Evaluation of multiple transcriptomic gene risk signatures in male breast cancer.

Male breast cancer (BCa) is a rare disease accounting for less than 1% of all breast cancers and 1% of all cancers in males. The clinical management is largely extrapolated from female BCa. Several multigene assays are increasingly used to guide clinical treatment decisions in female BCa, however, there are limited data on the utility of these tests in male BCa. Here we present the gene expression results of 381 M0, ER+ve, HER2-ve male BCa patients enrolled in the Part 1 (retrospective analysis) of the International Male Breast Cancer Program. Using a custom NanoString™ panel comprised of the genes from the commercial risk tests Prosigna®, OncotypeDX®, and MammaPrint®, risk scores and intrinsic subtyping data were generated to recapitulate the commercial tests as described by us previously. We also examined the prognostic value of other risk scores such as the Genomic Grade Index (GGI), IHC4-mRNA and our prognostic 95-gene signature. In this sample set of male BCa, we demonstrated prognostic utility on univariate analysis. Across all signatures, patients whose samples were identified as low-risk experienced better outcomes than intermediate-risk, with those classed as high risk experiencing the poorest outcomes. As seen with female BCa, the concordance between tests was poor, with C-index values ranging from 40.3% to 78.2% and Kappa values ranging from 0.17 to 0.58. To our knowledge, this is the largest study of male breast cancers assayed to generate risk scores of the current commercial and academic risk tests demonstrating comparable clinical utility to female BCa.

Quantification of 18F-fluorodeoxyglucose uptake to detect residual nodal disease in locally advanced head and neck squamous cell carcinoma after chemoradiotherapy: results from the ECLYPS study.

BACKGROUND: The Hopkins criteria were introduced for nodal response evaluation after therapy in head and neck cancer, but its superiority over quantification is not yet confirmed. METHODS: SUVbody weight thresholds and lesion-to-background ratios were explored in a prospective multicenter study of standardized FDG-PET/CT 12 weeks after CRT in newly diagnosed locally advanced head and neck squamous cell carcinoma (LAHNSCC) patients (ECLYPS). Reference standard was histology, negative FDG-PET/CT at 12 months after treatment or ≥ 2 years of negative follow-up. Area under the receiver operator characteristics curves (AUROC) were estimated and obtained thresholds were validated in an independent cohort of HNSCC patients (n = 127). RESULTS: In ECLYPS, 124 patients were available for quantification. With a median follow-up of 20.4 months, 23 (18.5%) nodal neck recurrences were observed. A SUV70 threshold of 2.2 (AUROC = 0.89; sensitivity = 79.7%; specificity = 80.8%) was identified as optimal metric to identify nodal recurrence within 1 year after therapy. For lesion-to-background ratios, an SUV50/SUVliver threshold of 0.96 (AUROC = 0.89; sensitivity = 79.7%; specificity = 82.8%) had the best performance. Compared with Hopkins criteria (AUROC = 0.81), SUV70 and SUV50/SUVliver provided a borderline significant (p = 0.040 and p = 0.094, respectively) improvement. Validation of thresholds yielded similar AUROC values (SUV70 = 0.93, SUV50/SUVliver = 0.95), and were comparable to the Hopkins score (AUROC = 0.91; not statistically significant). CONCLUSION: FDG quantification detects nodal relapse in LAHNSCC patients. When using EARL standardized PET acquisitions and reconstruction, absolute SUV metrics (SUV70 threshold 2.2) prove robust, yet ratios (SUV50/SUVliver, threshold 0.96) may be more useful in routine clinical care. In this setting, the diagnostic value of quantification is comparable to the Hopkins criteria. TRIAL REGISTRATION: US National Library for Medicine, NCT01179360. Registered 11 August 2010, https://clinicaltrials.gov/ct2/show/NCT01179360.

Evolution of self-perceived swallowing function, tongue strength and swallow-related quality of life during radiotherapy in head and neck cancer patients.

