Changes in multimodality functional imaging parameters early during chemoradiation predict treatment response in patients with locally advanced head and neck cancer.

OBJECTIVE: To assess the optimal timing and predictive value of early intra-treatment changes in multimodality functional and molecular imaging (FMI) parameters as biomarkers for clinical remission in patients receiving chemoradiation for head and neck squamous cell carcinoma (HNSCC). METHODS: Thirty-five patients with stage III-IVb (AJCC 7th edition) HNSCC prospectively underwent 18F-FDG-PET/CT, and diffusion-weighted (DW), dynamic contrast-enhanced (DCE) and susceptibility-weighted MRI at baseline, week 1 and week 2 of chemoradiation. Patients with evidence of persistent or recurrent disease during follow-up were classed as non-responders. Changes in FMI parameters at week 1 and week 2 were compared between responders and non-responders with the Mann-Whitney U test. The significance threshold was set at a p value of <0.05. RESULTS: There were 27 responders and 8 non-responders. Responders showed a greater reduction in PET-derived tumor total lesion glycolysis (TLG40%; p = 0.007) and maximum standardized uptake value (SUVmax; p = 0.034) after week 1 than non-responders but these differences were absent by week 2. In contrast, it was not until week 2 that MRI-derived parameters were able to discriminate between the two groups: larger fractional increases in primary tumor apparent diffusion coefficient (ADC; p < 0.001), volume transfer constant (Ktrans; p = 0.012) and interstitial space volume fraction (Ve; p = 0.047) were observed in responders versus non-responders. ADC was the most powerful predictor (∆ >17%, AUC 0.937). CONCLUSION: Early intra-treatment changes in FDG-PET, DW and DCE MRI-derived parameters are predictive of ultimate response to chemoradiation in HNSCC. However, the optimal timing for assessment with FDG-PET parameters (week 1) differed from MRI parameters (week 2). This highlighted the importance of scanning time points for the design of FMI risk-stratified interventional studies.

HSP90 inhibition sensitizes head and neck cancer to platin-based chemoradiotherapy by modulation of the DNA damage response resulting in chromosomal fragmentation.

BACKGROUND: Concurrent cisplatin radiotherapy (CCRT) is a current standard-of-care for locally advanced head and neck squamous cell carcinoma (HNSCC). However, CCRT is frequently ineffective in patients with advanced disease. It has previously been shown that HSP90 inhibitors act as radiosensitizers, but these studies have not focused on CCRT in HNSCC. Here, we evaluated the HSP90 inhibitor, AUY922, combined with CCRT. METHODS: The ability of AUY922 to sensitize to CCRT was assessed in p53 mutant head and neck cell lines by clonogenic assay. Modulation of the CCRT induced DNA damage response (DDR) by AUY922 was characterized by confocal image analysis of RAD51, BRCA1, 53BP1, ATM and mutant p53 signaling. The role of FANCA depletion by AUY922 was examined using shRNA. Cell cycle checkpoint abrogation and chromosomal fragmentation was assessed by western blot, FACS and confocal. The role of ATM was also assessed by shRNA. AUY922 in combination with CCRT was assessed in vivo. RESULTS: The combination of AUY922 with cisplatin, radiation and CCRT was found to be synergistic in p53 mutant HNSCC. AUY922 leads to significant alterations to the DDR induced by CCRT. This comprises inhibition of homologous recombination through decreased RAD51 and pS1524 BRCA1 with a corresponding increase in 53BP1 foci, activation of ATM and signaling into mutant p53. A shift to more error prone repair combined with a loss of checkpoint function leads to fragmentation of chromosomal material. The degree of disruption to DDR signalling correlated to chromosomal fragmentation and loss of clonogenicity. ATM shRNA indicated a possible rationale for the combination of AUY922 and CCRT in cells lacking ATM function. CONCLUSIONS: This study supports future clinical studies combining AUY922 and CCRT in p53 mutant HNSCC. Modulation of the DDR and chromosomal fragmentation are likely to be analytical points of interest in such trials.

DARS: a phase III randomised multicentre study of dysphagia- optimised intensity- modulated radiotherapy (Do-IMRT) versus standard intensity- modulated radiotherapy (S-IMRT) in head and neck cancer.

