Prospective evaluation of relationships between radiotherapy dose to masticatory apparatus and trismus.

AIMS: This feasibility study aimed to identify relationships between radiation doses to the masticatory apparatus as a combined block or as individual subunits with changes in trismus following radiotherapy. MATERIAL AND METHODS: Twenty patients from a single center were recruited prospectively as part of a randomized trial comparing proactive exercises in the management of trismus. Patients with stage III/IV oral cavity or oropharyngeal squamous cell cancers received intensity-modulated radiotherapy with concurrent systemic therapy. All patients had trismus prior to radiotherapy. Maximal inter-incisor distance (MID) was measured pre- and 6 months from the start of radiotherapy. Bilateral muscles of mastication: medial and lateral pterygoids (MP and LP), masseters (M), temporalis (T), temporomandibular joint (TMJ) were contoured on CT images. The block comprised all muscles excluding the TMJ below the orbital floor. Mean dose, equivalent uniform dose (EUD) and V35-V60 Gy were compared with change in MID. RESULTS: In six patients, the MID deteriorated at 6 months from the start of radiotherapy compared with 14 whose MID improved. No significant association was observed between age, gender, smoking, alcohol status, exercise compliance, cisplatin, tumor site, stage, V35-V60 Gy or EUD with change in MID. A clinical outlier was excluded. Without the outlier (n = 19), a significant association was seen between mean dose and change in MID at 6 months for the ipsilateral block (p = .01), LP (p = .04) and M (p < .01). All patients where trismus deteriorated at 6 months received mean doses >40 Gy to the block. CONCLUSION: Higher mean radiation doses to the ipsilateral block, LP and M were significantly associated with deterioration in trismus. Limiting dose to these structures to ≤40 Gy for tumors not invading the masticatory muscles may improve treatment-related sequelae. The ipsilateral block, LP and M should be studied further as possible alternative avoidance structures in radiotherapy treatment planning.

Dose intensified hypofractionated intensity-modulated radiotherapy with synchronous cetuximab for intermediate stage head and neck squamous cell carcinoma.

BACKGROUND: For stage II and III head and neck squamous cell carcinoma (HNSCC) treated with radiotherapy alone, loco-regional recurrence is the main cause of treatment failure. Strategies to improve loco-regional control should not be at the expense of increased late normal tissue toxicity. We investigated dose-intensified hypofractionated intensity-modulated radiotherapy (IMRT) with synchronous cetuximab. MATERIAL AND METHODS: In a phase I/II trial, 27 patients with stage III or high risk stage II HNSCC were recruited. They received three dose level simultaneous integrated boost IMRT, 62.5 Gy in 25 daily fractions to planning target volume one over five weeks with synchronous cetuximab. The primary endpoint was acute toxicity. Secondary endpoints included: late toxicity and quality of life; loco-regional control, cause-specific and overall survival. RESULTS: Radiotherapy was completed by 26/27 patients; for one (4%) the final fraction was omitted due to skin toxicity. All cycles of cetuximab were received by 23/27 patients. Grade 3 acute toxicities included: pain (81%), oral mucositis (78%) and dysphagia (41%). There were few grade 3 physician-recorded late toxicities, including: pain (11%), problems with teeth (8%) and weight loss (4%). At 12 months, only one (4%) patient required a feeding tube, inserted prior to treatment due to dysphagia. The maximal/peak rates of patient-reported late toxicities included: severe pain (11%), any dry mouth (89%) and swallowing dysfunction that required a soft/liquid diet (23%). At 12 months, all quality of life and most symptoms mean scores had resolved to baseline or were only a little worse; dry mouth, sticky saliva and dentition scores remained very much worse. At a median follow-up of 47 months, there were five (18.5%) loco-regional recurrences and the overall cause-specific survival was 79% (95% CI 53-92). CONCLUSIONS: This regimen is safe with acceptable acute toxicity, low rates of late toxicity and impact on quality of life at 12 months following treatment. Further evaluation is recommended.

IMRT dose fractionation for head and neck cancer: variation in current approaches will make standardisation difficult.

