The effect of parotid gland-sparing intensity-modulated radiotherapy on salivary composition, flow rate and xerostomia measures.

OBJECTIVES: To describe parotid gland (PG) saliva organic and inorganic composition and flow rate changes, after curative intensity-modulated radiotherapy (IMRT) for head and neck cancer (HNC), and analyse the relationship between PG saliva analytes and xerostomia measures. METHODS AND MATERIALS: Twenty-six patients recruited to five prospective phase 2 or 3 trials which assessed toxicity and efficacy of IMRT by HNC subsite, provided longitudinal PG saliva. Salivary flow rate, and subjective and objective xerostomia measures were prospectively collected and saliva tested for inorganic and organic analytes. Statistical comparisons of longitudinal analyte changes and analysis for a relationship between dichotomized xerostomia score and saliva analytes were performed. RESULTS: One hundred and forty-two PG saliva samples from 26 patients were analysed. At 3-6 months after IMRT, stimulated and unstimulated saliva showed significantly decreased flow rate, total protein (TP) secretion rate, phosphate concentration and increased lactoferrin (LF) concentration. Stimulated saliva alone had elevated LF secretion rate and beta-2-microglobulin (B2 M) concentration with decreased calcium (Ca2+ ) and magnesium (Mg2+ ) concentrations and Ca2+ secretion rate. At >12 months, under stimulated and unstimulated conditions, increased LF concentration and decreased Mg2+ and phosphate concentration persisted and, in stimulated saliva, there was decreased potassium (K+ ) and Mg2+ concentration. Unstimulated TP secretion rate was lower in the presence of high-grade xerostomia. Otherwise, no relationship between xerostomia grade and PG salivary flow rate, TP and Ca2+ secretion rate was found. CONCLUSION: Fewer significant differences in PG saliva analytes >12 months after IMRT indicate good functional recovery. Residual xerostomia after IMRT will only be further reduced by addressing the sparing of subsites of the PG or other salivary gland tissues, in addition to the PG.

Delayed DNA double-strand break repair following platin-based chemotherapy predicts treatment response in head and neck squamous cell carcinoma.

INTRODUCTION: The aim of this study was to investigate if defective repair of DNA double-strand break (DSB) in head and neck squamous cell carcinoma (HNSCC) could be used as an early predictor of treatment response. METHODS: Tumour biopsy 24-36 h following induction chemotherapy (IC) and pre-treatment biopsies were stained for RAD51 and geminin (S-phase marker) for immunofluorescence in patients with HNSCC. The difference between RAD51 score (percentage of geminin-positive cells that were also positive for RAD51) was calculated for the two specimens. Tumours with a percentage difference of⩽10% were deemed to have repaired IC-induced DSBs, and were classified as 'RAD51 negative'. Response at 3 months post treatment and human papilloma virus (HPV) status were assessed. RESULTS: Thirteen pairs of samples were available for analyses. Three samples were classified as RAD51 negative and 10 as RAD51 positive at 24 h post IC. All of the three patients with tumours classified as RAD51 negative had partial response or progressive disease and the 10 patients with tumours deemed RAD51 positive had a complete response. 100% of the HPV-positive tumours were RAD51 positive and had a complete response. CONCLUSIONS: We have demonstrated that impaired DSB DNA repair may underlie enhanced treatment sensitivity of HPV-positive HNSCC and repair capacity following platinum-induced DNA damage predicts response in HNSCC. This has potential as a biomarker for patient selection in trials of DNA damage response pathway modulation.

Evaluation of radiotherapy techniques for radical treatment of lateralised oropharyngeal cancers : Dosimetry and NTCP.

AIM: The aim of this study was to investigate potential advantages and disadvantages of three-dimensional conformal radiotherapy (3DCRT), multiple fixed-field intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc therapy (VMAT) in terms of dose to the planning target volume (PTV), organs at risk (OARs) and normal tissue complication probability (NTCP) for delivering ipsilateral radiotherapy. MATERIALS AND METHODS: 3DCRT, IMRT and VMAT were compared in patients with well-lateralised primary tonsillar cancers who underwent primary radical ipsilateral radiotherapy. The following parameters were compared: conformity index (CI); homogeneity index (HI); dose-volume histograms (DVHs) of PTVs and OARs; NTCP, risk of radiation-induced cancer and dose accumulation during treatment. RESULTS: IMRT and VMAT were superior to 3DCRT in terms of CI, HI and dose to the target volumes, as well as mandible and dose accumulation robustness. The techniques were equivalent in terms of dose and NTCP for the contralateral oral cavity, contralateral submandibular gland and mandible, when specific dose constraint objectives were used on the oral cavity volume. Although the volume of normal tissue exposed to low-dose radiation was significantly higher with IMRT and VMAT, the risk of radiation-induced secondary malignancy was dependant on the mathematical model used. CONCLUSION: This study demonstrates the superiority of IMRT/VMAT techniques over 3DCRT in terms of dose homogeneity, conformity and consistent dose delivery to the PTV throughout the course of treatment in patients with lateralised oropharyngeal cancers. Dosimetry and NTCP calculations show that these techniques are equivalent to 3DCRT with regard to the risk of acute mucositis when specific dose constraint objectives were used on the contralateral oral cavity OAR.