BACKGROUND: Persistent dysphagia following primary chemoradiation (CRT) for head and neck cancers can have a devastating impact on patients' quality of life. Single arm studies have shown that the dosimetric sparing of critical swallowing structures such as the pharyngeal constrictor muscle and supraglottic larynx can translate to better functional outcomes. However, there are no current randomised studies to confirm the benefits of such swallow sparing strategies. The aim of Dysphagia/Aspiration at risk structures (DARS) trial is to determine whether reducing the dose to the pharyngeal constrictors with dysphagia-optimised intensity- modulated radiotherapy (Do-IMRT) will lead to an improvement in long- term swallowing function without having any detrimental impact on disease-specific survival outcomes. METHODS/DESIGN: The DARS trial (CRUK/14/014) is a phase III multicentre randomised controlled trial (RCT) for patients undergoing primary (chemo) radiotherapy for T1-4, N0-3, M0 pharyngeal cancers. Patients will be randomised (1:1 ratio) to either standard IMRT (S-IMRT) or Do-IMRT. Radiotherapy doses will be the same in both groups; however in patients allocated to Do-IMRT, irradiation of the pharyngeal musculature will be reduced by delivering IMRT identifying the pharyngeal muscles as organs at risk. The primary endpoint of the trial is the difference in the mean MD Anderson Dysphagia Inventory (MDADI) composite score, a patient-reported outcome, measured at 12 months post radiotherapy. Secondary endpoints include prospective and longitudinal evaluation of swallow outcomes incorporating a range of subjective and objective assessments, quality of life measures, loco-regional control and overall survival. Patients and speech and language therapists (SLTs) will both be blinded to treatment allocation arm to minimise outcome-reporting bias. DISCUSSION: DARS is the first RCT investigating the effect of swallow sparing strategies on improving long-term swallowing outcomes in pharyngeal cancers. An integral part of the study is the multidimensional approach to swallowing assessment, providing robust data for the standardisation of future swallow outcome measures. A translational sub- study, which may lead to the development of future predictive and prognostic biomarkers, is also planned. TRIAL REGISTRATION: This study is registered with the International Standard Randomised Controlled Trial register, ISRCTN25458988 (04/01/2016).

Repeatability and sensitivity of T2* measurements in patients with head and neck squamous cell carcinoma at 3T.

PURPOSE: To determine whether quantitation of T2* is sufficiently repeatable and sensitive to detect clinically relevant oxygenation levels in head and neck squamous cell carcinoma (HNSCC) at 3T. MATERIALS AND METHODS: Ten patients with newly diagnosed locally advanced HNSCC underwent two magnetic resonance imaging (MRI) scans between 24 and 168 hours apart prior to chemoradiotherapy treatment. A multiple gradient echo sequence was used to calculate T2* maps. A quadratic function was used to model the blood transverse relaxation rate as a function of blood oxygenation. A set of published coefficients measured at 3T were incorporated to account for tissue hematocrit levels and used to plot the dependence of fractional blood oxygenation (Y) on T2* values, together with the corresponding repeatability range. Repeatability of T2* using Bland-Altman analysis, and calculation of limits of agreement (LoA), was used to assess the sensitivity, defined as the minimum difference in fractional blood oxygenation that can be confidently detected. RESULTS: T2* LoA for 22 outlined tumor volumes were 13%. The T2* dependence of fractional blood oxygenation increases monotonically, resulting in increasing sensitivity of the method with increasing blood oxygenation. For fractional blood oxygenation values above 0.11, changes in T2* were sufficient to detect differences in blood oxygenation greater than 10% (Δ T2* > LoA for ΔY > 0.1). CONCLUSION: Quantitation of T2* at 3T can detect clinically relevant changes in tumor oxygenation within a wide range of blood volumes and oxygen tensions, including levels reported in HNSCC. J. Magn. Reson. Imaging 2016;44:72-80.

Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial.