INTRODUCTION: Altered fractionation has demonstrated clinical benefits compared to the conventional 2 Gy/day standard of 70 Gy. When using synchronous chemotherapy, there is uncertainty about optimum fractionation. IMRT with its potential for Simultaneous Integrated Boost (SIB) adds further to this uncertainty. This survey will examine international practice of IMRT fractionation and suggest possible reasons for diversity in approach. MATERIAL AND METHODS: Fourteen international cancer centres were surveyed for IMRT dose/fractionation practised in each centre. RESULTS: Twelve different types of dose fractionation were reported. Conventional 70-72 Gy (daily 2 Gy/fraction) was used in 3/14 centres with concurrent chemotherapy while 11/14 centres used altered fractionation. Two centres used >1 schedule. Reported schedules and number of centres included 6 fractions/week DAHANCA regime (3), modest hypofractionation (< or =2.2 Gy/fraction) (3), dose-escalated hypofractionation (> or =2.3 Gy/fraction) (4), hyperfractionation (1), continuous acceleration (1) and concomitant boost (1). Reasons for dose fractionation variability include (i) dose escalation; (ii) total irradiated volume; (iii) number of target volumes; (iv) synchronous systemic treatment; (v) shorter overall treatment time; (vi) resources availability; (vii) longer time on treatment couch; (viii) variable GTV margins; (ix) confidence in treatment setup; (x) late tissue toxicity and (xi) use of lower neck anterior fields. CONCLUSIONS: This variability in IMRT fractionation makes any meaningful comparison of treatment results difficult. Some standardization is needed particularly for design of multi-centre randomized clinical trials.

Use of a novel atlas for muscles of mastication to reduce inter observer variability in head and neck radiotherapy contouring.

PURPOSE/OBJECTIVE(S): Trismus is caused by injury to the masticatory muscles resulting from cancer or its treatment. Contouring these muscles to reduce dose and radiation related trismus can be problematic due to interobserver variability. This study aimed to evaluate the reduction in interobserver variability achievable with a new contouring atlas. MATERIALS/METHODS: The atlas included: medial and lateral pterygoids (MP, LP), masseter (M) and temporalis (T) muscles, and the temporo-mandibular joint (TMJ). Seven clinicians delineated five paired structures on CT scans from 5 patients without the atlas. After ≥5 weeks, contouring was repeated using the atlas. Using contours generated by the clinicians on the same 5 CT scans as reference, dice similarity coefficient (DSC), mean distance-to-agreement (DTA) and centre of mass (COM) difference were compared with and without the atlas. Comparison was also performed split by training grade. Mean and standard deviation (SD) values were measured. RESULTS: The atlas reduced interobserver variability for all structures. Mean DTA significantly improved for MP (p = 0.01), M (p < 0.01), T (p < 0.01) and TMJ (p < 0.01). Mean DTA improved using the atlas for the trainees across all muscles, with the largest reduction in variability observed for the T (4.3 ±â€¯7.1 v 1.2 ±â€¯0.4 mm, p = 0.06) and TMJ (2.1 ±â€¯0.7 v 0.8 ±â€¯0.3 mm, p < 0.01). Distance between the COM and interobserver variability reduced in all directions for MP and T. CONCLUSION: A new atlas for contouring masticatory muscles during radiotherapy planning for head and neck cancer reduces interobserver variability and could be used as an educational tool.

Patterns of relapse following radiotherapy for differentiated thyroid cancer: implication for target volume delineation.