A phase II trial of induction chemotherapy and chemo-IMRT for head and neck squamous cell cancers at risk of bilateral nodal spread: the application of a bilateral superficial lobe parotid-sparing IMRT technique and treatment outcomes.

PURPOSE: To determine the feasibility of induction chemotherapy and chemo-IMRT in head and neck squamous cell cancers at risk of bilateral nodal spread (midline tumours) and to evaluate whether bilateral superficial lobe parotid-sparing IMRT can reduce the incidence of ⩾G2 subjective xerostomia. METHODS: Patients with midline tumours were enrolled to a phase II trial to receive induction platinum/5-fluorouracil and concomitant platinum with combined superficial lobe parotid-sparing IMRT. The primary site and involved nodal levels received 65 Gy in 30 fractions (f) and at risk nodal levels, 54 Gy/30f. Incidence of ⩾G2 subjective xerostomia was defined as the primary endpoint. Secondary endpoints included incidences of acute and late toxicities and survival outcomes dependent on human papilloma virus (HPV) status. RESULTS: One hundred and twenty patients with midline cancers completed treatment between December 2005 and May 2010 with median follow-up of 50 months. Incidences of ⩾G2 acute toxicities were: dysphagia 75%; xerostomia 65%; mucositis 86%; pain 83%; and fatigue 64%. At 12 months, ⩾G2 subjective xerostomia was observed in 21% (17% in HPV +ve). Two-year loco-regional progression-free survival (PFS) was 90.7% (95% CI: 85.2-96.2). According to HPV status, there was a significant difference for 2-year loco-regional PFS, 76.8% (HPV-negative) vs 98.6% (HPV-positive), P=0.001. 2-year overall survival was 93% for HPV-positive compared with 52% for HPV-negative cases, P<0.001. CONCLUSIONS: Sequential chemotherapy/chemo-IMRT for midline tumours is feasible, with excellent survival outcomes. At 1 year, 21% experience ⩾G2 subjective xerostomia. Two-year survival outcomes differ significantly between HPV-positive and HPV-negative disease, suggesting development of different treatment schedules for the different disease entities.

Phase 2, open-label, 1:1 randomized controlled trial exploring the efficacy of EMD 1201081 in combination with cetuximab in second-line cetuximab-naïve patients with recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN).

AIM: To determine whether EMD 1201081, a TLR9 agonist, added to cetuximab had antitumor activity in second-line recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). METHODS: This was a phase 2, open-label, randomized trial of EMD 1201081 0.32 mg/kg subcutaneously weekly plus cetuximab (combination) vs cetuximab monotherapy (control) in cetuximab-naïve patients with R/M SCCHN who progressed on 1 cytotoxic regimen. Crossover to combination was permitted after progression. RESULTS: Objective response rate in both arms was 5.7% (95% CI 1.2-15.7%) by independent assessment. Disease control was 37.7% for patients on combination (24.8-52.1%) and 43.4% on control (29.8-57.7%). Neither independent nor investigator assessments showed significant differences between study arms. Median progression-free survival was 1.5 months (1.3-2.6) for patients on combination, and 1.9 months (1.5-2.9) on control. The most frequent adverse events in the combination arm were rash (29.6%), acneiform dermatitis (22.2%), and injection site reactions (20.4%). Grade 3/4 dyspnea and hypokalemia were more frequent with cetuximab monotherapy (7.5% and 5.7% vs 1.9% each, respectively), and grade 3/4 respiratory failure and disease progression were more frequent with combination (5.6% each vs 1.9% each). CONCLUSION: EMD 1201081 was well tolerated combined with cetuximab, but there was no incremental clinical efficacy.