BACKGROUND: Patients with radioactive iodine ((131)I)-refractory locally advanced or metastatic differentiated thyroid cancer have a poor prognosis because of the absence of effective treatment options. In this study, we assessed the efficacy and safety of orally administered sorafenib in the treatment of patients with this type of cancer. METHODS: In this multicentre, randomised, double-blind, placebo-controlled, phase 3 trial (DECISION), we investigated sorafenib (400 mg orally twice daily) in patients with radioactive iodine-refractory locally advanced or metastatic differentiated thyroid cancer that had progressed within the past 14 months. Adult patients (≥18 years of age) with this type of cancer were enrolled from 77 centres in 18 countries. To be eligible for inclusion, participants had to have at least one measurable lesion by CT or MRI according to Response Evaluation Criteria In Solid Tumors (RECIST); Eastern Cooperative Oncology Group performance status 0-2; adequate bone marrow, liver, and renal function; and serum thyroid-stimulating hormone concentration lower than 0·5 mIU/L. An interactive voice response system was used to randomly allocate participants in a 1:1 ratio to either sorafenib or matching placebo. Patients, investigators, and the study sponsor were masked to treatment assignment. The primary endpoint was progression-free survival, assessed every 8 weeks by central independent review. Analysis was by intention to treat. Patients in the placebo group could cross over to open-label sorafenib upon disease progression. Archival tumour tissue was examined for BRAF and RAS mutations, and serum thyroglobulin was measured at baseline and at each visit. This study is registered with ClinicalTrials.gov, number NCT00984282, and with the EU Clinical Trials Register, number EudraCT 2009-012007-25. FINDINGS: Patients were randomly allocated on a 1:1 basis to sorafenib or placebo. The intention-to-treat population comprised 417 patients (207 in the sorafenib group and 210 in the placebo group) and the safety population was 416 patients (207 in the sorafenib group and 209 in the placebo group). Median progression-free survival was significantly longer in the sorafenib group (10·8 months) than in the placebo group (5·8 months; hazard ratio [HR] 0·59, 95% CI 0·45-0·76; p<0·0001). Progression-free survival improved in all prespecified clinical and genetic biomarker subgroups, irrespective of mutation status. Adverse events occurred in 204 of 207 (98·6%) patients receiving sorafenib during the double-blind period and in 183 of 209 (87·6%) patients receiving placebo. Most adverse events were grade 1 or 2. The most frequent treatment-emergent adverse events in the sorafenib group were hand-foot skin reaction (76·3%), diarrhoea (68·6%), alopecia (67·1%), and rash or desquamation (50·2%). INTERPRETATION: Sorafenib significantly improved progression-free survival compared with placebo in patients with progressive radioactive iodine-refractory differentiated thyroid cancer. Adverse events were consistent with the known safety profile of sorafenib. These results suggest that sorafenib is a new treatment option for patients with progressive radioactive iodine-refractory differentiated thyroid cancer. FUNDING: Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals (an Amgen subsidiary).

Ablation with low-dose radioiodine and thyrotropin alfa in thyroid cancer.

BACKGROUND: It is not known whether low-dose radioiodine (1.1 GBq [30 mCi]) is as effective as high-dose radioiodine (3.7 GBq [100 mCi]) for treating patients with differentiated thyroid cancer or whether the effects of radioiodine (especially at a low dose) are influenced by using either recombinant human thyrotropin (thyrotropin alfa) or thyroid hormone withdrawal. METHODS: At 29 centers in the United Kingdom, we conducted a randomized noninferiority trial comparing low-dose and high-dose radioiodine, each in combination with either thyrotropin alfa or thyroid hormone withdrawal before ablation. Patients (age range, 16 to 80 years) had tumor stage T1 to T3, with possible spread to nearby lymph nodes but without metastasis. End points were the rate of success of ablation at 6 to 9 months, adverse events, quality of life, and length of hospital stay. RESULTS: A total of 438 patients underwent randomization; data could be analyzed for 421. Ablation success rates were 85.0% in the group receiving low-dose radioiodine versus 88.9% in the group receiving the high dose and 87.1% in the thyrotropin alfa group versus 86.7% in the group undergoing thyroid hormone withdrawal. All 95% confidence intervals for the differences were within ±10 percentage points, indicating noninferiority. Similar results were found for low-dose radioiodine plus thyrotropin alfa (84.3%) versus high-dose radioiodine plus thyroid hormone withdrawal (87.6%) or high-dose radioiodine plus thyrotropin alfa (90.2%). More patients in the high-dose group than in the low-dose group were hospitalized for at least 3 days (36.3% vs. 13.0%, P<0.001). The proportions of patients with adverse events were 21% in the low-dose group versus 33% in the high-dose group (P=0.007) and 23% in the thyrotropin alfa group versus 30% in the group undergoing thyroid hormone withdrawal (P=0.11). CONCLUSIONS: Low-dose radioiodine plus thyrotropin alfa was as effective as high-dose radioiodine, with a lower rate of adverse events. (Funded by Cancer Research UK; ClinicalTrials.gov number, NCT00415233.).

Stereotactic body radiotherapy for oligometastases.

The management of metastatic solid tumours has historically focused on systemic treatment given with palliative intent. However, radical surgical treatment of oligometastases is now common practice in some settings. The development of stereotactic body radiotherapy (SBRT), building on improvements in delivery achieved by intensity-modulated and image-guided radiotherapy, now allows delivery of ablative doses of radiation to extracranial sites. Many non-randomised studies have shown that SBRT for oligometastases is safe and effective, with local control rates of about 80%. Importantly, these studies also suggest that the natural history of the disease is changing, with 2-5 year progression-free survival of about 20%. Although complete cure might be possible in a few patients with oligometastases, the aim of SBRT in this setting is to achieve local control and delay progression, and thereby also postpone the need for further treatment. We review published work showing that SBRT offers durable local control and the potential for progression-free survival in non-liver, non-lung oligometastatic disease at a range of sites. However, to test whether SBRT really does improve progression-free survival, randomised trials will be essential.

