing from normal to slight impairment, with scores increasing from 1.8 to 2.4 (difference = 0.6, 95% CI = 0.3–1.1). QOL scores indicate a good level of VR-QOL that were unchanged at long-term follow-up when compared with 1 year posttreatment. Conclusions Improvement in voice outcomes found at 1 year postradiotherapy were largely maintained long term, with only minor changes observed. QOL scores indicate that a high level of VR-QOL was maintained many years after curative radiotherapy. [ABSTRACT FROM AUTHOR]

Background: We assessed the non-inferiority of accelerated fractionation (AF) (2.4 Gy/fraction) compared with standard fractionation (SF) (2 Gy/fraction) regarding progression-free survival (PFS) in patients with T1-2N0M0 glottic cancer (GC). Patients and methods: In this multi-institutional, randomized, phase III trial, patients were enrolled from 32 Japanese institutions. Key inclusion criteria were GC T1-2N0M0, age 20-80, Eastern Cooperative Oncology Group performance status of 0-1, and adequate organ function. Patients were randomly assigned to receive either SF of 66-70 Gy (33-35 fractions), or AF of 60-64.8 Gy (25-27 fractions). The primary end point was the proportion of 3-year PFS. The planned sample size was 360 with a non-inferiority margin of 5%. Results: Between 2007 and 2013, 370 patients were randomized (184/186 to SF/AF). Three-year PFS was 79.9% (95% confidence interval [CI] 73.4-85.4) for SF and 81.7% (95% CI 75.4-87.0) for AF (difference 1.8%, 91% CI-5.1% to 8.8%; onesided P=0.047>0.045). The cumulative incidences of local failure at 3 years for SF/AF were 15.9%/10.3%. No significant difference was observed in 3-year overall survival (OS) between SF and AF. Grade 3 or 4 acute and late toxicities developed in 22 (12.4%)/21 (11.5%) and 2 (1.1%)/1 (0.5%) in the SF/AF arms. Conclusion: Although the non-inferiority of AF was not confirmed statistically, the similar efficacy and toxicity of AF compared with SF, as well as the practical convenience of its fewer treatment sessions, suggest the potential of AF as a treatment option for early GC. [ABSTRACT FROM AUTHOR]

Objectives: Among patients with T2N0M0 glottic larynx cancer undergoing definitive radiotherapy, recent retrospective and prospective data have suggested improved outcomes with altered fractionation over conventional fractionation (CFxn). We sought to characterize national fractionation patterns and to compare outcomes among them.Materials and Methods: We queried the National Cancer Database for T2N0M0 squamous cell carcinomas of the glottis diagnosed from 2004-2014 and managed with definitive radiotherapy. Dose-per-fraction and duration of radiotherapy were used to define cohorts undergoing CFxn, hypofractionation (HypoFxn), and hyperfractionation (HyperFxn). Logistic regression was performed to identify predictors of receiving altered fractionation. Cox regression and propensity-score matching (PSM) analyses were used to compare survival between schedules.Results: We abstracted 2 006 CFxn patients, 1 166 HypoFxn patients, and 161 HyperFxn patients. Fractionation patterns changed significantly from 2004 to 2014, with use of HyperFxn decreasing from 6.3% to 1.8% and use of HypoFxn increasing from 23.9% to 54.1% (p<0.001). Receipt of altered fractionation was independently associated with later year of diagnosis and higher facility volume. On Cox regression, both HypoFxn (hazard ratio [HR] for mortality 0.84, 95% confidence interval [95%CI] 0.73-0.97) and HyperFxn (HR 0.74, 95%CI 0.56-0.99) were associated with improved survival over CFxn. The survival advantage of each altered fractionation schedule over CFxn was redemonstrated on comparison of PSM groups.Conclusion: Increasing utilization of HypoFxn for T2N0M0 glottic cancer is driving national practice patterns away from CFxn. Our findings support the use of altered fractionation, particularly HypoFxn, for patients undergoing definitive radiotherapy, although HyperFxn remains understudied in a prospective fashion. [ABSTRACT FROM AUTHOR]