BACKGROUND: Radiation-associated-dysphagia is a serious side effect of radiotherapy (RT) for head and neck cancer (HNC). METHODS: Seventy-six patients had a weekly prospective follow-up from baseline until one week post-RT. Combined mixed model analysis (n = 43) determined the evolution of self-perceived swallowing function, isometric tongue strength (MIP), tongue strength (TS) during swallowing (Pswal), and quality of life (QoL) in these patients during RT. RESULTS: Swallowing deteriorated from the third week on, resulting in an increase of tube dependency from 10% at baseline toward 31% post-RT. Both MIP and Pswal are reduced, with anterior MIP decreasing in 29% of patients and posterior MIP in 17%. Pswal decreases for saliva and a bolus swallow. All QoL subscales except "sleep" were affected during RT. CONCLUSIONS: Self-perceived swallowing function, TS and QoL decrease during RT for HNC. Current findings highlight the need for early monitoring of these parameters.

Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography After Concurrent Chemoradiotherapy in Locally Advanced Head-and-Neck Squamous Cell Cancer: The ECLYPS Study.

Purpose To assess the standardized implementation and reporting of surveillance [18F]fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) scan of the neck in locoregionally advanced head-and-neck squamous cell carcinoma (LAHNSCC) after concurrent chemoradiotherapy (CCRT). Patients and Methods We performed a prospective multicenter study of FDG-PET/CT scanning 12 weeks after CCRT in newly diagnosed patients with LAHNSCC (stage IVa/b) that used standardized reconstruction and Hopkins reporting criteria. The reference standard was histology or > 12 months of clinical follow-up. The primary outcome measure was the negative predictive value (NPV) of FDG-PET/CT scans and other supporting diagnostic test characteristics, including time dependency with increasing follow-up time. Results Of 152 patients, 125 had adequate primary tumor control after CCRT and entered follow-up (median, 20.4 months). Twenty-three (18.4%) had residual neck disease. Overall, NPV was 92.1% (95% CI, 86.9% to 95.3%; null hypothesis: NPV = 85%; P = .012) with sensitivity of 65.2% (95% CI, 44.9% to 81.2%), specificity of 91.2% (95% CI, 84.1% to 95.3%), positive predictive value of 62.5% (95% CI, 45.5% to 76.9%), and accuracy of 86.4% (95% CI, 79.3% to 91.3%). Sensitivity was time dependent and high for residual disease manifesting up to 9 months after imaging but lower (59.7%) for disease detected up to 12 months after imaging. Standardized reporting criteria reduced the number of equivocal reports (95% CI for the difference, 2.6% to 15.0%; P = .003). Test characteristics were not improved with the addition of lymph node CT morphology criteria. Conclusion FDG-PET/CT surveillance using Hopkins criteria 12 weeks after CCRT is reliable in LAHNSCC except for late manifesting residual disease, which may require an additional surveillance scan at 1 year after CCRT to be detected.

18F-FDG-PET/CT for the detection of disease in patients with head and neck cancer treated with radiotherapy.

OBJECTIVE: The aim of this study is to evaluate the diagnostic performance of FDG-PET/CT for the detection of residual disease after (chemo)radiotherapy in patients with head and neck squamous cell carcinoma (HNSCC) and to evaluate the prognostic value of the FDG-PET/CT findings. METHODS: Patients with HNSCC who underwent FDG-PET/CT after (chemo)radiotherapy were studied retrospectively. RESULTS: 104 FDG-PET/CT-scans were performed at a median of 13.2 weeks post-treatment (5.4-19.0 weeks). The diagnostic performance was time dependent with decreasing sensitivity and slightly increasing specificity over time. Sensitivity, specificity, PPV and NPV at 9 months after imaging were 91%, 87%, 77% and 95%, respectively. In a logistic regression model, the odds of a correct FDG-PET/CT increased with 33% every additional week after end of therapy (p = 0.01) and accuracy plateaued after 11 weeks (97%; p<0.001). A complete response on FDG-PET/CT was associated with an overall survival benefit (50.7 versus 10.3 months; p<0.001). Residual disease on FDG-PET/CT increased the risk of death 8-fold (p<0.001). CONCLUSION: FDG-PET/CT is able to detect residual disease after (chemo)radiotherapy, with an optimal time point for scanning between 11-12 weeks after therapy. However, a reevaluation is probably necessary 10-12 months after the FDG-PET/CT to detect late recurrences. In addition, FDG-PET/CT can guide decisions about neck dissection and identifies patients with poor prognosis.

Feasibility of tongue strength measurements during (chemo)radiotherapy in head and neck cancer patients.