Effects of lapatinib monotherapy: results of a randomised phase II study in therapy-naive patients with locally advanced squamous cell carcinoma of the head and neck.

BACKGROUND: Lapatinib is a dual inhibitor of epidermal growth factor receptor (EGFR) and human EGFR-2 (HER-2) tyrosine kinases. This study investigated the pharmacodynamic and clinical effects of lapatinib in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). METHODS: In total, 107 therapy-naive patients with locally advanced SCCHN were randomised (2 : 1) to receive lapatinib or placebo for 2-6 weeks before chemoradiation therapy (CRT). Endpoints included apoptosis and proliferation rates, clinical response, and toxicity. RESULTS: Versus placebo, lapatinib monotherapy did not significantly increase apoptosis detected by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labelling or caspase-3 assays. A statistically significant decrease in proliferation using Ki67 assay was observed (P=0.030). In a subset of 40 patients that received 4 weeks of lapatinib or placebo, objective response rate (ORR) was 17% (n=4/24) vs 0% (n=0/16). In the lapatinib single-agent responders, all had EGFR overexpression, 50% had EGFR amplification, and 50% had HER2 expression by immunohistochemistry (including one patient with HER2 amplification). However, these patients showed variable modulation of apoptosis, proliferation, and phosphorylated EGFR on drug treatment. Following CRT, there was a statistically non-significant difference in ORR between lapatinib (70%) and placebo (53%). There was no clear correlation between changes in apoptosis or proliferation and response to chemoradiation. Mucosal inflammation, asthenia, odynophagia, and dysphagia were the most commonly reported adverse events with lapatinib. CONCLUSION: Short-term lapatinib monotherapy did not demonstrate apoptotic changes, but provided evidence of clinical activity in locally advanced SCCHN, and warrants further investigation in this disease.

Improvement in Dysphagia Outcomes Following Clinical Target Volume Reduction in the De-ESCALaTE Study.

AIMS: The De-ESCALaTE study showed an overall survival advantage for the administration of synchronous cisplatin chemotherapy with radiotherapy in low-risk oropharyngeal cancer when compared with synchronous cetuximab. During the trial, a radiotherapy quality assurance protocol amendment permitted centres to swap from the original radiotherapy contouring protocol (incorporating the whole oropharynx into the high-dose clinical target volume (CTV); anatomical protocol) to a protocol that incorporated the gross tumour volume with a 10 mm margin into the CTV (volumetric protocol). The purpose of this study was to examine both toxicity and tumour control related to this protocol amendment. MATERIALS AND METHODS: Overall survival and recurrence at 2 years were used to compare tumour control in the two contouring cohorts. For toxicity, the cohorts were compared by both the number of severe (grades 3-5) and all grades acute and late toxicities. In addition, quality of life and swallowing were compared using EORTC-C30 and MD Anderson Dysphagia Inventory, respectively. RESULTS: Of 327 patients included in this study, 185 were contoured according to the anatomical protocol and 142 by the volumetric protocol. The two cohorts were well balanced, with the exception of significantly more patients in the anatomical cohort undergoing prophylactic feeding tube insertion (P < 0.001). With a minimum of 2 years of follow-up there was no significant difference in overall survival or recurrence between the two contouring protocols. Similarly, there was no significant difference in the rate of reported severe or all grades acute or late toxicity and no sustained significant difference in quality of life. However, there was a significant difference in favour of volumetric contouring in several domains of the MD Anderson Dysphagia Inventory questionnaire at 1 year, which persisted to 2 years in the dysphagia functional (P = 0.002), dysphagia physical (P = 0.009) and dysphagia overall function (P = 0.008) domains. CONCLUSION: In the context of the unplanned post-hoc analysis of a randomised trial, measurable improvement in long-term dysphagia has been shown following a reduction in the CTV. Further reductions in the CTV should be subject to similar scrutiny within the confines of a prospective study.

Recent advances in radiotherapy.

Radiation therapy has come a long way from treatment planning based on orthogonal radiographs with large margins around tumours. Advances in imaging and radiation planning software have led to three-dimensional conformal radiotherapy and, further, to intensity modulated radiotherapy (IMRT). IMRT permits sparing of normal tissues and hence dose-escalation to tumours. IMRT is the current standard in treatment of head and prostate cancer and is being investigated in other tumour sites. Exquisitely sculpted dose distributions (increased geographical miss) with IMRT, plus tumour motion and anatomical changes during radiotherapy make image guided radiotherapy an essential part of modern radiation delivery. Various hardware and software tools are under investigation for optimal IGRT.

