J. Glaholm

External Beam Radiotherapy in the Management of Differentiated Thyroid Cancer

AIMS No randomised trials have addressed the use of external beam radiotherapy (EBRT) in the treatment of differentiated thyroid cancer. The indications for EBRT, the technique and recommended dose all remain controversial. MATERIALS AND METHODS We included patients treated with EBRT with curative intent from two cancer centres between 1988 and 2001. Data were collected from hospital notes, radiotherapy prescriptions and local cancer registry. RESULTS The indications for treatment in the 41 identified patients were macroscopic residual disease 23 (56%), microscopic residual disease 10 (25%), Hurthle cell variants 3 (7%), multiple lymph-node involvement 3 (7%) and other 2 (5%). Delivered doses ranged from 37.5-66 Gy over 3-6.5 weeks. Rate of local recurrence and overall survival at 5 years were as follows: papillary 26% and 67%; follicular 43% and 48%; well differentiated 21% and 67%; focus of poor differentiation/Hurthle cell variants 69% and 32%; complete excision 25% and 61%; residual disease 37% and 59%; EBRT total dose < 50 Gy 63% and 42%; 50-54 Gy 15% and 72%; > 54 Gy 18%, and 68%. CONCLUSIONS The results in this study are consistent with previous retrospective studies of EBRT. The wide range of indications and doses used with radical intent highlights the lack of clinical and radiobiological data on the response of differentiated thyroid cancer to EBRT. Despite the small study size, the 5-year local recurrence results indicate a possible dose response within the dose range used.

Chemoradiotherapy for locally advanced head and neck cancer: 10-year follow-up of the UK Head and Neck (UKHAN1) trial.

Summary Background Between 1990 and 2000, we examined the effect of timing of non-platinum chemotherapy when combined with radiotherapy. We aimed to determine whether giving chemotherapy concurrently with radiotherapy or as maintenance therapy, or both, affected clinical outcome. Here we report survival and recurrence after 10 years of follow-up. Methods Between Jan 15, 1990, and June 20, 2000, 966 patients were recruited from 34 centres in the UK and two centres from Malta and Turkey. Patients with locally advanced head and neck cancer, and who had not previously undergone surgery, were randomly assigned to one of four groups in a 3:2:2:2 ratio, stratified by centre and chemotherapy regimen: radical radiotherapy alone (n=233); radiotherapy with two courses of chemotherapy given simultaneously on days 1 and 14 of radiotherapy (SIM alone; n=166); or 14 and 28 days after completing radiotherapy (SUB alone, n=160); or both (SIM+SUB; n=154). Chemotherapy was either methotrexate alone, or vincristine, bleomycin, methotrexate, and fluorouracil. Patients who had previously undergone radical surgery to remove their tumour were only randomised to radiotherapy alone (n=135) or SIM alone (n=118), in a 3:2 ratio. The primary endpoints were overall survival (from randomisation), and event-free survival (EFS; recurrence, new tumour, or death; whichever occurred first) among patients who were disease-free 6 months after randomisation. Analyses were by intention to treat. This trial is registered at www.Clinicaltrials.gov, number NCT00002476. Findings All 966 patients were included in the analyses. Among patients who did not undergo surgery, the median overall survival was 2·6 years (99% CI 1·9–4·2) in the radiotherapy alone group, 4·7 (2·6–7·8) years in the SIM alone group, 2·3 (1·6–3·5) years in the SUB alone group, and 2·7 (1·6–4·7) years in the SIM+SUB group (p=0·10). The corresponding median EFS were 1·0 (0·7–1·4), 2·2 (1·1–6·0), 1·0 (0·6–1·5), and 1·0 (0·6–2·0) years (p=0·005), respectively. For every 100 patients given SIM alone, there are 11 fewer EFS events (99% CI 1–21), compared with 100 given radiotherapy, 10 years after treatment. Among the patients who had previously undergone surgery, median overall survival was 5·0 (99% CI 1·8–8·0) and 4·6 (2·2–7·6) years in the radiotherapy alone and SIM alone groups (p=0·70), respectively, with corresponding median EFS of 3·7 (99% CI 1·1–5·9) and 3·0 (1·2–5·6) years (p=0·85), respectively. The percentage of patients who had a significant toxicity during treatment were: 11% (radiotherapy alone, n=25), 28% (SIM alone, n=47), 12% (SUB alone, n=19), and 36% (SIM+SUB, n=55) among patients without previous surgery; and 9% (radiotherapy alone, n=12) and 20% (SIM alone, n=24) among those who had undergone previous surgery. The most common toxicity during treatment was mucositis. The percentage of patients who had a significant toxicity at least 6 months after randomisation were: 6% (radiotherapy alone, n=13), 6% (SIM alone, n=10), 4% (SUB alone, n=7), and 6% (SIM+SUB, n=9) among patients who had no previous surgery; and 7% (radiotherapy alone, n=10) and 11% (SIM alone, n=13) among those who had undergone previous surgery. The most common toxicity 6 months after treatment was xerostomia, but this occurred in 3% or less of patients in each group. Interpretation Concurrent non-platinum chemoradiotherapy reduces recurrences, new tumours, and deaths in patients who have not undergone previous surgery, even 10 years after starting treatment. Chemotherapy given after radiotherapy (with or without concurrent chemotherapy) is ineffective. Patients who have undergone previous surgery for head and neck cancer do not benefit from non-platinum chemotherapy. Funding Cancer Research UK, with support from University College London and University College London Hospital Comprehensive Biomedical Research Centre.