PURPOSE: The aim of this study was to investigate the feasibility of tongue strength measures (TSMs) and the influence of bulb location, sex, and self-perceived pain and mucositis in head and neck cancer (HNC) patients during chemoradiotherapy (CRT). METHODS: Twenty-six newly diagnosed HNC patients treated with CRT performed anterior and posterior maximal isometric tongue pressures by means of the Iowa Oral Performance Instrument (IOPI). The Oral Mucositis Weekly Questionnaire (OMWQ) and a Visual Analogue Scale (VAS) for pain during swallowing were completed weekly from baseline to 1 week post CRT. RESULTS: Feasibility of TSMs during CRT declines significantly from 96 to 100% at baseline to 46% after 6 weeks of CRT. But post-hoc analyses reveal only significant differences in feasibility between baseline and measurements after 4 weeks of treatment. No effect of gender or bulb location was established, but feasibility is influenced by pain and mucositis. CONCLUSIONS: Feasibility of TSMs declines during CRT and is influenced by mucositis and pain. For the majority of subjects, TSMs were feasible within the first 4 weeks, which provides a window of scientific and clinical opportunities in this patient population.

Reduction of the dose of radiotherapy to the elective neck in head and neck squamous cell carcinoma; a randomized clinical trial. Effect on late toxicity and tumor control.

BACKGROUND AND PURPOSE: A multi-center prospective randomized clinical trial has been performed investigating whether a reduction of the dose to the elective nodal sites in head and neck cancer delivered by intensity modulated radiotherapy (IMRT) would result in a reduction of late side effects without compromising tumor control. MATERIALS AND METHODS: Two hundred patients were included. The prescription dose to the elective nodal volumes was a normalized iso-effective dose in 2Gy fractions (NID2Gy) of 50Gy in the standard arm and of 40Gy in the experimental arm. Late toxicity was scored at 6, 12, 18 and 24months using the RTOG scoring system. RESULTS: We observed a trend toward less dysphagia at 6months in the experimental arm, however this was not confirmed after longitudinal analysis. Regarding moderate salivary gland toxicity we observed lower incidence of salivary gland toxicity ⩾grade 1, at 6 (p=0.01) and 18months (p=0.03). After two years of follow up, we did not observe significant differences in estimated local failure rate (14.1% in the 40Gy arm vs 14.4% in the 50Gy arm), estimated regional failure rate (13.0% vs 5.5% in the 40 and the 50Gy arm respectively), estimated metastatic recurrence (13.4% vs 18.5% in the 40 and the 50Gy arm respectively), estimated disease-free survival (57.9% vs 65.3% in the 40 and the 50Gy arm respectively) nor estimated overall survival (72.0% vs 73.2% in the 40 and the 50Gy arm respectively). CONCLUSIONS: In our study population there was no statistically significant difference regarding survival and estimated recurrence rates between both arms of this study. We found a trend toward less dysphagia at 6months (however not significant after longitudinal analysis) and found a significant reduction of any salivary gland toxicity at 6 and 18months in the 40Gy arm.

A European Organisation for Research and Treatment of Cancer randomized, double-blind, placebo-controlled, multicentre phase II trial of anastrozole in combination with gefitinib or placebo in hormone receptor-positive advanced breast cancer (NCT00066378).

BACKGROUND: Preclinical data suggest that epidermal growth factor receptor (EGFR) inhibitors (e.g. gefitinib) can delay endocrine resistance in breast cancer. A double-blind, placebo-controlled, phase II trial investigated whether adding gefitinib (G) to anastrozole (A) would improve outcome in advanced breast cancer (ABC). METHODS: Postmenopausal pre-treated hormone receptor-positive ABC patients (locally recurrent or metastatic) were 1:1 randomized to A (1 mg/d) plus G 250 mg/d or plus placebo (P). Patients who had prior treatment with an aromatase inhibitor in metastatic setting or with trastuzumab, anti-EGFR or anti-VEGF agents were excluded. Treatment was given until disease progression, unacceptable toxicity or patient withdrawal. Progression-free survival (PFS) rate at 1 year was assessed according to Response Evaluation Criteria in Solid Tumours, version 1.0. RESULTS: Of 108 planned patients, 71 were recruited (36 in A/G and 35 in A/P). The trial closed prematurely due to slow recruitment; 31 patients had prior chemotherapy and 53 prior endocrine therapy (all except one received tamoxifen); 60% in adjuvant and 16% in metastatic setting received tamoxifen; 59 patients had visceral disease. Median follow-up was 18 months. PFS rate at 1 year was 35% for A/G and 32% for A/P arm. Objective responses were six (22%) in the A/G and nine (28%) in the A/P arm. Median duration of response was 13.8 and 18.6 months in the A/G and A/P arms, respectively. Fatigue (35%), diarrhoea (31%), rash (32%), dry skin (27%), and arthralgia/myalgia (27%) were the commonest adverse events in the A/G arm. CONCLUSIONS: This phase II study, although prematurely closed, did not show a signal that adding G to A improves PFS at 1 year and its use is not supported. Gastrointestinal and skin toxicities were more pronounced with G resulting in premature therapy interruption in almost 1 in 3 patients (ClinicalTrials.gov number, NCT00066378).