Purpose The main objective of this study was to evaluate the 5-year efficacy of exclusive laryngeal radiotherapy without node prophylactic irradiation for localized cancers of the vocal cords. Patients and methods We retrospectively reviewed charts from 258 patients with T1-T2N0 glottic carcinoma irradiated from April 1987 to March 2015 in four France western centers, including pretreated patients. Toxicity was analyzed according to CTCAE v4.0 classification. Results The median follow-up was 50 months. The median age was 67 years with 87% men and 85.5% had T1 tumor. Five years overall survival was 77.5% (95% confidence interval [95% CI]: 71.4–83.5), 5 years local control was 86.8% (95% CI: 82.3–91.3), specific survival rate was 95% (95% CI: 92.2–97.9) and final laryngectomy-free survival was 87.5% (95% CI: 82.2–92.9). Most toxicities were grade 1 and 2. Grade 3 acute toxicity was 15.5% for the radiation laryngitis, 3.5% for radiodermatitis and 7.7% for dysphonia. Grade 3 chronic toxicity was 3.5% for dysphonia and there were two cases of tracheal stenosis treated by tracheotomy. Conclusion Radiotherapy provides good results in local control of stage I and II vocal cords cancers as well as the toxicity level. [ABSTRACT FROM AUTHOR]

Aims Recently, carotid-sparing intensity-modulated radiotherapy (IMRT) for early laryngeal glottis (T1/T2N0M0) cancer has generated interest in the hope of avoiding long-term carotid toxicity, as well as concerns relating to geographical misses and long-term normal tissue toxicity. The aim of this review was to summarise the current literature on carotid-sparing IMRT for early glottis cancer, with particular focus on definitions of target volumes and the carotid arteries as organs at risk. In addition, we make suggestions for standardisation of these structures, dose constraints and dose reporting. Materials and methods From 73 references, 16 articles met the criteria for inclusion in this systematic review. These papers described two case reports, 11 planning studies and three prospective studies. Results There was variation in all target volume definitions with no clear consensus. The greatest variability was in clinical target volume definition. Carotid artery and spinal cord delineation were not always defined and most studies did not use a carotid artery constraint. Of the eight studies that reported carotid artery delineation, no two studies delineated the same length of carotid artery, yet most studies reported mean doses. Most studies used IMRT with three to seven fields. Five studies used arc therapy and two studies used tomotherapy. Conclusion This review highlights a lack of consensus in target volume definitions in carotid-sparing IMRT. Ultimately, long-term prospective data are required to show the benefit of carotid-sparing IMRT. Pooled data will prove useful as most studies will report on small numbers of patients. Therefore, adopting a consensus now on target volume definition, dose constraints and dose reporting will be crucial. [ABSTRACT FROM AUTHOR]

Purpose The DAHANCA 6 trial evaluated tumor response and morbidity after moderate accelerated radiotherapy compared to conventional fractionated radiotherapy in patients treated for glottic squamous cell carcinoma (SCC). Further, the failure pattern and incidence of new primary tumors were explored. Patients and methods Six hundred and ninety-four patients with non-metastatic glottic SCC were randomized between six or five weekly fractions (fx/w) of radiotherapy to the same total dose. The median treatment time was 38 and 46 days, respectively. The primary endpoint was loco-regional failure. Results Median follow-up time was 14.5 years. Of the 177 failures, 167 involved T-site. The cumulative incidence of loco-regional failure (LRF) was 21.6% in the 6 fx/w group and 29.3% in the 5 fx/w group and the corresponding hazard rate (HR) of LRF was 0.72 (CI: 0.53–0.97, p = 0.04). The effect of acceleration on LRF was especially evident in well differentiated tumors (HR = 0.42 (CI: 0.23–0.75) and in T1–2 tumors (HR = 0.60 (CI: 0.41–0.89)). The HR of laryngectomy was 0.72 (CI: 0.50–1.04) in the 6 fx/w group compared to the 5 fx/w group. The hazards of disease-specific death, event-free survival, and overall survival were comparable between the two groups. Significantly more patients experienced severe acute mucositis in the 6 fx/w group but the incidence of late morbidity was comparable between the groups. New primary tumors occurred in 22.5% of the patients. Conclusion Moderate accelerated radiotherapy significantly improved loco-regional control in patients with glottic SCC. [ABSTRACT FROM AUTHOR]