INTRODUCTION: Post-operative residual disease in differentiated thyroid cancer is an indication for external beam radiotherapy (EBRT) especially if there is poor radioiodine uptake by the residual disease. There are no standardized guidelines or consensus in target delineation for radiotherapy in thyroid cancer. AIMS: To determine the pattern of recurrence in patients with well differentiated thyroid cancer who received adjuvant or definitive radiotherapy as well as radioiodine ablation following surgery or biopsy with a view to better defining future target volume delineation for radiotherapy. MATERIALS AND METHODS: Forty-nine patients with differentiated thyroid cancer received radical external beam radiotherapy and radioiodine ablation (3.5GBq) following thyroidectomy or biopsy between 1990 and 2000. Nineteen patients had macroscopic residual (11) or inoperable disease (8), whilst 30 patients had clear (5) or microscopic positive resection margin (24), and 1 patient the resection margin status was unknown. All the patients were deemed high risk for local recurrence or progressive disease. The thyroid bed and regional nodes were irradiated using two radiotherapy techniques: (1) non co-planar lateral fields (NCLF) in coronal plane using 6MV photons to a dose of 45-50Gy in 16 fractions over 22 days and (2) anterior-posterior parallel pair of 6MV photons to a dose of 40-42.5Gy in 16 fractions over 22 days. There was no attempt to irradiate the lymph nodes in that part of the anterior and posterior mediastinum extending from the brachiocephalic veins to the carina. RESULTS: The median follow-up was 5.4 years (range 0.9-12.4 years). The actuarial 5-year cause-specific survival and local control for the whole group was 75.7% and 81.4%, respectively. Of the 4 patients with mediastinal recurrence, all had neck recurrences and two had distant metastases. All the medisastinal recurrences occurred in superior mediastinum (level VII) and all were treated with NCLF in coronal plane radiotherapy technique. Furthermore, mediastinal recurrences did not occur in isolation. The 5-years loco-regional control rate was 89.1% for those with clear or microscopic positive margins and 69.2% for those with macroscopic residual or inoperable disease. Five-year cause specific survival was 58.3% for patients with macroscopic residual or inoperable disease and 91.4% for those with clear or microscopic positive margins. CONCLUSION: The status of postoperative margin relating to bulk of disease influences local control and cause specific survival. Surgical resection in locally advanced thyroid cancer should be performed by an experienced surgeon to achieve macroscopic clearance where possible. The majority of recurrences were loco-regional. The few superior mediastinal recurrences did not occur in isolation. All the mediastinal recurrences occurred in the superior mediastinum (level VII). We recommend the target volume should encompass the thyroid bed and regional neck nodes and the superior mediastinum level VII excluding the lymph nodes on both sides of the trachea within the anterior and posterior mediastinum extending from the brachiocephalic veins to the carina (compartment 4). Thus, this should facilitate dose escalation to improve loco-regional control and avoiding radiation induced mediastinal toxicity.

Conventional fractionation should not be the standard of care for T2 glottic cancer.

BACKGROUND: The aim of this study was to report outcomes and late toxicity following hypofractionated accelerated radiotherapy for T2 glottic cancers. We highlight the importance of hypofractionated treatments with shorter overall treatment times, in improving outcomes for T2 glottic cancers. We also compare the biologically effective dose of hypofractionated regimes, with conventional fractionation. METHODS: One hundred twelve patients with T2 glottic cancer were treated between January 1999 and December 2005. All patients were prescribed a hypofractionated accelerated radiotherapy dose of 52.5 Gray in 3.28 Gray per fraction, delivered over 22 days. Radiobiological calculations were used to assess the relationship of fraction size and overall treatment time on local control outcomes and late toxicity. RESULTS: The 5-year overall survival was 67%, the 5-year local control was 82%, and the 5-year disease-specific survival was 90%. The respective 5-year local control for T2a and T2b disease was 88.8 and 70.8% (p = 0.032). Severe late toxicity occurred in two patients (1.8%). Radiobiological calculations showed an increase in local control of nearly 12%, with a 10 Gray increase in biologically effective dose. CONCLUSION: This study has demonstrated that accelerated hypofractionated regimes have improved local control and similar late toxicity compared with conventional fractionation schedules. This supports the use of hypofractionated regimes as the standard of care for early glottic laryngeal cancers.

Relative plan robustness of step-and-shoot vs rotational intensity-modulated radiotherapy on repeat computed tomographic simulation for weight loss in head and neck cancer.

