Radiotherapy & Oncology - Articles in Press

Feasibility of contrast-enhanced cone-beam CT for target localization and treatment monitoring - Corrected Proof

2010-07-28

Abstract: A dog with a spontaneous maxillary tumour was given 40Gy of fractionated radiotherapy. At five out of 10 fractions cone-beam CT (CBCT) imaging before and after administration of an iodinated contrast agent were performed. Contrast enhancement maps were overlaid on the pre-contrast CBCT images. The tumour was clearly visualized in the images thus produced.

Dasatinib blocks cetuximab- and radiation-induced nuclear translocation of the epidermal growth factor receptor in head and neck squamous cell carcinoma - Corrected Proof

Chunrong Li, Mari Iida, Emily F. Dunn, Deric L. Wheeler — 2010-07-28

Abstract: Background and purpose: The aberrant expression of epidermal growth factor receptor (EGFR) has been linked to the etiology of head and neck squamous cell carcinoma (HNSCC). The first major phase III trial combining cetuximab with radiation confirmed a strong survival advantage. However, both cetuximab and radiation can promote EGFR translocation to the nucleus where it enhances resistance to both of these modalities. In this report we sought to determine how to block cetuximab- and radiation-induced translocation of EGFR to the nucleus in HNSCC cell lines.Material and methods: We utilized three established HNSCC cell lines, SCC1, SCC6 and SCC1483 and measured nuclear translocation of EGFR after treatment with cetuximab or radiation. We then utilized dasatinib (BMS-354825), a potent, orally bioavailable inhibitor of several tyrosine kinases, including the Src family kinases, to determine if SFKs blockade could abrogate cetuximab- and radiation-induced nuclear EGFR translocation.Results: Cetuximab and radiation treatment of all three HNSCC lines lead to translocation of the EGFR to the nucleus. Blockade of SFKs abrogated cetuximab- and radiation-induced EGFR translocation to the nucleus.Conclusions: The data presented in this report suggest that both cetuximab and radiation can promote EGFR translocation to the nucleus and dasatinib can inhibit this process. Collectively these findings may suggest that dasatinib can limit EGFR translocation to the nucleus and may enhance radiotherapy plus cetuximab in HNSCC.

Effect of cetuximab and fractionated irradiation on tumour micro-environment - Corrected Proof

2010-07-28

Abstract: Background and purpose: Previous experiments have shown that application of the anti-EGFR monoclonal antibody C225 (cetuximab) improves local tumour control after irradiation in FaDu human squamous cell carcinoma (hSCC) due to the combined effect of decreased repopulation and improved reoxygenation. The present study investigates early changes of the pimonidazole hypoxic fraction of FaDu tumours and the expression and phosphorylation of the EGFR and its downstream signal transduction molecules after treatment with C225 alone or in combination with irradiation.Material and methods: FaDu tumour xenografts were irradiated with up to 3×3Gy with or without additional C225 treatment and excised at different time points. Tumour hypoxia was evaluated using pimonidazole. EGFR expression and phosphorylation and intratumoural distribution of C225 were assessed by immunofluorescence analysis. Western blots were performed to evaluate expression and phosphorylation of EGFR, ErbB2, AKT and MAPK (ERK1/2).Results: Hypoxia did not change during the 4days of treatment in the tumours treated with C225 alone or combined with irradiation. C225 treatment led to downregulation of the total EGFR in FaDu tumours, accompanied by a change of the spatial distribution of the receptor favouring the membranous expression. An induction of phosphorylation of the EGFR (tyr992, tyr1173) was observed with C225 alone or combined with irradiation. AKT phosphorylation was decreased, whereas MAPK phosphorylation remained unchanged. C225 membrane staining was homogeneously distributed over the whole tumour with no differences between hypoxic and non-hypoxic tumour cells.Conclusion: Pimonidazole-hypoxia of FaDu tumours during the initial part of fractionated irradiation is not influenced by C225, indicating that external hypoxia markers may not be promising as biomarkers for tumour response to combined treatment. The downregulation of the total EGFR, but at the same time higher membrane staining, as well as the changes in downstream signal transduction molecules, warrants further investigation in other tumour models.