Evaluation of swallowing by Sydney Swallow Questionnaire (SSQ) in oral and oropharyngeal cancer patients treated with primary surgery.

This work aimed at evaluating patients' swallowing functions by a newly validated swallow-specific questionnaire, the Sydney Swallow Questionnaire (SSQ), in a cohort of oral and oropharyngeal cancer patients. Mean/median SSQ scores were calculated and compared with study variables using the Mann-Whitney U test and Kruskal-Wallis test. The mean composite SSQ scores (SD) for the base of tongue, oral tongue, and tonsillar cancer patients were 663.8 (382.8), 456.2 (407.6), and 283.0 (243.1), respectively (p = 0.005); for advanced vs. early T stage disease they were 918.1 (319.5) vs. 344.8 (292.1) (p ≤ 0.001); for patients <60 years vs. ≥60 years they were 549.3 (415.1) vs. 314.0 (247.3) (p = 0.02); and for patients with reconstruction vs. without reconstruction they were 676.5 (410.5) vs. 331.9 (286.5) (p = 0.002). SSQ is a useful tool for evaluation of swallowing in head and neck cancer patients. Site of cancer, T stage, patient's age, and reconstruction directly affect post-treatment swallow outcome.

An exploratory study of the influence of clinico-demographic variables on swallowing and swallowing-related quality of life in a cohort of oral and oropharyngeal cancer patients treated with primary surgery.

There are insufficient data on swallowing and the consequences of its dysfunction in patients with cancers of the oral cavity (OC) and oropharynx (OP) that are treated with primary surgery. The study attempts to explore the effect of important clinico-demographic variables on post-treatment swallowing and related quality of life (QOL) in post-surgical OC and OP cancer patients. Sixty-two consecutive OC and OP cancer patients completed the MD Anderson Dysphagia Inventory (MDADI) questionnaire. Mean scores were computed. Comparison of scores based on mean ranks were performed using Mann-Whitney U test or Kruskal-Wallis test. Level of significance was set at P ≤ 0.02. Adjustments were made for multiple comparisons. Significantly worse mean (SD) QOL scores were observed in late T-stage (T3/T4) versus early T-stage (T1/T2) patients for global domain, physical domain, functional domain and emotional domains [44.4 (21.9) vs. 78.7 (22.7) (P < 0.001); 50.0 (9.4) vs. 75.9 (16.3), (P < 0.0001); 57.8 (20.6) vs. 84.1 (16.7), (P < 0.001) and 55.2 (18.0) vs. 78.5 (16.3), (P < 0.001)], respectively. Patients undergoing reconstruction versus without reconstruction had worse QOL scores; 58.8 (26.9) versus 79.5 (22.8), (P < 0.01); 61.2 (15.1) versus 76.4 (17.5), (P = 0.002); 65.4 (20.5) versus 86.3 (15.9), (P < 0.0001) and 63.3 (18.8) versus 79.8 (16.3), (P < 0.01), respectively, for global, physical, functional and emotional domains. Advanced T-stage, reconstruction, younger age and base of tongue tumours have a negative impact on post-treatment swallow function and related QOL in these patients.

Evaluation of factors affecting post-treatment quality of life in oral and oropharyngeal cancer patients primarily treated with curative surgery: an exploratory study.

The aim was to explore the impact of important clinico-demographic factors on the post-treatment quality of life (QOL) in surgically treated oral and oropharyngeal cancer patients. 63 consecutive follow-up oral and oropharyngeal cancer patients treated primarily with surgery were recruited. 55 patients sent the completed questionnaires and finally included in this study. QOL and important sub-domains of the QOL were assessed. Mean QOL scores (SD) were computed, level of significance was set at P < 0.05. The mean composite QOL score and standard deviation (SD) for oral and oropharyngeal cancer patients were 76.6 (15.2) and 73.4 (13.9), respectively. Patients with higher T-stage (T3 and T4) and higher overall-stage (III and IV) had lower mean QOL scores as against early T (T1 and T2) and overall early-stage (I and II); mean scores (SD) 64.3 (13.6) and 72.3 (13.8), and 76.6 (13.6) and 81.7 (14.1), respectively. Younger patients had lower mean scores (SD) than older patients; mean QOL scores (SD) 69.7 (14.0) and 79.6 (SD), respectively. Patients with reconstruction had lower mean QOL scores as compared to those without reconstruction; mean scores (SD) 67.6 (16.0) and 77.4 (12.5), respectively. In conclusion, tumor-stage, overall-stage, age of patients, and reconstruction had a significant direct effect on the post-treatment QOL of oral and oropharyngeal cancer patients.