Long-term remission of locally recurrent oropharyngeal cancer after docetaxel-based chemotherapy plus cetuximab.

BACKGROUND: In recurrent head and neck squamous cell carcinoma ineligible for resection or irradiation, treatment aims primarily at symptom control and quality of life enhancement with an expected outcome of 6-12 months. METHODS: In 2005, a male patient, born in 1944, with a second local recurrence of human papillomavirus negative tonsil cancer was enrolled in the EXTREME trial, and randomized to platinum/5-fluorouracil/cetuximab arm resulting in partial remission with progression-free survival of 12 months. The second-line systemic therapy comprised 5 cycles of 3-weekly docetaxel/cisplatin/5-fluorouracil regimen plus weekly cetuximab. RESULTS: As confirmed on imaging and repeated biopsies, complete response was achieved with disease-free survival of 8 years and follow-up period of 12 years. Severe acute toxicities during the taxane-based chemotherapy plus cetuximab included grade 4 anorexia and grade 3 febrile neutropenia. CONCLUSIONS: Poor tumor differentiation, no weight loss, oropharyngeal location, white race, and particularly the induced complete response were most likely the key favorable prognostic factors in the reported patient. The possibility of a synergistic interaction between taxanes and cetuximab should be further explored.

Gemcitabine-Based Chemoradiation in the Treatment of Locally Advanced Head and Neck Cancer: Systematic Review of Literature and Meta-Analysis.

BACKGROUND: Platinum-based concurrent chemoradiation (CCRT) improves locoregional control and overall survival of locoregionally advanced (LA) squamous cell carcinoma of the head and neck (SCCHN) when compared to radiotherapy alone, but this approach is hampered by significant toxicity. Therefore, alternative ways to enhance the radiation effects are worth investigating. Gemcitabine (2',2'-difluorodeoxycytidine), in addition to its activity against a variety of solid tumors, including SCCHN, is one of the most potent radiosensitizers, and it has an overall favorable safety profile. In this paper, the clinical experience with gemcitabine-based chemoradiation in the treatment of patients with LA-SCCHN is reviewed. METHODS: We conducted a review of the literature on the clinical experience with radiotherapy combined with either single-agent gemcitabine or gemcitabine/cisplatin-based polychemotherapy for the treatment of patients with LA-SCCHN. We also searched abstracts in databases of major international oncology meetings from the last 20 years. A meta-analysis was performed to calculate pooled proportions with 95% confidence intervals (CIs) for complete response rate and grade 3-4 acute mucositis rate. RESULTS: A total of 13 papers were eligible for the literature review. For schedules using a gemcitabine dose intensity (DI) below 50 mg/m(2) per week, the complete response rate was 86% (95% CI, 74%-93%) with grade 3-4 acute mucositis rate of 38% (95% CI, 27%-50%) and acceptable late toxicity. In one of the studies employing such low DIs, survival data were provided showing a 3-year overall survival of 50%. Compared with DI ≥50 mg/m(2) per week, there was no difference in the complete response rate (71%; 95% CI, 55%-83%; p = .087) but a significantly higher (p < .001) grade 3-4 acute mucositis rate of 74% (95% CI, 62%-83%), often leading to treatment interruptions (survival data provided in 8 studies; 3-year overall survival, 27%-63%). Late toxicity comprising mainly dysphagia was generally underreported, whereas information about xerostomia and skin fibrosis was scarce. CONCLUSION: This review highlights the radiosensitizing potential of gemcitabine and suggests that even very low dosages (less than 50 mg/m(2) per week) provide a sufficient therapeutic ratio and therefore should be further investigated. Refinements in radiation schemes, including intensity-modulated radiation therapy, in combination with low-dose gemcitabine and targeted agents, such as cetuximab, are currently being investigated. IMPLICATIONS FOR PRACTICE: Cisplatin-based concurrent chemoradiation (CCRT) has become the standard treatment of locally advanced head and neck cancer (LAHNC). This approach is hampered by significant toxicity. This paper reviews the studies using gemcitabine as an alternative radio-sensitizer for CCRT in patients with LAHNC. In this capacity, despite its mild intrinsic toxicity, gemcitabine comes with high rates of severe mucositis when used in dosages exceeding 50 mg/m(2) per week. CCRT with low-dose gemcitabine provides a sufficient therapeutic ratio, combining clinical activity, similar to the higher-dose regimens, with lower toxicity. Further investigation is warranted.