Summary Background Although intensity-modulated radiotherapy (IMRT) is a standard of care for many head and neck cancers, its use for carotid-sparing (CS) therapy in early-stage laryngeal carcinoma is controversial. Methods 330 consecutive patients with early-stage laryngeal carcinoma were treated from 1/1989 to 5/2011, including 282 conventional radiotherapy (CRT) and 48 CS-IMRT patients. The median follow-up was 43 (CS-IMRT) and 66 (CRT) months. Results There was no difference in local failure rates comparing patients undergoing CS-IMRT with CRT, with 3-year local control rates of 88% vs. 89%, respectively ( p = 0.938). Using a 1 cm circumferential margin, the average dose to the left and right carotid arteries was 48.3 and 47.9 Gy, respectively. 88% of locoregional recurrences involved the ipsilateral true vocal cord, including all local recurrences in the IMRT group. Conclusions These results warrant further prospective evaluation of CS-IMRT for early-stage glottic larynx cancer. [ABSTRACT FROM AUTHOR]

Summary: Objective: Study of patients with stage T1N0M0 or T2N0M0 glottic cancer treated by exclusive radiotherapy and comparison of the survival and functional results of this series with those of the literature. Method: Retrospective study of stage T1N0M0 or T2N0M0 glottic cancers diagnosed between 1st January 2000 and 31st December 2010 and treated by exclusive radiotherapy. Evaluation of survival, recurrence and larynx preservation rates. Study centres: CLCC François-Baclesse and CHU de Caen. Patients: Fifty-nine patients (53 men and sixwomen) treated for glottic cancer (57 squamous cell carcinomas, two verrucous carcinomas) comprising 51 T1N0M0 and eight T2N0M0 tumours. Treatment with exclusive radiotherapy (mean dose of 70Grays limited to the thyroid cartilage for 57 patients, with lymph node irradiation for two patients). Results: In this series, five (9.8%) patients with stage T1N0M0 glottic cancer and three patients (37.5%) with stage T2N0M0 glottic cancer relapsed, corresponding to a global recurrence rate of 13.6%. Three of the eight recurrences involved lymph nodes exclusively (N), two patients relapsed exclusively at the primary tumour site (T) and three patients presented local and lymph node recurrence (T and N). Treatment consisted of salvage total laryngectomy with bilateral cervical lymph node dissection in three cases, bilateral cervical lymph node dissection and sensitized radiotherapy in two cases, exclusive chemotherapy in one case, cervical lymph node dissection and cervical radiotherapy in one case. The last patient with recurrence died prior to salvage therapy. The larynx preservation rate was 94.9%. Conclusion: In comparison with the literature, treatment of stage T1-T2N0M0 glottic cancer by exclusive radiotherapy gives very good results, with a larynx preservation rate of 95%. [Copyright &y& Elsevier]

Summary: Objective: To evaluate the long-term voice characteristics and quality of life of early glottic cancer patients after definitive treatment. Study Design: Case series with chart review in a tertiary care medical center in Taiwan. Methods: Forty-two consecutive patients who received radiation therapy (RT) or transoral laser microsurgery (TLM) for early glottic cancer over 12 months were evaluated for voice laboratory data and quality-of-life measurements. Results: Twenty-four patients received RT, and 18 underwent TLM. There was no difference between the two groups on acoustic and aerodynamic voice measures except for modal fundamental frequency in males. In the Functional Assessment of Cancer Therapy-Head and Neck survey, the TLM group had better communication than the RT group, but there were no differences in voice quality and strength. There was also no significant difference in the Voice Handicap Index 10 evaluation. Conclusions: Male patients who received TLM have higher modal fundamental frequency than male patients who received RT and norms. Voice-related life quality is similar in patients regardless of RT or TLM treatment for early glottic cancer, but those who receive TLM have better communication abilities than those who receive RT. [Copyright &y& Elsevier]