Curative chemoradiotherapy for isolated retroperitoneal lymph node recurrence of colorectal cancer - Corrected Proof

2010-07-28

Abstract: Purpose: To investigate the efficacy of curative chemoradiotherapy for isolated retroperitoneal lymph node recurrence of colorectal cancer.Materials and methods: Twenty-two colorectal cancer patients who received three-dimensional conformal radiotherapy (n=20) or helical tomotherapy (n=2) for isolated retroperitoneal lymph node recurrence were analyzed retrospectively. Radiation dose was 55.8Gy in 31 fractions or 63Gy in 35 fractions, and 60Gy in 20 fractions by helical tomotherapy. All patients received concurrent chemotherapy and 16 (72.7%) received adjuvant chemotherapy.Results: The treatment response was complete in 13 (59.1%), partial in 6 (27.3%), and stable in 3 (13.6%) patients. Median follow-up for 11 (50%) surviving patients was 32months (range, 27–61). The 3- and 5-year overall survival rates were 64.7% and 36.4%, and median overall survival was 41months. Recurrences developed in 15 (68.2%) patients; outside the retroperitoneum in 13. The 3- and 5-year recurrence-free survival rates were 34.1% and 25.6%, and median recurrence-free survival was 20months. Response and adjuvant chemotherapy were significant prognostic factors for overall survival. Gastrointestinal toxicity⩾Grade 3 was not observed.Conclusions: Definitive chemoradiotherapy is an effective salvage treatment for isolated retroperitoneal lymph node recurrence of colorectal cancer without severe complications.

PET scans in radiotherapy planning of lung cancer - Corrected Proof

Dirk De Ruysscher, Carl-Martin Kirsch — 2010-07-26

Abstract: Especially for non-small cell lung cancer, FDG-PET has in the majority of the patients led to the safe decrease of radiotherapy volumes, enabling radiation-dose escalation and, experimentally, redistribution of radiation doses within the tumor. In limited-disease small cell lung cancer, the role of FDG-PET is emerging.

Quantitative analysis of PET studies - Corrected Proof

Wolfgang A. Weber — 2010-07-26

Abstract: Quantitative analysis can be included relatively easily in clinical PET-imaging protocols, but in order to obtain meaningful quantitative results one needs to follow a standardized protocol for image acquisition and data analysis. Important factors to consider are the calibration of the PET scanner, the radiotracer uptake time and the approach for definition of regions of interests. Using such standardized acquisition protocols quantitative parameters of tumor metabolism or receptor status can be derived from tracer kinetic analysis and simplified approaches such as calculation of standardized uptake values (SUVs).

Loco-regional recurrence risk and post-mastectomy radiotherapy in breast cancer - Corrected Proof

Rodrigo Arriagada, Serge Koscielny — 2010-07-26

The indication of post-mastectomy radiotherapy (PMRT) in breast cancer patients with 1–3 histologically involved axillary nodes (N+) is controversial . It has been clearly established that PMRT decreases threefold the risk of loco-regional recurrences (LRR) . However, to have a beneficial impact on breast cancer and overall survival, the PMRT-related absolute decrease of LRR must be large enough (i.e. more than 10%) to compensate deleterious effects on non-breast cancer mortality . Ongoing randomised trials are evaluating the role of PMRT in node negative and 1–3 N+ patients but the recruitment remains low .

Dynamic contrast-enhanced magnetic resonance imaging of human cervical carcinoma xenografts: Pharmacokinetic analysis and correlation to tumor histomorphology - Corrected Proof

Christine Ellingsen, Tormod A.M. Egeland, Kanthi Galappathi, Einar K. Rofstad — 2010-07-26

Abstract: Background and purpose: Biomarkers that can predict the outcome of treatment accurately are needed for treatment individualization in advanced carcinoma of the uterine cervix. The potential of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was investigated in the present preclinical study.Materials and methods: CK-160 and TS-415 human cervical carcinoma xenografts were subjected to DCE-MRI at 1.5T using a spatial resolution of 0.23×0.47×2.0mm3. Parametric images of Ktrans (the volume transfer constant of Gd-DTPA) and ve (the extravascular extracellular volume fraction) were produced by pharmacokinetic analysis of the DCE-MRI data and compared with the histomorphology of the imaged tissue.Results: Analysis of small homogeneous tumor regions showed that Ktrans, but not ve, differed significantly between parenchymal tissue, connective tissue, and necrotic tissue, consistent with the vascularity of these compartments. However, strong correlations between Ktrans and the fractional volume of the compartments could not be detected for larger tumor regions, primarily because the majority of the voxels represented a chaotic mixture of parenchymal, connective, and necrotic tissue.Conclusion: The potential of DCE-MRI in providing detailed information on the histomorphology of cervical carcinoma is limited, mainly because the tumor tissue shows significant morphological heterogeneity at the subvoxel level.