Evaluation of the optimal combinations of modulation factor and pitch for Helical TomoTherapy plans made with TomoEdge using Pareto optimal fronts.

BACKGROUND: Modulation factor (MF) and pitch have an impact on Helical TomoTherapy (HT) plan quality and HT users mostly use vendor-recommended settings. This study analyses the effect of these two parameters on both plan quality and treatment time for plans made with TomoEdge planning software by using the concept of Pareto optimal fronts. METHODS: More than 450 plans with different combinations of pitch [0.10-0.50] and MF [1.2-3.0] were produced. These HT plans, with a field width (FW) of 5 cm, were created for five head and neck patients and homogeneity index, conformity index, dose-near-maximum (D2), and dose-near-minimum (D98) were analysed for the planning target volumes, as well as the mean dose and D2 for most critical organs at risk. For every dose metric the median value will be plotted against treatment time. A Pareto-like method is used in the analysis which will show how pitch and MF influence both treatment time and plan quality. RESULTS: For small pitches (≤0.20), MF does not influence treatment time. The contrary is true for larger pitches (≥0.25) as lowering MF will both decrease treatment time and plan quality until maximum gantry speed is reached. At this moment, treatment time is saturated and only plan quality will further decrease. CONCLUSION: The Pareto front analysis showed optimal combinations of pitch [0.23-0.45] and MF > 2.0 for a FW of 5 cm. Outside this range, plans will become less optimal. As the vendor-recommended settings fall within this range, the use of these settings is validated.

Helical tomotherapy in head and neck cancer: a European single-center experience.

BACKGROUND: We report on a retrospective analysis of 147 patients with early and locoregionally advanced squamous cell head and neck cancer (SCCHN) treated with helical tomotherapy (HT). PATIENTS AND METHODS: Included were patients with SCCHN of the oral cavity (OC), oropharynx (OP), hypopharynx (HP), or larynx (L) consecutively treated in one radiotherapy center in 2008 and 2009. The prescribed HT dose was 60-66 Gy in the postoperative setting (group A) and 66-70 Gy when given as primary treatment (group B). HT was given alone, concurrent with systemic therapy (ST), that is, chemotherapy, biotherapy, or both, and with or without induction therapy (IT). Acute and late toxicities are reported using standard criteria; locoregional failure/progression (LRF), distant metastases (DM), and second primary tumors (SPT) were documented, and event-free survival (EFS) and overall survival (OS) were calculated from the start of HT. RESULTS: Group A patients received HT alone in 22 cases and HT + ST in 20 cases; group B patients received HT alone in 17 cases and HT + ST in 88 cases. Severe (grade ≥ 3) acute mucosal toxicity and swallowing problems increased with more additional ST. After a median follow-up of 44 months, grade ≥2 late toxicity after HT + ST was approximately twice that of HT alone for skin, subcutis, pharynx, and larynx. Forty percent had grade ≥2 late xerostomia, and 29% had mucosal toxicity. At 3 years, LRF/DM/SPT occurred in 7%/7%/17% and 25%/13%/5% in groups A and B, respectively, leading to a 3-year EFS/OS of 64%/74% and 56%/63% in groups A and B, respectively. CONCLUSION: The use of HT alone or in combination with ST is feasible and promising and has a low late fatality rate. However, late toxicity is nearly twice as high when ST is added to HT.

The radiosensitising effect of gemcitabine and its main metabolite dFdU under low oxygen conditions is in vitro not dependent on functional HIF-1 protein.