Summary: Objectives: Human papillomavirus (HPV) infection is controversial as a causative factor of head and neck cancers despite the relatively high frequency of HPV infection in extragenital organ cancers. We aimed to clarify whether HPV directly affects the oncogenesis and biologic behavior of glottis cancer (GC). Methods: Paraffin block was obtained from 95 patients who were diagnosed as GC and 15 normal controls. HPV genotyping chip, real-time polymerase chain reaction (PCR) was used for identification of prevalence, phenotype, and physical status of HPV. We compared results with the clinicopathological parameters of GC patients. Results: HPV was detected in 7.4% (7 of 95) of GC patients, whereas 0% (0 of 15) of controls. Of the HPV-positive tumors in GCs, HPV-16 was the single most common type and HPV-16 prevalence rate was 57.1% (4 of 7). Among the HPV-16 infected GCs, integration of HPV-16 was found only in one case (1 of 4). There was no significant difference in HPV prevalence between GC and controls and HPV had no significant relation with any clinicopathologic parameters of GC patients. Conclusion: HPV infection may not be a causative factor in the oncogenesis and biologic behavior of GC. [Copyright &y& Elsevier]

Abstract: Objective: Evaluation of clinical and oncological safety of the modified fronto-lateral laryngectomy in the treatment of T1a-b glottic cancer. Methods: Retrospective review of charts of patients managed with classical fronto-lateral laryngectomy or with our modified technique using a cervical fascia flap and a false cord flap to reconstruct the defect. Results: No recurrence of cancer was observed in the present series and slight dysphonia was present in all cases. The patients managed with classical technique required a revision surgery for granulations or anterior synechia in 4 cases; those managed with modified technique did not need a second intervention. Conclusion: The fronto-lateral laryngectomy should be present in the head-neck surgeon armamentarium. In T1a-b glottic cancer this technique gives a good oncological resection, but the postoperative period requires an intensive rehabilitation process. The modification of the classical technique reduces the incidence of a second intervention. [Copyright &y& Elsevier]

Purpose: To investigate the dosimetry and feasibility of carotid-sparing intensity-modulated radiotherapy (IMRT) for early glottic cancer and to report preliminary clinical experience. Methods and Materials: Digital Imaging and Communications in Medicine radiotherapy (DICOM-RT) datasets from 6 T1–2 conventionally treated glottic cancer patients were used to create both conventional IMRT plans. We developed a simplified IMRT planning algorithm with three fields and limited segments. Conventional and IMRT plans were compared using generalized equivalent uniform dose and dose–volume parameters for in-field carotid arteries, target volumes, and organs at risk. We have treated 11 patients with this simplified IMRT technique. Results: Intensity-modulated radiotherapy consistently reduced radiation dose to the carotid arteries (p < 0.05) while maintaining the clinical target volume coverage. With conventional planning, median carotid V35, V50, and V63 were 100%, 100%, and 69.0%, respectively. With IMRT planning these decreased to 2%, 0%, and 0%, respectively (p < 0.01). Radiation planning and treatment times were similar for conventional radiotherapy and IMRT. Treatment results have been excellent thus far. Conclusions: Intensity-modulated radiotherapy significantly reduced unnecessary radiation dose to the carotid arteries compared with conventional lateral fields while maintaining clinical target volume coverage. Further experience and longer follow-up will be required to demonstrate outcomes for cancer control and carotid artery effects. [Copyright &y& Elsevier]