Parotid-sparing intensity modulated versus conventional radiotherapy in head and neck cancer (PARSPORT): a phase 3 multicentre randomised controlled trial.

BACKGROUND: Xerostomia is the most common late side-effect of radiotherapy to the head and neck. Compared with conventional radiotherapy, intensity-modulated radiotherapy (IMRT) can reduce irradiation of the parotid glands. We assessed the hypothesis that parotid-sparing IMRT reduces the incidence of severe xerostomia. METHODS: We undertook a randomised controlled trial between Jan 21, 2003, and Dec 7, 2007, that compared conventional radiotherapy (control) with parotid-sparing IMRT. We randomly assigned patients with histologically confirmed pharyngeal squamous-cell carcinoma (T1-4, N0-3, M0) at six UK radiotherapy centres between the two radiotherapy techniques (1:1 ratio). A dose of 60 or 65 Gy was prescribed in 30 daily fractions given Monday to Friday. Treatment was not masked. Randomisation was by computer-generated permuted blocks and was stratified by centre and tumour site. Our primary endpoint was the proportion of patients with grade 2 or worse xerostomia at 12 months, as assessed by the Late Effects of Normal Tissue (LENT SOMA) scale. Analyses were done on an intention-to-treat basis, with all patients who had assessments included. Long-term follow-up of patients is ongoing. This study is registered with the International Standard Randomised Controlled Trial register, number ISRCTN48243537. FINDINGS: 47 patients were assigned to each treatment arm. Median follow-up was 44·0 months (IQR 30·0-59·7). Six patients from each group died before 12 months and seven patients from the conventional radiotherapy and two from the IMRT group were not assessed at 12 months. At 12 months xerostomia side-effects were reported in 73 of 82 alive patients; grade 2 or worse xerostomia at 12 months was significantly lower in the IMRT group than in the conventional radiotherapy group (25 [74%; 95% CI 56-87] of 34 patients given conventional radiotherapy vs 15 [38%; 23-55] of 39 given IMRT, p=0·0027). The only recorded acute adverse event of grade 2 or worse that differed significantly between the treatment groups was fatigue, which was more prevalent in the IMRT group (18 [41%; 99% CI 23-61] of 44 patients given conventional radiotherapy vs 35 [74%; 55-89] of 47 given IMRT, p=0·0015). At 24 months, grade 2 or worse xerostomia was significantly less common with IMRT than with conventional radiotherapy (20 [83%; 95% CI 63-95] of 24 patients given conventional radiotherapy vs nine [29%; 14-48] of 31 given IMRT; p<0·0001). At 12 and 24 months, significant benefits were seen in recovery of saliva secretion with IMRT compared with conventional radiotherapy, as were clinically significant improvements in dry-mouth-specific and global quality of life scores. At 24 months, no significant differences were seen between randomised groups in non-xerostomia late toxicities, locoregional control, or overall survival. INTERPRETATION: Sparing the parotid glands with IMRT significantly reduces the incidence of xerostomia and leads to recovery of saliva secretion and improvements in associated quality of life, and thus strongly supports a role for IMRT in squamous-cell carcinoma of the head and neck. FUNDING: Cancer Research UK (CRUK/03/005).

Rationale and design of decision: a double-blind, randomized, placebo-controlled phase III trial evaluating the efficacy and safety of sorafenib in patients with locally advanced or metastatic radioactive iodine (RAI)-refractory, differentiated thyroid cancer.

BACKGROUND: The incidence of thyroid cancer and the number of patients who die from this disease are increasing globally. Differentiated thyroid cancer (DTC) is the histologic subtype present in most patients and is primarily responsible for the increased overall incidence of thyroid cancer. Sorafenib is a multikinase inhibitor that targets several molecular signals believed to be involved in the pathogenesis of thyroid cancer, including those implicated in DTC. In phase II studies of patients with DTC, sorafenib treatment has yielded a median progression-free survival (PFS) of 58 to 84 weeks and disease control rates of 59% to 100%. The DECISION trial was designed to assess the ability of sorafenib to improve PFS in patients with locally advanced or metastatic, radioactive iodine (RAI)-refractory DTC. METHODS/DESIGN: DECISION is a multicenter, double-blind, randomized, placebo-controlled phase III study in patients with locally advanced/metastatic RAI-refractory DTC. Study treatment will continue until radiographically documented disease progression, unacceptable toxicity, noncompliance, or withdrawal of consent. Efficacy will be evaluated every 56 days (2 cycles), whereas safety will be evaluated every 28 days (1 cycle) for the first 8 months and every 56 days thereafter. Following disease progression, patients may continue or start sorafenib, depending on whether they were randomized to receive sorafenib or placebo, at investigator discretion. Patients originally randomized to receive sorafenib will be followed up every 3 months for overall survival (OS); patients originally randomized to receive placebo will be followed up every month for 8 months after cross-over to sorafenib. The duration of the trial is expected to be 30 months from the time the first patient is randomized until the planned number of PFS events is attained. The primary endpoint is PFS; secondary endpoints include OS, time to disease progression, disease control rate, response rate, duration of response, safety, and pharmacokinetic analysis. DISCUSSION: The DECISION study has been designed to test whether sorafenib improves PFS in patients with locally advanced or metastatic RAI-refractory DTC. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00984282; EudraCT: 2009-012007-25.