BACKGROUND: Regions within solid tumours often experience oxygen deprivation, which is associated with resistance to chemotherapy and irradiation. The aim of this study was to evaluate the radiosensitising effect of gemcitabine and its main metabolite dFdU under normoxia versus hypoxia and to determine whether hypoxia-inducible factor 1 (HIF-1) is involved in the radiosensitising mechanism. METHODS: Stable expression of dominant negative HIF-1α (dnHIF) in MDA-MB-231 breast cancer cells, that ablated endogenous HIF-1 transcriptional activity, was validated by western blot and functionality was assessed by HIF-1α activity assay. Cells were exposed to varying oxygen environments and treated with gemcitabine or dFdU for 24 h, followed by irradiation. Clonogenicity was then assessed. Using radiosensitising conditions, cells were collected for cell cycle analysis. RESULTS: HIF-1 activity was significantly inhibited in cells stably expressing dnHIF. A clear radiosensitising effect under normoxia and hypoxia was observed for both gemcitabine and dFdU. No significant difference in radiobiological parameters between HIF-1 proficient and HIF-1 deficient MDA-MB-231 cells was demonstrated. CONCLUSIONS: For the first time, radiosensitisation by dFdU, the main metabolite of gemcitabine, was demonstrated under low oxygen conditions. No major role for functional HIF-1 protein in radiosensitisation by gemcitabine or dFdU could be shown.

Mutation analysis of genes in the EGFR pathway in Head and Neck cancer patients: implications for anti-EGFR treatment response.

BACKGROUND: Targeted therapy against the Epidermal Growth Factor Receptor (EGFR) is among the most promising molecular therapeutics for Head and Neck Squamous Cell Carcinoma (HNSCC). However, drug resistance limits the clinical efficacy of anti-EGFR monoclonal antibodies and no predictive biomarker has entered the clinic yet. METHODS: A retrospective clinical study was performed utilizing pathological specimens from 52 newly diagnosed HNSCC patients. These patients were screened for mutations in EGFR and KRAS. Tyrosine kinase mutations in EGFR and KRAS mutations were evaluated by high resolution melting analysis (HRMA), whereas EGFRvIII was determined using one-step real-time PCR. Finally, patient samples were screened for HPV-DNA by GP5+/6+ PCR. Survival analysis was performed using Kaplan-Meier analysis and significance was calculated using log-rank statistic. RESULTS: In our study population no EGFRvIII mutations were present. However, two silent mutations were found; T785T in exon 20 and R836R in exon 21 of the EGFR gene. Additionally, HRMA revealed an abnormal KRAS melting pattern in 7.0% of the samples. However, the KRAS StripAssay could confirm only one sample with a G12S mutation and none of these samples could be confirmed by direct sequencing. HPV DNA was present in 3/25 larynx and 9/27 oropharynx tumors. CONCLUSION: The low rate of EGFR and KRAS mutations in this Belgian HNSCC population suggests that these genes will probably not play a major role in predicting response to anti-EGFR therapy in HNSCC. Hence, other predictive markers need to be discovered in order to optimize EGFR targeting therapy.

An international phase 3 trial in head and neck cancer: quality of life and symptom results: EORTC 24954 on behalf of the EORTC Head and Neck and the EORTC Radiation Oncology Group.

BACKGROUND: The European Organization for Research and Treatment of Cancer (EORTC) 24954 phase 3 randomized clinical trial compared 2 schemes of combined chemotherapy for patients with resectable cancers of the hypopharynx and larynx: sequential induction chemotherapy and radiotherapy versus alternating chemoradiotherapy. The current study reports detailed effects of both treatment arms on health-related quality of life (HRQOL) and symptoms. METHODS: A total of 450 patients aged 35 years to 76 years (World Health Organization performance status (WHO PS) ≤ 2) with untreated, resectable advanced squamous cell carcinoma of the larynx (tumor classification of T3-T4) or hypopharynx (tumor classification of T2-T3-T4) with regional lymph nodes in the neck classified as N0 to N2 with no metastases were randomized in this prospective phase 3 trial into either the sequential arm (control) or the alternating arm (experimental). QOL assessment was performed at randomization; at baseline; at 42 days; and at 6, 12, 24, 36, and 48 months. RESULTS: There were no observed differences with regard to the primary endpoint of Fatigue and secondary endpoint of Dyspnea. Significant differences were found in the secondary endpoints of Swallowing and Speech problems at 42 days after randomization in favor of patients in the sequential arm. Explanatory and sensitivity analysis revealed that the primary analysis favored the sequential arm, but the majority of differences in HRQOL did not exist at the end of treatment, and returned to baseline levels. CONCLUSIONS: In the current study, a trend toward worse scores was noted in the patients treated on the alternating chemoradiotherapy arm but very few differences reached the level of statistical significance. The HRQOL scores of the majority of patients returned to baseline after therapy.