Purpose: To confirm that total number of microvessels per tumor area (TN/TA) and total microvessel perimeter per tumor area (TP/TA) are predictors for radiosensitivity in early-stage glottic carcinoma. Methods and Materials: One hundred twenty consecutive patients with T1-2N0M0 glottic cancer who were treated with radical radiotherapy in three different hospitals in Japan were included in this study. Biopsy specimens from patients were immunostained with anti-CD31 antibody. The TN/TA and TP/TA of each sample were analyzed using a computer-assisted image analysis system. Patients were stratified into high and low groups according to the cut-off values derived from receiver operating characteristic curve analysis. Progression-free survival rates of the different groups were compared. The relationship of microvessel perimeter to vessel maturation was also discussed. Results: Survival analysis showed higher TP/TA to be associated significantly with longer progression-free survival, as compared with the lower-level group (p = 0.031). In multivariate analysis, both TP/TA (p = 0.037) and T stage (p < 0.001) proved to be independent predictive factors. Microvessel perimeter correlated closely with vessel maturity, which suggests that a tumor with high TP/TA contains more functional vessels and as a result contains more oxygenated and radiosensitive cells. Conclusion: Assessment of TP/TA in biopsy specimens, using a computer-assisted analysis system, can predict the radiosensitivity of early-stage glottic carcinoma. High TP/TA may be a better indication for radiotherapy than for partial laryngectomy or laser excision. [Copyright &y& Elsevier]

Abstract: Aims: To prospectively analyze the objective voice quality before and after radiotherapy (RT) for early glottic cancer and to evaluate the role of different factors that may affect it. Methods: Patients with T1-T2N0M0 glottic cancer underwent voice quality assessment before treatment and after radical RT. Post-RT voice quality was compared to the voice at diagnosis and the voice of healthy individuals used as controls. A comprehensive set of voice parameters were measured. The effects of age, smoking history, T stage, anterior commissure (AC) involvement, radiation dose, fractionation and volumes on pre-treatment and post-treatment voice quality were analyzed. Results: The voice quality data of 50 patients were analyzed. Following treatment, there was a significant improvement in the majority of measured parameters. However, perturbation and HNR remained inferior compared to controls. A history of smoking, AC involvement and larger RT volumes resulted in poorer voice parameters following RT. There was no significant impact of age alone. T2 tumors had an inferior voice quality before treatment, but did not remain inferior following RT. Hypofractionated RT did not show any negative impact. Conclusions: There is a considerable improvement of voice quality following RT. Several factors may have specific effects on pre-treatment and post-treatment voice. [Copyright &y& Elsevier]

Abstract: Objective: TNM staging system is not a sufficiently accurate method for predicting the response of an individual patient to a course of radiotherapy. After irradiation, it can become very difficult to assess data obtained by imaging and endoscopy for the diagnosis of both minimal persistent disease and early recurrence. The search for biological parameters that could be used to identify patients who will respond to radiotherapy is crucial. At this study we aimed at evaluating the prognostic significance of immunohistochemical expression of Ki-67, p53 and epidermal growth factor receptor (EGFR) in laryngeal glottic cancer involving the anterior commissure and treated with radiotherapy. Methods: From January 1995 to August 2005, 24 patients with glottic cancer involving the anterior commissure were primary treated with radiotherapy. Six patients presented with T1a, 12 patients with T1b and 6 patients with T2. Biopsies were taken before the radiotherapy treatment started. Radiotherapy was done with the same technique for all patients using a linear accelerator device with beam energy of 4-MV photons. Immunohistochemical staining was performed using avidine–biotin–peroxidase technique with antibodies to Ki-67, p53 and EGFR. Results: p53 and EGFR positive expression values and labeling indices were greater in radioresistant than in radiosensitive tumors but without significant differences. On the other hand, Ki-67 was expressed in all radiosensitive tumors and Ki-67 labeling indices were significantly higher in radiosensitive tumors than radioresistant tumors (p =0.01). Conclusion: We identified overexpression of Ki-67 as predictive marker of radiosensitivity in glottic cancer involving the anterior commissure, with the results showing significant difference between radiosensitive and radioresistant tumors. [Copyright &y& Elsevier]