The effect of head and neck irradiation on taste dysfunction: a prospective study.

Taste loss is a major cause of morbidity in patients undergoing head and neck irradiation. In a prospective study, 26 patients undergoing radical head and neck irradiation at the Royal Marsden Hospital, Sutton, and the Queen Elizabeth Hospital, Birmingham, were assessed for taste loss and xerostomia. Taste was tested using a subjective questionnaire and by objective taste testing with a series of solute solutions (sucrose, sodium chloride, urea and hydrochloric acid) at increasing concentrations, to determine the threshold level of taste sensation, both before and after radiotherapy. Xerostomia was assessed using a patient questionnaire. The volume of tongue and parotid contained within the high dose volume of the radiation treatment field was determined for each patient and correlated with the degree of objective and subjective taste loss as well as the degree of xerostomia. The results have shown that both objective (r = 0.59; P = 0.0016) and subjective taste loss (r = 0.78; P = 0.0001) was significantly associated with the proportion of tongue, but not parotid, contained within the radiation treatment field. The data gave no evidence to suggest any relationship between recovery of taste loss and volume of parotid or tongue irradiated. However, recovery of subjective taste loss, 1 month after completing radiotherapy was seen in two patients, both of whom had been treated using a wedge pair technique to avoid the contralateral area of the tongue. Changes in xerostomia were significantly correlated with the proportions of both tongue (r = 0.54; P = 0.004) and parotid (r = 0.82; P = 0.0001) within the radiation treatment fields.(ABSTRACT TRUNCATED AT 250 WORDS)

HYPOFRACTIONATED ACCELERATED RADIOTHERAPY WITH CONCURRENT CHEMOTHERAPY FOR LOCALLY ADVANCED SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK

AIMS Hypofractionated accelerated radiotherapy with concurrent carboplatin utilises both advantages of altered fractionation and synchronous chemotherapy to maximise local control in locally advanced head and neck cancer. Such fractionation schedules are increasingly used in the intensity-modulated radiotherapy era and the aim of this study was to determine the outcome of hypofractionated accelerated radiotherapy with carboplatin. MATERIALS AND METHODS One hundred and fifty consecutive patients with squamous cell carcinoma of the larynx, oropharynx, oral cavity and hypopharynx (International Union Against Cancer [IUAC] stage II-IV) treated with 55Gy in 20 fractions over 25 days with concurrent carboplatin were analysed. Outcome measures were 2 year overall survival, local control and disease-free survival. RESULTS The median follow-up in surviving patients was 25 months. IUAC stages: II n=15; III n=42; IV n=93. Two year overall survival for all patients was 74.9% (95% confidence interval 66.0-81.7%). Two year local control was 78.3% (95% confidence interval 69.6-84.8%). Two year disease-free survival was 67.2% (95% confidence interval 58.3-74.7%). There were 135 patients with stage III and IV disease. For these patients, the 2 year overall survival, local control and disease-free survival were 74.3% (95% confidence interval 64.7-81.6%), 79.1% (95% confidence interval 69.8-85.9%) and 67.6% (95% confidence interval 58.0-75.4%), respectively. Prolonged grade 3 and 4 mucositis seen at ≥4 weeks were present in 9 and 0.7%, respectively. Late feeding dysfunction (determined by dependence on a feeding tube at 1 year) was seen in 13% of the surviving patients at 1 year. CONCLUSION Hypofractionated accelerated radiotherapy with concurrent carboplatin achieves a high local control. This regimen should be considered for a radiotherapy dose-escalation study using intensity-modulated radiotherapy.