The use of PET in assessing tumor response after neoadjuvant chemoradiation for rectal cancer - Corrected Proof

2010-07-02

Abstract: Purpose: To assess the correlation of 18F-FDG-PET (PET) response to pathological response after neoadjuvant chemoradiation (CRT) for locally advanced rectal cancer.Methods and materials: Twenty patients with locally advanced rectal cancer were identified between 2001 and 2005. The median age was 57years (range 37–72) with 14 males and 6 females. All patients were staged with endorectal ultrasound and/or MRI, CT, and PET. The clinical staging was T3N0M0 (16), T3N1M0 (2), and T3N0M1 (2). Restaging PET was performed after CRT, and prior to definitive surgery. The response on PET and pathology was assessed and correlated. Patient outcome according to PET response was also assessed.Results: Following CRT, a complete PET response occurred in 7 patients, incomplete response in 10, and no response in 3 patients. At surgery, complete pathological response was recorded in 7 patients, incomplete response in 10 and no response in 3. There was a good correlation of PET and pathological responses in complete responders (5/7 cases) and non-responders (3/3 cases). After a median follow-up of 62months (range 7–73), twelve patients were alive with no evidence of disease. All patients achieving complete metabolic response were alive with no evidence of disease, while as those who had no metabolic response, all died as a result of metastatic disease.Conclusions: PET is a promising complementary assessment tool for assessing tumor response after CRT if there is a complete or no response. PET response may also predict for outcome.

FDG for dose painting: A rational choice - Corrected Proof

Hugo J.W.L. Aerts, Philippe Lambin, Dirk De Ruysscher — 2010-06-21

Radiotherapy has improved considerably the last decades to a significant part due to improvements in target visualisation by new imaging methodologies and in more accurate dose delivery techniques. Despite this progress, local tumour failure is still observed in a large proportion of patients with advanced cancer treated with radiotherapy, e.g. in 70% of non-small cell lung cancer (NSCLC) patients . A straightforward way to improve local tumour control is to increase the radiation dose further, which is hampered by normal tissue constraints . However, as current treatment strategies strive for a homogeneous dose distribution to the target volume, this may not be the most rational way to deliver the dose because many tumours show significant spacial variation in biologic characteristics, such as proliferation, hypoxia, cell density, and perfusion. Therefore, the concept of “dose painting” has been introduced, i.e. delivering a higher dose towards the more resistant tumour areas and reducing the dose towards the more sensitive areas . Using this individualized strategy, the burden to the normal tissues can be kept constant, or even be decreased, thereby not increasing the incidence of dose-limiting side-effects. As a result, the identification of intra tumour sensitivity and resistance to radiotherapy using non-invasive imaging has been an important research focus over the past decades.

Dose volume parameter D2cc does not correlate with vaginal side effects in individual patients with cervical cancer treated within a defined treatment protocol with very high brachytherapy doses - Corrected Proof

2010-06-21

Abstract: The study aimed to determine whether post-radiation vaginal side effects in cervical cancer patients can be correlated with DVH parameter D2cc. The result was negative in that no correlation could be demonstrated between D2cc and the presence and grade of side effects in this patients’ subset treated with high brachytherapy doses.