Purpose: To retrospectively evaluate local control rates, late damage incidence, functional results, and second-tumor occurrence according to the different patient, tumor, and treatment features in a large bi-institutional series of T2 glottic cancer. Methods and Materials: A total of 256 T2 glottic cancer cases treated consecutively with radical intent at the Florence University Radiation Oncology Department (FLO) and at the Radiation Oncology Department of the University of Brescia, Istituto del Radio “O. Alberti” (BS) were studied. Cumulative probability of local control (LC), disease-specific survival (DSS), and overall survival (OS) rates were calculated and compared in the different clinical and therapeutic subgroups by both univariate and multivariate analysis. Types of relapse and their surgical salvage were evaluated, along with the functional results of treatment. Late-damage incidence and second-tumor cumulative probability (STP) were also calculated. Results: In the entire series, 3-year, 5-year, and 10-year OS rates were, respectively, 73%, 59%, and 37%. Corresponding values for cumulative LC probability were 73%, 73%, and 70% and for DSS, 89%, 86%, and 85%, taking into account surgical salvage of relapsed cases. Seventy-three percent of the patients were cured with function preserved. Main determinants of a worse LC at univariate analysis were larger tumor extent and impaired cord mobility. At multivariate analysis, the same factors retained statistical significance. Twenty-year STP was 23%, with second-tumor deaths less frequent than larynx cancer deaths (20 of 256 vs. 30 of 256). Incidence of late damage was higher in the first decade of accrual (22%) than in the last decade (10%, p = 0.03); the same was true for severe late damage (9% vs. 1.8%). Conclusion: Present-day radical radiotherapy can be considered a standard treatment for T2 glottic cancer. Better results are obtained in patients with less extended disease. Late damage is relatively infrequent, but a careful follow-up is warranted for early detection not only of relapses (because salvage surgery is feasible) but also of second malignant tumors, which constitute a relevant but not the leading cause of death in these patients and are potentially curable. [Copyright &y& Elsevier]

Purpose: To retrospectively evaluate local control rates, late damage incidence, functional results, and second tumor occurrence according to the different patient, tumor, and treatment features in a large bi-institutional series of T1 glottic cancer. Methods and Materials: A total of 831 T1 glottic cancer cases treated consecutively with radical intent at the Florence University Radiation Oncology Department (FLO) and at the Radiation Oncology Department of the University of Brescia–Istituto del Radio “O. Alberti” (BS) were studied. Actuarial cumulative local control probability (LC), disease-specific (DSS), and overall survival (OS) rates have been calculated and compared in the different clinical and therapeutic subgroups with both univariate and multivariate analysis. Types of relapse and their surgical salvage have been evaluated, along with the functional results of treatment. Late damage incidence and second tumor cumulative probability (STP) have been also calculated. Results: In the entire series, 3-, 5-, and 10-year OS was equal to 86%, 77%, and 57%, respectively. Corresponding values for LC were 86%, 84%, and 83% and for DSS 96%, 95%, and 93%, taking into account surgical salvage of relapsed cases. Eighty-seven percent of the patients were cured with function preserved. Main determinants of a worse LC at univariate analysis were: male gender, earlier treatment period, larger tumor extent, anterior commissure involvement, and the use of Cobalt 60. At multivariate analysis, only gender, tumor extent, anterior commissure involvement, and beam type retained statistical significance. Higher total doses and larger field sizes are significantly related (logistic regression) with a higher late damage incidence. Scatterplot analysis of various combinations of field dimensions and total dose showed that field dimensions >35 and <49 cm2, together with doses of >65 Gy, offer the best local control results together with an acceptably low late damage incidence. Twenty-year STP was equal to 23%, with second tumor deaths being more frequent than larynx cancer deaths (67 of 831 vs. 46/831). Conclusion: The results of this study support the opinion, suggested by some international guidelines, that radiotherapy is standard treatment for T1 glottic cancer. Better results are obtained in patients with less extended disease and with 4–6 MV photon beams. The use of doses in excess of 65 Gy and of field sizes of 36–49 cm2 is probably the best technical choice available. Late damage is infrequent, but careful follow-up is warranted to detect early not only relapses (because conservative salvage surgery is feasible), but also second malignant tumors, which constitute the main cause of death in these patients and are potentially curable. [Copyright &y& Elsevier]