Radiobiological Modelling of the Therapeutic Ratio for the Addition of Synchronous Chemotherapy to Radiotherapy in Locally Advanced Squamous Cell Carcinoma of the Head and Neck

AIMS To model the therapeutic gain from the addition of synchronous chemotherapy to radiotherapy in locally advanced head and neck cancer. MATERIALS AND METHODS Refinements to previous methodology, including the derivation of weighted estimates of key parameters from randomised studies and the use of the expected mucosal biologically effective dose concept, have been used to produce an evidence-based assessment of the benefit from the addition of chemotherapy when considering acute grade 3 mucositis and rates of 5-year local control. RESULTS For a value of alpha=0.3Gy(-1) the additional contribution from chemotherapy to local control was estimated to be 9.3Gy(10) and to grade 3 mucositis 6.4Gy(10). The additional expected mucosal biologically effective dose if radiotherapy dose escalation had been used instead of chemotherapy would have been 11.6Gy(10). Therefore, the mucosal sparing by using synchronous chemotherapy rather than radiotherapy dose escalation was found to be 5.2Gy(10) or the equivalent dose in 2Gy fractions 4.3Gy EQD(2). CONCLUSION This modelling suggests a small therapeutic gain for the use of synchronous chemotherapy instead of radiotherapy dose escalation. This conclusion is dependent on the linear quadratic model and takes no account of late side-effects. This gain would be greater for agents that enhance the mucosal reaction to a lesser degree. This gain may be less when data for radiotherapy dose escalation to smaller high dose volumes using intensity-modulated radiotherapy are considered.

Correlation of currently used radiobiological parameters with local control and acute and late mucosal toxicity in randomised studies of altered fractionation for locally advanced head and neck cancer.

AIMS There has been a resurgence in interest in radiobiological modelling in head and neck cancer. The aim of this study was to determine if currently used parameters accurately predict both tumour and toxicity outcomes. MATERIALS AND METHODS Trials were identified from a recent meta-analysis of altered fractionation. The tumour biologically effective dose (tBED; α/β=10Gy, t(k) [onset time of accelerated repopulation]=22 days, t(p) [average doubling time during accelerated repopulation]=3 days, α=0.3Gy(-1)), acute mucosal biologically effective dose (amBED; α/β=10Gy, t(k)=7 days, t(p)=2.5 days, α=0.3Gy(-1)) and late mucosal biologically effective dose (lmBED; α/β=3Gy) were calculated for each arm of each trial. The correlation between the absolute percentage difference in BED between treatment arms and the observed percentage difference in local control, acute grade 3 mucositis and late grade 3 mucosal reaction was then assessed. RESULTS A strong correlation was observed between the percentage difference in tBED and the percentage difference in local control (P=0.006). A trend towards a correlation was seen between the percentage difference in amBED and the percentage difference in acute grade 3 mucositis (P=0.06). A significant correlation was observed between the percentage difference in lmBED and the percentage difference in grade 3 late mucosal toxicity (P=0.02). However, a 15% decrease in lmBED between control and experimental arms of the study was necessary for any sparing of late mucosal toxicity to be observed. CONCLUSIONS Currently used parameters for tumour accurately predict outcomes in randomised trials of altered fractionation. Although the relationship may be more complex for late mucosal reaction, the presence of a correlation is noteworthy given the infrequent reporting or occurrence of this toxicity. In the future, radiobiological modelling with the addition of volumetric parameters will be highly relevant, given attempts to dose escalate with intensity-modulated radiotherapy in poor risk patients and de-escalate in patients with an excellent prognosis.

Revising the Radiobiological Model of Synchronous Chemotherapy in Head-and-Neck Cancer: A New Analysis Examining Reduced Weighting of Accelerated Repopulation

PURPOSE Previous studies of synchronous chemoradiation therapy have modeled the additional effect of chemotherapy as additional radiation therapy biologically effective dose (BED). Recent trials of accelerated versus conventional fractionation chemoradiation have cast doubt on such modeling. The purpose of this study was to identify alternative models. METHODS AND MATERIALS Nine trials of platinum-based chemoradiation were identified. In radiation therapy-alone arms, the radiation therapy BED for tumor was calculated using standard parameters. In chemoradiation arms, 3 methods were used to calculate tumor BED (tBED): additional BED, addition of 9.3 Gy BED for tumor to the radiation therapy BED; zero repopulation, BED with no correction for repopulation; variable t(p) (the average doubling time during accelerated repopulation), values of t(p) 3-10 were used to examine a partial suppression of repopulation. The correlations between the calculated percentage change in tBED for each method and observed percentage change in local control were assessed using the Pearson product moment correlation. RESULTS Significant correlations were obtained for all 3 methods but were stronger with zero repopulation (P=.0002) and variable tp (t(p) = 10) (P=.0005) than additional BED (P=.02). CONCLUSIONS Radiobiological models using modified parameters for accelerated repopulation seem to correlate strongly with outcome in chemoradiation studies. The variable tp method shows strong correlation for outcome in local control and is potentially a more suitable model in the chemoradiation setting. However, a lack of trials with an overall treatment time of more than 46 days inhibits further differentiation of the optimal model.