Therapeutic effect of sodium iodide symporter gene therapy combined with external beam radiotherapy and targeted drugs that inhibit DNA repair.

Adenoviral (AdV) transfer of sodium iodide symporter (NIS) gene has translational potential, but relatively low levels of transduction and subsequent radioisotope uptake limit the efficacy of the approach. In previous studies, we showed that combining NIS gene delivery with external beam radiotherapy (EBRT) and DNA damage repair inhibitors increased viral gene expression and radioiodide uptake. Here, we report the therapeutic efficacy of this strategy. An adenovirus expressing NIS from a telomerase promoter (Ad-hTR-NIS) was cytotoxic combined with relatively high-dose (50 microCi) (131)I therapy and enhanced the efficacy of EBRT combined with low-dose (10 and 25 microCi) (131)I therapy in colorectal and head and neck cancer cells. Combining this approach with ataxia-telangiectasia mutated (ATM) or DNA-dependent protein kinase (DNA-PK) inhibition caused maintenance of double-stranded DNA breaks (DSBs) at 24 hours and increased cytotoxicity on clonogenic assay. When the triplet of NIS-mediated (131)I therapy, EBRT, and DNA-PKi was used in vivo, 90% of mice were tumor-free at 5 weeks. Acute radiation toxicity in the EBRT field was not exacerbated. In contrast, DNA-PKi did not enhance the therapeutic efficacy of EBRT plus adenovirus-mediated HSVtk/ganciclovir (GCV). Therefore, combining NIS gene therapy and EBRT represents an ideal strategy to exploit the therapeutic benefits of novel radiosensitizers.

Dose-escalated intensity-modulated radiotherapy in patients with locally advanced laryngeal and hypopharyngeal cancers: ART DECO, a phase III randomised controlled trial.

BACKGROUND: Radical (chemo)radiotherapy offers potentially curative treatment for patients with locally advanced laryngeal or hypopharyngeal cancer. We aimed to show that dose-escalated intensity-modulated radiotherapy (DE-IMRT) improved locoregional control. METHODS: We performed a phase III open-label randomised controlled trial in patients with laryngeal or hypopharyngeal cancer (AJCC III-IVa/b, TNM 7). Patients were randomised (1:1) to DE-IMRT or standard dose IMRT (ST-IMRT) using a minimisation algorithm, balancing for centre, tumour site, nodal status and chemotherapy use. DE-IMRT was 67.2 gray (Gy) in 28 fractions (f) to the primary tumour and 56Gy/28f to at-risk nodes; ST-IMRT was 65Gy/30f to primary tumour and 54Gy/30f to at-risk nodes. Suitable patients received 2 cycles of concomitant cisplatin and up to 3 cycles of platinum-based induction chemotherapy. The primary end-point was time to locoregional failure analysed by intention-to-treat analysis using competing risk methodology. FINDINGS: Between February 2011 and October 2015, 276 patients (138 ST-IMRT; 138 DE-IMRT) were randomised. A preplanned interim futility analysis met the criterion for early closure. After a median follow-up of 47.9 months (interquartile range 37.5-60.5), there were locoregional failures in 38 of 138 (27.5%) ST-IMRT patients and 42 of 138 (30.4%) DE-IMRT patients; an adjusted subhazard ratio of 1.16 (95% confidence interval: 0.74-1.83, p = 0.519) indicated no evidence of benefit with DE-IMRT. Acute grade 2 pharyngeal mucositis was reported more frequently with DE-IMRT than with ST-IMRT (42% vs. 32%). No differences in grade ≥3 acute or late toxicity rates were seen. CONCLUSION: DE-IMRT did not improve locoregional control in patients with laryngeal or hypopharyngeal cancer. The trial is registered: ISRCTN01483375.