Reduction of the dose to the elective neck in head and neck squamous cell carcinoma, a randomized clinical trial using intensity modulated radiotherapy (IMRT). Dosimetrical analysis and effect on acute toxicity.

BACKGROUND AND PURPOSE: A randomized trial was initiated to investigate whether a reduction of the dose to the elective nodal sites and the swallowing apparatus delivered by IMRT would result in a reduction of acute and late side effects without compromising tumor control. The aim of this paper is to report on dosimetrical analysis and acute toxicity. MATERIALS & METHODS: Two-hundred patients were randomized. In the standard arm, elective nodal volumes (PTVelect) were irradiated up to an equivalent dose of 50Gy. In the experimental arm an equivalent dose of 40Gy was prescribed to the PTVelect. The dose to the swallowing apparatus was kept as low as possible without compromising therapeutic PTV (PTVther) coverage. RESULTS: No significant difference was seen between both arms concerning PTVther coverage. The median D95 of the PTVelect was significantly lower in the experimental arm (39.5 vs 49.8Gy; p<0.001). Concerning the organs at risk, the dose to swallowing structures and spinal cord was significantly reduced. There was no significant difference in acute toxicity. Three months after radiotherapy there was significantly less grade ⩾3 dysphagia in the experimental arm (2% vs 11%; p=0.03). With a median follow-up of 6months no significant differences were observed in locoregional control, disease free survival or overall survival. CONCLUSIONS: Using IMRT we were able to significantly reduce the dose to the PTVelect and several organs at risk without compromising PTVther coverage. This resulted in a significant reduction of severe dysphagia 3months after radiotherapy. Further follow-up is necessary to investigate whether these observations translate into a benefit on late treatment related dysphagia without affecting treatment outcome.

The potential of helical tomotherapy in the treatment of head and neck cancer.

A decade after its first introduction into the clinic, little is known about the clinical impact of helical tomotherapy (HT) on head and neck cancer (HNC) treatment. Therefore, we analyzed the basics of this technique and reviewed the literature regarding HT's potential benefit in HNC. The past two decades have been characterized by a huge technological evolution in photon beam radiotherapy (RT). In HNC, static beam intensity-modulated radiotherapy (IMRT) has shown superiority over three-dimensional conformal RT in terms of xerostomia and is considered the standard of care. However, the next-generation IMRT, the rotational IMRT, has been introduced into the clinic without any evidence of superiority over static beam IMRT other than being substantially faster. Of these rotational techniques, HT is the first system especially developed for IMRT in combination with image-guided RT. HT is particularly promising for the treatment of HNC because its sharp dose gradients maximally spare the many radiosensitive organs at risk nearby. In addition, HT's integrated computed tomography scan assures a very precise dose administration and allows for some adaptive RT. Because HT is specifically developed for IMRT in combination with (integrated) image-guidance, it allows for precise dose distribution ("dose painting"), patient setup, and dose delivery. As such, it is an excellent tool for difficult HNC irradiation. The literature on the clinical results of HT in HNC all show excellent short-term (≤2 years) results with acceptable toxicity profiles. However, properly designed trials are still warranted to further substantiate these results.

RapidArc, SmartArc and TomoHD compared with classical step and shoot and sliding window intensity modulated radiotherapy in an oropharyngeal cancer treatment plan comparison.