Variation in Volume Definition between UK Head and Neck Oncologists Treating Oropharyngeal Carcinoma

technique [3]. In order to establish UK volume definition practice in oropharyngeal cancer, the Birmingham Clinical Trials Unit distributed questionnaires to known UK head and neck oncologists in JuneeJuly 2010. Forty oncologists responded from 33 centres. Twenty-two of the 33 centres (27 of 40 oncologists) used intensity-modulated radiotherapy (22/ 33; 66.7%) of whom 19 (70.1%) used three dose levels and eight (29.6%) used two dose levels. The intensitymodulated radiotherapy high dose ranged from 65 to 70 Gy in 30e35 fractions; intermediate dose 54e63.7 Gy in 30e35 fractions; elective dose 44e56 Gy in 22e30 fractions. The growth of the high dose clinical target volume (CTV) from the GTV was as follows: anatomical alone: two oncologists (7.4%), geometric alone: seven (25.9%), combined anatomical and geometric: 18 (66.7%). The minimum margin used to construct the high dose CTV from the GTV ranged between 5 and 20 mm. The growth of the CTV from the GTV for the intermediate dose was as follows: anatomical alone: six (31.6%), geometric alone: two (10.5%), combined anatomical and geometric: nine (47.4%), information unavailable from two oncologists. The minimum geometric margin varied between 0 and 15 mm. This survey illustrates the variability in UK contouring strategies for oropharyngeal carcinoma, with most responding clinicians using combined anatomical and geometric growth and a three dose level technique. This technique relies on the hypothesis that only the GTV requires a radical dose and surrounding tissues can be adequately treated with an intermediate ‘microscopic’ dose. However, there are no prospective studies with long-term follow-up to validate the safety of this approach.

Outcome of T1N0M0 Squamous Cell Carcinoma of the Larynx Treated with Short-course Radiotherapy to a Total Dose of 50 Gy in 16 Fractions: the Birmingham Experience

AIMS To review the results of hypofractionated radiotherapy in T1N0M0 squamous cell carcinoma of the larynx. MATERIALS AND METHODS A series of 100 patients treated with radiotherapy between 1993 and 2001 was reviewed. The median age was 67 years. The median follow-up was 7 years (range 3-14 years). Radiotherapy was delivered to a total dose of 50 Gy in 16 fractions treating daily, 5 days a week over 21 days. RESULTS Locoregional control rates with radiotherapy alone were 92% at 2 years and 88% at 5 years. After salvage surgery, the ultimate locoregional control rate was 96%. The relapse-free survival rates at 2 and 5 years were 85 and 70%, respectively. The cause-specific survival rates at 2 and 5 years were 99 and 97%, respectively. Overall survival rates at 2 and 5 years were 91 and 76%, respectively. Second primary cancers occurred in 21% of patients, primarily in the lung. CONCLUSIONS Radiotherapy to a total dose of 50 Gy in 16 fractions for T1N0M0 squamous cell carcinoma of the larynx offers high locoregional control rates with voice preservation. These results from a hypofractionated radiotherapy schedule are comparable with other longer fractionation schedules and offer potential for optimising resource usage.

The use of MuGard™, Caphosol® and Episil® in patients undergoing chemoradiotherapy for squamous cell carcinoma of the head and neck

IntroductionOral mucositis is common for patients undergoing chemoradiotherapy for squamous cell carcinoma of the head and neck (SCCHN). Despite the significant detrimental sequelae associated, there is no consensus on the optimum mouth care regimen. This prospective audit aims to record mucositis and dysphagia toxicity and the level of analgesia prescribed when recent products: MuGard™, Caphosol® and Episil® are compared with our standard departmental mouth care regimen.MethodsPatients undergoing concurrent chemoradiotherapy for locally advanced SCCHN at University Hospital Birmingham, UK were prospectively audited weekly for 8 consecutive weeks starting from week 1 of chemoradiotherapy from June 2009 until January 2011. Patients received either standard oral care regimen of aspirin, glycerin and sucralfate, or, MuGard™, Caphosol® or Episil®. Grade of mucositis, dysphagia and analgesia score were prospectively recorded using the common toxicity criteria v3·0.ResultsOne hundred and four patients were included. There was no difference in the grade and duration of mucositis (p = 0·82), dysphagia (p = 0·99) or analgesia score (p = 0·61) for either MuGard™, Caphosol® or Episil® compared with standard oral care.ConclusionThere is no evidence from this audit that Mugard™, Caphosol® or Episil® improves mucositis and dysphagia toxicity or the level of analgesia prescribed compared with our standard departmental mouth care regimen. Randomised trials comparing these approaches are required to detect any meaningful clinical benefit.