Determinants of response to epidermal growth factor receptor tyrosine kinase inhibition in squamous cell carcinoma of the head and neck.

Dramatic responses to epidermal growth factor receptor (EGFR) tyrosine kinase (TK) inhibitors may be seen in non-small cell lung cancers (NSCLCs) with a sensitizing mutation of the EGFR TK domain. It is not known how to predict response in patients with squamous cell carcinoma of the head and neck (SCCHN), where EGFR TK mutations are less frequent and where response rates in unselected patients are disappointing. We have characterized the intrinsic sensitivity of a panel of 18 SCCHN cell lines to gefitinib, an EGFR TK inhibitor, and have investigated correlations between putative markers of response and intrinsic sensitivity. Induction of G1 arrest was only seen in cell lines with GI(50) < 1 microM. Expression of EGFR, by three techniques, correlated with sensitivity to gefitinib. ERB-B2 expression appeared to influence sensitivity to gefitinib but ERB-B3 expression did not. While EGFR tyrosine kinase mutations were not detected, EGFR gene amplification was confirmed by fluorescence in situ hybridization in the most sensitive cell line. The number of cytosine adenine dinucleotide repeats in intron 1 of the EGFR gene did not correlate with sensitivity. E-cadherin expression was detected in cell lines with a range of sensitivities, whereas amphiregulin was secreted predominantly by sensitive cell lines. MET expression was an independent predictor of sensitivity to gefitinib, although neither expression nor phosphorylation of insulin-like growth factor 1 receptor correlated with intrinsic resistance. Breast receptor kinase (BRK) was more highly expressed in the sensitive cell lines, but siRNA knockdown of neither BRK nor MET affected sensitivity. Our data suggest that overexpression of EGFR and multiple related cell surface receptors may be associated with sensitivity to gefitinib and that differences between our data and the literature highlight that biomarkers of response are tumour type- and cell line-dependent.

Impact of antibiotic use during curative treatment of locally advanced head and neck cancers with chemotherapy and radiotherapy.

BACKGROUND: Pre-clinical evidence suggests reduced efficacy of anticancer treatment in patients exposed to broad-spectrum antibiotics. It is hypothesised that this phenomenon may be explained by the effects of antibiotics on the composition of the microbiota. To assess this in a clinical setting, we analysed the impact of antibiotics in patients with locally advanced head and neck cancer (LAHNC) treated with curative intent with chemotherapy and radiotherapy (RT). MATERIAL AND METHODS: Retrospective data for LAHNC patients treated with curative intent (245 induction chemotherapy followed by chemoradiation [CRT], 17 surgery followed by post-operative CRT, six CRT, three RT alone and one RT with concurrent cetuximab) were analysed. We evaluated the impact of antibiotics prescribed during primary anti-cancer treatment on progression-free survival (PFS), overall survival (OS) and disease-specific survival (DSS) rates by multivariate Kaplan-Meier and Cox proportional hazards regression analysis. RESULTS: Among 272 patients, those receiving antibiotics between within 1 week before and 2 weeks after treatment (N = 124) progressed significantly earlier and had lower OS and DSS rates. In the multivariate analysis, administration of antibiotics was independently associated with reduced PFS (hazards ratio [HR] 1.98, P = 0.001), OS (HR 1.85, P = 0.001) and DSS (HR 1.95, P = 0.004). This effect was maintained with independence of reason for prescription, type and time of antibiotic prescription. The negative impact was greater for patients who received two or more courses of antibiotics. Antibiotic treatment was correlated with increased risk of locoregional relapse. CONCLUSIONS: Our data suggest a negative impact of antibiotic therapy on treatment outcomes following CRT with curative intent in patients with LAHNC. This potential harm should be considered when prescribing broad-spectrum and prophylactic antibiotics for such patients.

Radiation-mediated up-regulation of gene expression from replication-defective adenoviral vectors: implications for sodium iodide symporter gene therapy.