Purpose: To study the relationship between the durations of symptoms before the start of radiotherapy and treatment outcome in Stage I–III glottic cancer. Methods and materials: From 1965 to 1997, 611 glottic cancer patients from the Southern Region of Denmark were treated with primary radiotherapy. A total of 544 patients fulfilled the criteria for inclusion to the study (Stage I–III glottic cancer, a duration of symptoms less than or equal to 36 months, primary radiotherapy with at least 50 Gy and sufficient data for analysis). The total radiation dose ranged from 50.0 to 71.6 Gy in 22 to 42 fractions, and the median dose per fraction was 2.00 Gy (range, 1.56–2.29 Gy). All patients had 5 years of follow-up, and the 5-year recurrence-free survival rate was used as the primary endpoint. Results: The 5-year recurrence-free survival rate was 74%. In a multivariate Cox regression analysis, duration of symptoms was a significant factor (p < 0.0001) with a hazard ratio of 1.045 (95% CI 1.023, 1.069). Other significant factors included tumor stage and radiation dose, whereas duration of treatment time was borderline significant (p = 0.06). Conclusions: The duration of symptoms was statistically significantly related to a decrease in recurrence-free survival. One-month delay from onset of symptoms to start of radiotherapy was equivalent to a 4.5% decrease in recurrence-free survival. [Copyright &y& Elsevier]

The purpose of this paper was to compare intensity-modulated radiation therapy (IMRT) and conventional planning for T2N0M0 squamous cell carcinoma (SQCC) of the glottic larynx. Three patients with T2N0M0 SQCC are presented who were treated with IMRT. Conventional plans were also generated for comparison purposes. Isodose distributions and dose-volume histograms (DVHs) were generated for all the plans to evaluate the fitness of the plan as well as the differential benefit of IMRT vs. conventional treatment. The isodose distributions that were obtained by the IMRT plan are much more conformal to the planning target volume (PTV) and clearly show that less healthy tissue is subjected to a high-dose level, thus reducing toxicity. IMRT offers better comformality without compromising the PTV coverage and delivers less dose to normal tissues as compared to conventional radiation therapy in T2N0M0 SQCC of the glottic larynx. With an increase in conformality, it is expected to have an increase in the therapeutic ratio. [Copyright &y& Elsevier]

The development of the glottic site, in particular of its ventral area, was studied to better understand the spreading pathways of T1, T2 cancer.Serial sections of larynges from human embryos, fetuses and adults were observed.A dorsal, a ventral and an intermediate compartment were found on the basis of their maturation schedule. A commissure muscle which develops in the anterior one third of the glottic site and wraps the connection system of vocal ligaments was recognized. The inferior paraglottic space, the compartment structures and the localization of superficial and deep blood vessels and of glands in the ventral compartment and the components of Broyles ligament were studied during ontogenesis.The compartments identified here have clinical and oncological relevance. Their detailed knowledge offers a prerequisite for planning and performing compartment conservative surgery in T1, T2 cancer, based on their spreading pathways. [Copyright &y& Elsevier]

Aims: To describe the variation in the delivery of radiation therapy to patients with T1N0 glottic cancer who were diagnosed in Ontario, Canada, between 1982 and 1995.Materials and Methods: The patient population consisted of a random sample of 461 patients treated with curative intent from the nine cancer centres that administer radiation therapy in the province. Abstracted variables included prescribed dose (Gy) and fractionation (f), beam energy and arrangement, set-up, field size, beam modifiers, positioning and treatment interruptions.Results: Thirteen prescribed dose-fractionation schemes (≥four cases each) were identified, including 50.0–53.0 Gy/20 f (54.5%), 55.0–61.0 Gy/25 f (30.3%), and 60.0–66.0 Gy/30–33 f (7.7%). All regimens used one fraction per day, 5 days per week. An isocentric set-up was used (94.3%), with megavoltage (MV) beam energies of Cobalt-60 (87.9%), 6 MV (6.1%) and 4 MV (6.1%). A lateral parallel-opposed pair of beams was the predominant technique (76.4%) versus an anterior oblique pair (17.2%) or angle-down pair (caudally directed fields to achieve shoulder clearance, 5.7%). Wedging (96.3%) and bolus (11.8%) were used as beam-modifying devices. Predominant field-width dimensions were 5.0–6.0 cm (43.4%) and 6.5–7.0 cm (43.1%), and field length dimensions were 5.0–6.0 cm (49.5%) and 6.5–7.0 cm (35.0%). Head, neck or chin immobilisation was used in 86.9% of the cases, with 94.6% of these being custom-made. We found that radiotherapy practice was stable over time, except for a trend of increasing field size and increasing use of immobilisation. In contrast, we found practice variations among the province''s cancer centres. On the basis of our findings, we defined a predominant technical practice consisting of Cobalt-60 (reflecting machine availability during the period of the study), an isocentric set-up, a lateral parallel-opposed pair technique with wedging, and supine-head neutral positioning with custom immobilisation. Forty-two per cent of the cases had one or more components of treatment that differed from this definition.Conclusions: Description of practice variation can provoke discussion about unrecognised differences in practice policies, perhaps identifying the need for better evidence, treatment guidelines, or both. [Copyright &y& Elsevier]