Microvascular free tissue transfer for gene delivery: in vivo evaluation of different routes of plasmid and adenoviral delivery.

Transfer of healthy autologous tissue as a microvascular free flap facilitates reconstruction during ablative cancer surgery. In addition to filling surgical defects, free flaps might concentrate viral vectors at the tumour bed and mediate local therapeutic effects. We evaluated the magnitude, topography and duration of luciferase gene expression after plasmid and adenoviral delivery in rat superficial inferior epigastric (SIE) flaps. For plasmid delivery, luciferase expression was significantly increased by all transduction routes (topical, intraflap injection, intravascular) (P<0.01) at day 1, but not at day 7. The spread of luciferase expression was significantly different between the 4 groups at 1 day (P=0.026) and was greatest for flaps transduced by intravascular injection. For adenoviral transduction, total radiance was significantly different between the transduced groups at 1, 14 and 28 days (P<0.05 for all comparisons). The highest levels of radiance were seen in the intravascular group. There was a statistically significant difference in the spread of light emission between the 3 groups at 1 (P=0.009) and 14 (P=0.013) days, but this was no longer evident at 28 days. Intravascular adenoviral delivery yields high-level, diffuse and durable gene expression in rat SIE flaps and is suitable for examination in therapeutic models.

Phase II study of 3-AP Triapine in patients with recurrent or metastatic head and neck squamous cell carcinoma.

BACKGROUND: Treatment options for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) are limited with response rates to cytotoxic chemotherapy of approximately 30% and median survival of 6 months. PATIENTS AND METHODS: In a multicentre phase II study, 32 patients with recurrent or metastatic HNSCC received 3-AP Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone), an inhibitor of ribonucleotide reductase, 96 mg/m2, daily for 4 days every 14 days (one cycle). Eligibility criteria required Eastern Cooperative Oncology Group performance status (ECOG PS) of zero to two with a life expectancy of >3 months; one prior chemotherapy regimen was allowed. RESULTS: Thirty patients were assessable for response and toxicity. Median age was 57 years (range 36-79) and median ECOG PS was one (range 0-2). Thirteen patients had previously been treated with chemotherapy. A total of 130 cycles were administered with a median number of cycles of 3.5 (range 1-8). Mild anaemia (40%), nausea (22%) and fatigue (22%) were commonly reported with G3 and G4 neutropenia documented in 22% and 22%, respectively. Overall response rate was 5.9% (95% confidence interval 0.2% to 28.7%). One patient achieved a partial response, eight had stable disease and 21 progressive disease. Median time to disease progression was 3.9 months. CONCLUSIONS: 3-AP Triapine as a single agent, at this dose and schedule, is well tolerated but has only minor activity in the treatment of advanced HNSCC.

Epirubicin, cisplatin and protracted venous infusion 5-Fluorouracil chemotherapy for advanced salivary adenoid cystic carcinoma.

AIMS: Adenoid cystic carcinoma (ACC) is a rare tumour that usually arises in the salivary glands. Initial management is surgery often combined with adjuvant radiotherapy. Chemotherapy is reserved for treatment of symptomatic recurrence. We evaluated the combination of epirubicin, cisplatin and protracted venous infusion 5-fluorouracil (ECF) in the management of ACC. MATERIALS AND METHODS: Patients referred for treatment of advanced, symptomatic ACC were considered. The drugs given were epirubicin 50 mg/m(2) 3-weekly, cisplatin 60 mg/m(2) 3-weekly and protracted venous infusion 5-fluorouracil 200 mg/m(2)/day. RESULTS: Eight patients (median age 46 years) received a median of five cycles of chemotherapy. All patients had had previous surgery, seven had had previous radiotherapy and one had had previous chemotherapy. One patient showed a partial response (duration 34 months) and five showed stable disease (median duration 13.6 months [6.8-15.9+ months]). Median survival was 27 months (3.5-62.3 months). CONCLUSIONS: The activity of ECF in ACC of the head and neck seems to be similar to the combination of cisplatin and 5-fluorouracil and single-agent epirubicin.

Future perspectives for health related quality of life (HRQOL) studies in head and neck cancer.