INTRODUCTION: Interfractional anatomical alterations may have a differential effect on the dose delivered by step-and-shoot intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc therapy (VMAT). The increased degrees of freedom afforded by rotational delivery may increase plan robustness (measured by change in target volume coverage and doses to organs at risk [OARs]). However, this has not been evaluated for head and neck cancer. MATERIALS AND METHODS: A total of 10 patients who required repeat computed tomography (CT) simulation and replanning during head and neck IMRT were included. Step-and-shoot IMRT and VMAT plans were generated from the original planning scan. The initial and second CT simulation scans were fused and targets/OAR contours transferred, reviewed, and modified. The plans were applied to the second CT scan and doses recalculated without repeat optimization. Differences between step-and-shoot IMRT and VMAT for change in target volume coverage and doses to OARs between first and second CT scans were compared by Wilcoxon signed rank test. RESULTS: There were clinically relevant dosimetric changes between the first and the second CT scans for both the techniques (reduction in mean D95% for PTV2 and PTV3, Dmin for CTV2 and CTV3, and increased mean doses to the parotid glands). However, there were no significant differences between step-and-shoot IMRT and VMAT for change in any target coverage parameter (including D95% for PTV2 and PTV3 and Dmin for CTV2 and CTV3) or dose to any OARs (including parotid glands) between the first and the second CT scans. CONCLUSIONS: For patients with head and neck cancer who required replanning mainly due to weight loss, there were no significant differences in plan robustness between step-and-shoot IMRT and VMAT. This information is useful with increased clinical adoption of VMAT.

Phase II trial of sorafenib in advanced salivary adenoid cystic carcinoma of the head and neck.

BACKGROUND: There is a need to improve the systemic treatment of advanced adenoid cystic carcinoma (ACC). Response rates to chemotherapy are poor and preliminary investigations of molecularly targeted agents have been disappointing. In this study, we evaluate sorafenib, an oral multikinase inhibitor, which has an attractive targeting profile for this disease. METHODS: In a single-arm phase II trial, patients with unresectable locally recurrent and/or metastatic ACC were treated with sorafenib 400 mg bid. RESULTS: Twenty-three patients, median age 51 years, were recruited from 2009 to 2011. Median progression-free survival (PFS) and overall survival (OS) were 11.3 and 19.6 months, respectively. PFS at 6 and 12 months were 69.3% and 46.2%, respectively. Sorafenib was only reasonably well tolerated, and 13 patients (57%) experienced grade 3 toxicity. CONCLUSION: Sorafenib showed modest activity in ACC with a 12-month PFS of 46.2%. Sorafenib 400 mg bid was associated with significant toxicity and, taken together with limited effectiveness, cannot be enthusiastically recommended for further evaluation.

Results of a phase I study to determine the maximum tolerated dose of capecitabine when given concurrently with radical radiotherapy in the treatment of squamous cell carcinoma of the head and neck.

Capecitabine is preferentially converted to 5-fluorouracil within tumours, exploiting the higher levels of thymidine phosphorylase (TP) found in areas of poor perfusion and hypoxia. In addition radiation leads to up regulation of TP expression. To exploit these advantages of capecitabine as a synchronous chemoradiotherapy agent patients with advanced squamous cell carcinoma of the head and neck were recruited into a phase I non-randomised dose finding study. Capecitabine was given twice daily, 7 days a week at a dose starting at 350 mg/m(2) bid. Radiotherapy using a beam directed technique was prescribed to 55 Gy in 20 fractions over 4 weeks. A total of 24 patients were treated. Dose-limiting toxicity (grade IV mucositis) was reached at a capecitabine dose of 550 mg/m(2) bid. Radiotherapy was completed without delay in all cases. There was no systemic drug related toxicity. Capecitabine offers the prospect of an orally administered drug for use synchronously with radiotherapy, which in doses up to 500 mg/m(2) bid is well tolerated.

Radiotherapy for head and neck cancer in elderly patients.