PURPOSE: To assess the effects of external beam radiotherapy (EBRT) on adenoviral-mediated transgene expression in vitro and in vivo and to define an optimal strategy for combining sodium iodide symporter (NIS)-mediated (131)I therapy with EBRT. EXPERIMENTAL DESIGN: Expression of reporter genes [NIS, green fluorescent protein (GFP), beta-galactosidase (lacZ), and luciferase (Luc)] from replication-deficient adenoviruses was assessed in tumor cell lines under basal conditions and following irradiation. The effects of viral multiplicity of infection (MOI) and EBRT dose on the magnitude and duration of gene expression were determined. In vivo studies were done with Ad-CMV-GFP and Ad-RSV-Luc. RESULTS: EBRT increased NIS, GFP, and beta-galactosidase expression in colorectal, head and neck, and lung cancer cells. Radiation dose and MOI were important determinants of response to EBRT, with greatest effects at higher EBRT doses and lower MOIs. Radiation exerted both transductional (through increased coxsackie-adenoviral receptor and integrin alpha(v)) and nontransductional effects, irrespective of promoter sequence (CMV, RSV, hTR, or hTERT). Analysis of the schedule of EBRT followed by viral infection revealed maximal transduction at 24 hours. Radiation maintained increasing radioiodide uptake from Ad-hTR-NIS over 6 days, in direct contrast to reducing levels in unirradiated cells. The effects of EBRT in increasing and maintaining adenovirus-mediated transgene expression were also seen in vivo using GFP- and luciferase-expressing adenoviral vectors. CONCLUSIONS: Radiation increased the magnitude and duration of NIS gene expression from replication-deficient adenoviruses. The transductional effect is maximal at 24 hours, but radioiodide uptake is maintained at an elevated level over 6 days after infection.

Electroglottographic comparison of voice outcomes in patients with advanced laryngopharyngeal cancer treated by chemoradiotherapy or total laryngectomy.

PURPOSE: To conduct prospective electroglottographic analyses of voice outcomes after radical chemoradiotherapy for locally advanced laryngopharyngeal cancers and to compare them with patients who have undergone total laryngectomy (TL). PATIENTS AND METHODS: Twenty-one patients (19 male, 2 female, median age [range] 65 [50-85] years) with Stage III/IV laryngopharyngeal cancer received induction chemotherapy followed by radical chemoradiotherapy. Electroglottography, using the sustained vowel /i/ and connected speech, was performed before treatment and 1, 6, and 12 months after treatment. In addition, single voice recordings were taken from 21 patients (16 male, 5 female, aged 65 [50-84] years) who had undergone TL and surgical voice restoration and from 21 normal controls (18 male, 3 female, aged 65 [33-80] years). RESULTS: Before treatment the vocal measures for the chemoradiotherapy patients were significantly different from normal controls in jitter (p = 0.02), maximum phonation time (MPT) (p = 0.001), and words per minute (WPM) (p = 0.01). At 12 months after treatment MPT and WPM had normalized, but jitter and normalized noise energy were significantly worse than in normal controls. Comparison of voice outcomes at 12 months for chemoradiotherapy patients revealed superiority over the TL group in all parameters except MPT (18.2 s vs. 10.4 s, p = 0.06). Analysis of the recovery of voice up to 12 months after treatment revealed progressive improvement in most electroglottographic measures. CONCLUSIONS: This prospective study demonstrates significantly better outcome for patients treated with chemoradiotherapy as compared with TL. Progressive normalization of many voice parameters occurs over the 12 months following chemoradiotherapy.

Evaluation of the role of 18FDG-PET/CT in radiotherapy target definition in patients with head and neck cancer.

BACKGROUND AND PURPOSE: As techniques for radiotherapy delivery have developed, increasingly accurate localisation of disease is demanded. Functional imaging, particularly PET and its fusion with anatomical modalities, such as PET/CT, promises to improve detection and characterisation of disease. This study evaluated the impact of (18)FDG-PET/CT on radiotherapy target volume definition in head and neck cancer (HNC). MATERIALS AND METHODS: The PET/CT scans of patients with HNC were used in a radiotherapy planning (RTP) study. The gross tumour volume (GTV), clinical target volume (CTV) and planning target volume (PTV) were defined conventionally and compared to those defined using the PET/CT. Data were reported as the median value with 95% confidence intervals. RESULTS: Eighteen patients were consented, 9 had known primary tumour site, 9 presented as unknown primary. In nine cases where the primary site was known, the combined primary and nodal GTV (GTVp+n) increased by a median of 6.1cm(3) (2.6, 12.2) or 78% (18, 313), p=0.008 with CTV increasing by a median of 10.1cm(3) (1.3, 30.6) or 4% (0, 13) p=0.012. In 9 cases of unknown primary the GTVp+n increased by a median 6.3 cm(3) (0.2, 15.7) or 61% (4, 210), p=0.012, with CTV increasing by a median 155.4 cm(3) (2.7, 281.7) or 95% (1, 137), p=0.008. CONCLUSION: (18)FDG-PET revealed disease lying outside the conventional target volume, either extending a known area or highlighting a previously unknown area of disease, including the primary tumour in 5 cases. We recommend PET/CT in the RTP of all cases of unknown primary. In patients with a known primary, although the change in volume was statistically significant the clinical impact is less clear. (18)FDG-PET can also show areas within the conventional target volume that are hypermetabolic which may be possible biological target volumes for dose escalation studies in the future.