The impact of a head and neck cancer (HNC) diagnosis on a person and the consequences of its treatment across multiple functional domains can profoundly alter quality of life (QOL). By pursuing patient-centered management and considering the entire gamut of physical, psychological and social problems, QOL studies contribute more than just routine mortality and morbidity data. Assessments can now be made using a variety of both specific and generic measures to optimise patient care and to aid the development of informed rehabilitation services. Unfortunately, there exists no 'gold-standard' questionnaire in the literature and the choice is largely based on clinician preference, research objectives and psychometric properties. Future efforts must be made to effectively use modern technological and computational advances to set up item banks and newer theoretical models. Longitudinal studies with pre-determined priori should be encouraged as should the utilisation of minimalist approaches and incisive item response theory. Most importantly, in order to link research to clinical practice, health related QOL (HRQOL) studies should be devised and utilised in a way as to provide clinically meaningful data to the treating physician useful for patient' care.

Oropharyngeal Cancers in the East and the West - Implications of Aetiopathogenesis on Prognosis and Research.

There has been a surge in human papillomavirus (HPV)-positive oropharyngeal cancers (OPCs) in the West. Although the prognosis of HPV-positive OPC is good, de-escalation strategies have so far not been able to confirm comparable cancer control. We examine the strategies implemented across the globe to safely reduce toxicities in HPV-positive disease. HPV-negative OPC has a poorer prognosis and is more prevalent in Eastern countries. We outline the intensification strategies currently used in HPV-negative cancers, with an aim to better prognosis. With recent improvements in clinical trial frameworks in Eastern countries such as India, we discuss areas where joint collaborative research between Western and Eastern countries could further improve outcomes in OPC.

Rapid advances in auto-segmentation of organs at risk and target volumes in head and neck cancer.

Advances in technical radiotherapy have resulted in significant sparing of organs at risk (OARs), reducing radiation-related toxicities for patients with cancer of the head and neck (HNC). Accurate delineation of target volumes (TVs) and OARs is critical for maximising tumour control and minimising radiation toxicities. When performed manually, variability in TV and OAR delineation has been shown to have significant dosimetric impacts for patients on treatment. Auto-segmentation (AS) techniques have shown promise in reducing both inter-practitioner variability and the time taken in TV and OAR delineation in HNC. Ultimately, this may reduce treatment planning and clinical waiting times for patients. Adaptation of radiation treatment for biological or anatomical changes during therapy will also require rapid re-planning; indeed, the time taken for manual delineation currently prevents adaptive radiotherapy from being implemented optimally. We are therefore standing on the threshold of a transformation of routine radiotherapy planning via the use of artificial intelligence. In this article, we outline the current state-of-the-art for AS for HNC radiotherapy in order to predict how this will rapidly change with the introduction of artificial intelligence. We specifically focus on delineation accuracy and time saving. We argue that, if such technologies are implemented correctly, AS should result in better standardisation of treatment for patients and significantly reduce the time taken to plan radiotherapy.

Sequential induction chemotherapy followed by radical chemo-radiation in the treatment of locoregionally advanced head-and-neck cancer.

We describe a retrospective series of patients with advanced head-and-neck cancer who were treated with induction chemotherapy followed by radical chemo-radiation. Patients treated with two cycles of induction chemotherapy followed by definitive chemo-radiation for squamous cell carcinoma of the head-and-neck region, from 2001 - 2006 at the Royal Marsden Hospital, formed the basis of this study. Cisplatin (75 mg m(-2)) on day 1 and 5-FU (1000 mg m(-2)) day 1 - 4 was the standard regimen used for induction treatment. Cisplatin (100 mg m(-2)) on day 1 and day 29 was used for concomitant treatment. The radiation was delivered using conformal technique. Tissues containing macroscopic and microscopic disease were treated to doses of 65 Gray (Gy) in 30 fractions and 50 Gy in 25 fractions, respectively. Data on patterns of relapse and acute toxicity (NCICTCv.3.0) were collected. A total of 129 patients were included, median age was 58 (range: 27 - 78). The site of tumour was: oropharynx 70 (54%), larynx 30 (23%), hypopharynx 24 (19%) and other 5 (4%). The median follow-up was 19 months (range: 4 - 58). Local control, disease-specific survival and overall survival at 2 years were 71%, 68% and 63%, respectively. The distant recurrence rate at 2 years was 9%. Ten patients required dose reduction during induction chemotherapy due to toxicity. The dose of 5-FU was reduced in six patients and that of cisplatin in four patients. The incidence of grade 3/4 toxicity was: neutropenia 5%, thrombocytopenia 1%, nausea and vomiting 3%. One cycle of concurrent cisplatin was omitted in 23 patients due to toxicity. Full-dose radiotherapy was administered to 98% of patients. The incidence of grade 3/4 toxicity was: skin 20%, dysphagia 65%, mucositis 60%, neutropenia 3%, anaemia 1%, nausea and vomiting 4%, nephrotoxicity 1%. Induction chemotherapy followed by radical chemo-radiation is a safe and tolerable regimen in the treatment of advanced head-and-neck cancer. Distant recurrence rates are lower with equivalent local control and survival compared to chemo-radiation alone (historical controls).