BACKGROUND AND PURPOSE: Elderly patients with head and neck cancer may not be treated aggressively with radiotherapy, due to concerns regarding tolerance of treatment and toxicity. A retrospective study was undertaken of patients aged 80 years and over, treated by definitive radiotherapy for head and neck cancer. MATERIAL AND METHODS: 98 patients aged 80-92 received radiotherapy for carcinoma of the head and neck between 1991 and 1995. All patients received beam directed radiotherapy with radical intent using an immobilisation shell. RESULTS: Cancer specific survival was 59% and overall local control was 70% at 5 years. Both were significantly affected by T stage and site of disease. Cancer specific survival was comparable to that of patients aged below 80 years. Seven patients died within 6 months of the treatment. Three patients developed severe late toxicity. Metastatic disease occurred in eight patients. CONCLUSIONS: Radiotherapy is a beneficial and well tolerated treatment in elderly patients with carcinoma of the head and neck.

Three weeks radiotherapy for T1 glottic cancer: the Christie and Royal Marsden Hospital Experience.

BACKGROUND AND PURPOSE: Radiotherapy for laryngeal carcinoma is conventionally given over a 6-7-week period. However, in a number of UK centres early lesions are treated over 3 weeks. We review recent results of this policy and discuss the reasons why short treatment times may be advantageous. MATERIALS AND METHODS: Two hundred patients (100 from each centre) with T1 glottic invasive squamous cell carcinoma treated with definitive radiotherapy between 1989 and 1997 were analysed. The median age was 68 years. All patients received once daily fractionation, 5 days a week to a total tumour dose of 50.0-52.5 Gy in 16 fractions over 21 days; the fraction size ranged from 3.12 to 3.28 Gy. The median follow-up period was 5 years and 10 months. RESULTS: The 5-year local control rates with radiotherapy for the whole group was 93%; there were 14 recurrences of which seven were salvaged by laryngectomy giving an ultimate local control of 96%. The 5-year overall survival was 80% and cause specific survival at 5 years was 97%. Univariate analysis revealed that T1 substaging (P=0.82) and anterior commissure involvement (P=0.47) did not significantly influence local control. A severe late radiation complication was seen in only one patient who continued to smoke heavily after treatment. There were no severe acute complications. CONCLUSIONS: Once daily radiotherapy over 3 weeks gives excellent local control in patients with T1 glottic squamous-cell carcinoma and has a low rate of severe complications. The short overall treatment time and large fraction size may be advantageous in radiotherapy of these well-differentiated tumours.

Comparison of patient-reported late treatment toxicity (LENT-SOMA) with quality of life (EORTC QLQ-C30 and QLQ-H&N35) assessment after head and neck radiotherapy.

PURPOSE: The patient's role in toxicity reporting is increasingly acknowledged but requires the adaptation and validation of toxicity reporting instruments for patient use as most toxicity scales are designed for physician use. Recording of radiotherapy related late toxicity is important and needs to be improved. A patient-scored symptom questionnaire of late treatment effects using LENT-SOMA was compared with a recognised quality of life tool (EORTC QLQ-C30/H&N35). MATERIALS/METHODS: LENT-SOMA and EORTC QLQ-C30 patient questionnaires were prospectively completed by 220 head and neck cancer patients over 3 years and 72 completed EORTC QLQ-H&N35 questionnaires at 2 years post-radiotherapy. RESULTS: Endpoints common to both questionnaires (pain, swallowing, dental pain, dry mouth, opening mouth, analgesics) were matched. Spearman rank correlation coefficients with ρ>0.6 (P<0.001) were obtained for all "matched" scales except for analgesics scale, ρ=0.267 (P<0.05). There was good agreement between LENT-SOMA and EORTC QLQ-H&N35 except for analgesic endpoints. Global quality of life scores correlated negatively with average LENT-SOMA scores (P<0.001). Significant differences in average LENT-SOMA scores between treatment modalities were found. The LENT-SOMA questionnaire has demonstrated a high Cronbach's α value (0.786) indicating good reliability. CONCLUSIONS: LENT-SOMA patient questionnaire results agreed well with those from the EORTC QLQ-H&N35 questionnaire for toxicity items where they could be compared explicitly, particularly for subjective endpoints. Patient-reported late toxicity had a negative impact on quality of life. The LENT-SOMA patient questionnaire is both reliable and sensitive to differences between patients treated with different modalities. A patient-based questionnaire is an important contributor to capturing late radiotherapy effects.