Purpose: To analyze the prognostic factors for early-stage glottic cancer (T1N0M0) treated with radiotherapy alone.Methods and Materials: Between 1958 and 1994, 238 patients (220 male) with T1N0M0 (UICC 1997) squamous cell carcinoma of the glottis were treated with 6- or 8 MV X-ray or 60Co radiation in parallel-opposed fields (median size: 22.5 cm2) over a median of 52 days to a median dose of 68 Gy. Locoregional control (LC) and overall survival (OS) were estimated by the Kaplan-Meier method. Log-rank and Cox regression analyses were used to identify prognostic factors.Results: The median follow-up time was 127 months (range: 4–410 months). Five- and 10-year OS rates were 84.0% and 74.9%. The 5-year LC rate was 82.2%. Forty-four patients had recurrent disease (41 locally, 2 in cervical lymph nodes, 1 lost to follow-up); 23 had second malignancies. On multivariate analysis, unfavorable prognostic factors for OS were age >65 years (p < 0.001) and second malignancy (p < 0.001). Unfavorable prognostic factors for LC were bulky tumor (p = 0.023), anterior commissure involvement (p = 0.024), and decrease in hemoglobin during treatment (p = 0.025).Conclusions: Radiotherapy alone provides good control of early-stage glottic cancer. Bulky tumor, anterior commissure involvement, and decreasing hemoglobin are negative prognostic factors for LC. [Copyright &y& Elsevier]

Abstract: Aims: To determine the influence of dose and fractionation on tumour characteristics, toxicity, disease control and survival outcomes in T1 glottic carcinoma. Materials and methods: Between 1975 and 2000, treatment charts of 652 patients with T1 glottic carcinoma who received curative radiation with four hypofractionated schedules (50 Gy/15 fractions [3.3 Gy/fraction] or 55 Gy/16 fractions [3.43 Gy/fraction] or 60 Gy/24 fractions or 62.5 Gy/25 fractions [2.5 Gy/fraction]) were analysed. The patients were divided into two groups based on fraction size <3 Gy and >3 Gy. Local control and overall survival were calculated. Patient- and tumour-related factors affecting local control were analysed using univariate and multivariate analysis. Factors affecting late toxicity were also analysed. Results: The local control and overall survival at 10 years were 84 and 86.1%, respectively, for T1 glottic carcinoma. The response to radiation had a significant effect on local control with univariate analysis (P = 0.001). Other factors, such as beam energy, anterior commissure involvement and fractionation, did not affect local control. Persistent radiation oedema was seen in 123 patients (23.4%) and was significantly worse in patients who received radiation with a larger field size (>36 cm2) on a telecobalt machine (P < 0.001). Conclusions: Radical radiotherapy schedules incorporating a higher dose per fraction yield acceptable local control rates and late toxicity. Telecobalt therapy for early glottic cancer is a safe alternative to treatment with 6 MV photons on a linear accelerator in terms of local control and late toxicity as long as field sizes smaller than 36 cm2 are used. [Copyright &y& Elsevier]