BACKGROUND: Radiotherapy techniques have evolved rapidly over the last decade with the introduction of Intensity Modulated RadioTherapy (IMRT) in different forms. It is not clear which of the IMRT techniques is superior in the treatment of head and neck cancer patients in terms of coverage of the planning target volumes (PTVs), sparing the organs at risk (OARs), dose to the normal tissue, number of monitor units needed and delivery time.The present paper aims to compare Step and Shoot (SS) IMRT, Sliding Window (SW) IMRT, RapidArc (RA) planned with Eclipse, Elekta VMAT planned with SmartArc (SA) and helical TomoHD™ (HT). METHODS: Target volumes and organs at risk (OARs) of five patients with oropharyngeal cancer were delineated on contrast enhanced CT-scans, then treatment plans were generated on five different IMRT systems. In 32 fractions, 69.12 Gy and 56 Gy were planned to the therapeutic and prophylactic PTVs, respectively. For the PTVs and 26 OARs ICRU 83 reporting guidelines were followed. Differences in the studied parameters between treatment planning systems were analysed using repeated measures ANOVA. RESULTS: Mean Homogeneity Index of PTV(therapeutic) is better with HT(.06) followed by SA(.08), RA(.10), SW(.10) and SS(.11). PTV(prophylactic) is most homogeneous with RA. Parotid glands prescribed mean doses are only obtained by SA and HT, 20.6 Gy and 21.7 Gy for the contralateral and 25.6 Gy and 24.1 Gy for the ipsilateral, against 25.6 Gy and 32.0 Gy for RA, 26.4 Gy and 34.6 Gy for SW, and 28.2 Gy and 34.0 Gy for SS. RA uses the least monitor units, HT the most. Treatment times are 3.05 min for RA, and 5.9 min for SA and HT. CONCLUSIONS: In the treatment of oropharyngeal cancer, we consider rotational IMRT techniques preferable to fixed gantry techniques due to faster fraction delivery and better sparing of OARs without a higher integral dose. TomoHD gives most homogeneous target coverage with more sparing of spinal cord, brainstem, parotids and the lower swallowing apparatus than most of the other systems. Between RA and SA, SA gives a more homogeneous PTV(therapeutic) while sparing the parotids more, but the delivery of RA is twice as fast with less overdose to the PTV(elective).

The intriguing interplay between therapies targeting the epidermal growth factor receptor, the hypoxic microenvironment and hypoxia-inducible factors.

Despite their individual key roles in promoting cancer progression and treatment resistance, our knowledge about the impact of tumor hypoxia on the activity of the epidermal growth factor receptor (EGFR) pathway in cancer and vice versa remains limited. Preclinical and clinical studies support an important link between hypoxia and upregulation of EGFR in cancers that do not display genetic alterations of the receptor. Subsequent EGFR signaling stimulates hypoxia-inducible factor (HIF) signaling and thus augments induction of proteins that promote cellular survival in a hostile microenvironment. Considering the effects of EGFR-targeting agents under reduced oxygen conditions, it is now accepted that, together with their demonstrated antiproliferative and proapoptotic effects, the antiangiogenic activity of these drugs also contributes to their overall antitumor activity in vivo. Treatment of human tumor cells with EGFR inhibitors leads to decreased HIF-1α and VEGF secretion by tumor cells, resulting in vascular normalization, improved blood flow and thus improved oxygenation. These findings may have major implications with respect to the efficacy of both radiotherapy and subsequent chemotherapy when combined with EGFR inhibitors. A major challenge remains to assess which sequence of these drugs with radiation or chemotherapy is optimal. Moreover, recent data suggest that the lack of clinical responses to EGFR-directed therapy may be circumvented by supplementation of the anti-EGFR therapy with additional approaches targeting HIF-1α or VEGF. Further studies thus are warranted to define the precise mechanistic and therapeutic implications of the hypoxic response relative to the EGFR signaling pathway in cancer.

Tongue cancers during pregnancy: Case reports and review of literature.

BACKGROUND: Due to its rarity, there is no standard treatment for tongue cancers that concur with pregnancy. Treatment depends on the stage of cancer, gestational age of the pregnancy, and the wish of the mother to maintain the pregnancy. The purpose of this study was to review the literature and to report 5 new cases. METHODS: Twelve cases of tongue cancer during pregnancy were already reported between 1987 and 2009. We report 5 new cases and first administration of concomitant radiochemotherapy for tongue cancer. RESULTS: Median age of the patients was 29 years, 65% of diagnoses were made after the first trimester of pregnancy. Different treatment modalities are used to treat tongue cancer during pregnancy. CONCLUSION: We hypothesize that tongue cancer treatment adhering to standard protocols provides the best guarantee to cure the mother. Based on a growing experience and insight taking fetal safety into consideration, the available data suggest that standard treatment is a realistic option.