Questionnaire analysis of swallowing-related outcomes following glossectomy.

OBJECTIVE: To determine the effects of a partial/total glossectomy on the swallow-related quality of life (QOL). DESIGN: Cross-sectional, single-centre cohort study. PATIENTS AND METHODS: Thirty-one patients who underwent partial/total glossectomy at our centre participated in the study. Main outcome was measured using the MD Andersen Dysphagia Inventory (MDADI) questionnaire. RESULTS: Responses were received from 24 males and 7 females (response rate of 77.5%) with a median age of 50 years (range: 28-72). Median follow-up in patients was 33 months (range 4-210). The mean MDADI total score in our series of patients was 71.7 (SD 18.8). Mean MDADI global score was 64.5 (SD 29.1), mean Emotional score was 71.9 (SD 19.1), mean Functional score was 73.7 (SD 19.1) and mean Physical score was 69.3 (SD 21.7). Statistically significant differences were seen between the global, emotional and physical scores of patients who had received radiotherapy (Mann-Whitney, p < 0.05) and tracheostomy (functional score, Mann-Whitney, p = 0.038). CONCLUSION: The presence of tracheostomy tube and previous radiotherapy affects swallowing outcome in patients who have had surgery for squamous cell carcinoma of the tongue.

Does flexible videostroboscopy compare with rigid videostroboscopy in the assessment of the neoglottis? A preliminary report.

OBJECTIVE: To evaluate rigid and flexible stroboscopy of the neoglottis. STUDY DESIGN: Prospective pilot study set at a tertiary level Head & Neck Unit. PARTICIPANTS: Twenty-four patients recruited. All had undergone a total laryngectomy and were voicing using a Blom-singer valve. All had stroboscopic evaluation of their neoglottis using flexible and rigid endoscopes. MAIN OUTCOME MEASURES: A rating form was devised based on six parameters with clear definitions. Secondary measures included ability to tolerate the procedure and completeness of the rating form for each parameter using the two systems. RESULTS: There was good reliability between individual raters for the assessment of each system based on Spearman Rho correlation. Importantly, two-thirds of the patients were unable to tolerate the rigid videostroboscopy managed flexible videostroboscopy. Correlation between rigid and flexible videostroboscopy was poor for both raters. Flexible systems picked up more mucosal waves and allowed further analysis of the mucosal wave pattern. CONCLUSIONS: To our knowledge, this is the first study to demonstrate that fibreoptic videstroboscopy is as good as rigid videostroboscopy in the assessment of the neoglottis. In fact, flexible videostroboscopy should be routinely used, as it is better tolerated and allows a more detailed analysis of the neoglottis.

Intensity modulated radiotherapy in locally advanced thyroid cancer: Outcomes of a sequential phase I dose-escalation study.

BACKGROUND AND PURPOSE: To determine the safety and tolerability of dose-escalation using modestly accelerated IMRT in high-risk locally advanced thyroid cancer requiring post-operative radiotherapy, and to report preliminary data on efficacy. MATERIALS AND METHODS: A sequential Phase I dose-escalation design was used. Dose level one (DL1) received 58.8 Gy/28F to the post-operative bed and 50 Gy/28F to elective nodes. DL2 received 66.6 Gy/30F to the thyroid bed, 60 Gy/30F to post-operative nodal levels and 54 Gy/30F to elective nodal levels. Acute (NCICTCv.2.0) and late toxicities (RTOG and modified LENTSOM) were recorded. The primary endpoint was the number of patients with ≥Grade 3 (G3) toxicity at 12 months post-treatment. RESULTS: Fifteen patients were recruited to DL1 and twenty-nine to DL2. At 12 months ≥G3 toxicities were 8.3% in both DL1 and DL2. At 60 months, ≥G3 toxicity was reported in 3 (33%) patients in DL1 and 1 (7%) in DL2. One patient in DL2 died at 24 months from radiation-induced toxicity. Time to relapse and overall survival rates were higher in DL2, but this was not statistically significant. Dose-escalation using this accelerated regimen can be safely performed with a toxicity profile similar to reported series using conventional doses.