Development of a patient-reported questionnaire for collecting toxicity data following prostate brachytherapy - Corrected Proof

2010-06-21

Abstract: Purpose: To improve a questionnaire used to collect patient-reported outcomes from patients with early stage prostate cancer treated with brachytherapy. A secondary aim was to adapt the Late Effects of Normal Tissue (LENT) subjective toxicity questionnaire for use to collect Common Terminology Criteria for Adverse Events (CTCAE) data, the current preferred platform for assessing radiation toxicity.Materials and methods: Three hundred and seventy-seven patients were treated with permanent iodine-125 seed implant brachytherapy for early prostate cancer. Toxicity data were collected before and at nine time points post-treatment (0–36months). Compliance rates for patients completing individual items and item-subsection correlation coefficients were calculated. A factor analysis was carried out to analyse responses to the questionnaire and identify less informative questions, which could be removed. Cronbach’s α coefficient was used to measure reliability.Results: Two thousand one hundred and eighty-eight questionnaires were analysed. There was poor compliance for questions specifically relating to operations and bowel medication. We found that the division of the questionnaire into subsections based on anatomical site was reasonable and that certain items could be safely removed. The high mean value for Cronbach’s α across all questionnaires (0.752; 95% CI: 0.726–0.779) indicated that the questionnaire was reliable. Fifteen of the 44 questions were removed from the original questionnaires. Questions on urinary incontinence severity, management of urinary and bowel incontinence, effects of reduced flow of urine and the effects of symptoms on activity of daily living and change in sexual function were required to adapt the LENT subjective questionnaire for use to collect CTCAE data.Conclusions: A questionnaire, validated over 6years to collect LENT subjective data were adapted and is a reliable approach for collecting CTCAE data after prostate brachytherapy.

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

2010-06-16

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

A systematic review on the role of FDG-PET/CT in tumour delineation and radiotherapy planning in patients with esophageal cancer - Corrected Proof

2010-06-11

Abstract: Purpose: FDG-PET/CT has proven to be useful in the staging process of esophageal tumours. This review analysed the role of FDG-PET/CT in tumour delineation and radiotherapy planning in comparison with CT alone among patients with esophageal cancer. Thereby we focused on the detection of the primary tumour and lymph nodes by FDG-PET/CT, changes in target volume (TV) delineation based on FDG-PET/CT and its validity, changes in inter- and intra-observer variability in TV delineation, consequences for radiotherapy treatment planning with regard to either target volumes or organs at risk and finally on the validation of FDG-PET/CT-based TVs in terms of treatment outcome. Methods: A literature search was performed in MEDLINE and Cochrane library databases for studies concerning the current value of FDG-PET/CT in tumour detection and delineation and radiotherapy-planning procedures among patients with esophageal cancer. Both prospective and retrospective studies were included. Results: Fifty publications met the eligibility criteria, of which 19 were review papers and one was a case report. The remaining 30 publications reported on the results of original studies. FDG-PET was able to identify most primary tumours, with a sensitivity and specificity for the detection of metastatic lymph nodes of 30–93% and 79–100%. The use of FDG-PET/CT resulted in changes of target volumes, and consequently in changes in treatment planning. However, evidence supporting the validity of the use of FDG-PET/CT in the tumour delineation process is very limited. Only three studies reported a significant positive correlation between FDG-PET-based tumour lengths and pathological findings. There were two studies that tested the influence of FDG-PET/CT to the inter- and intra-observer variability. One of them found a significant decrease in inter- and intra-observer variability, while the others did not. Furthermore, there are no studies demonstrating the use of PET/CT in terms of improved locoregional control or survival. Conclusion: Since the literature is very limited standard implementation of FDG-PET/CT into the tumour delineation process for radiation treatment seems unjustified and needs further clinical validation first.

The Groningen Radiotherapy-Induced Xerostomia questionnaire: Development and validation of a new questionnaire - Corrected Proof

2010-06-11

Abstract: Purpose: The purpose of this study was to develop and validate a questionnaire (Groningen Radiotherapy-Induced Xerostomia (GRIX) questionnaire) that has the ability to distinguish between patient-rated xerostomia during day and night and can be used to evaluate the impact of emerging radiation delivery techniques aiming at prevention of xerostomia in more detail.Materials and methods: All questions in the GRIX were generated from an exhaustive list of relevant questions according to xerostomia as reported in the literature and reported by patients and health care providers. Finally the GRIX was reduced from 56 questions to a 14-item questionnaire, with four subscales; xerostomia during day and night and sticky saliva during day and night. 315 patients filled out 2936 questionnaires and the GRIX was evaluated by calculating Crohnbach’s α for all subscales. Criterion validity was evaluated to compare the GRIX with patient-rated xerostomia scored with the EORTC QLQ-HN35 and physician-rated xerostomia, test–retest analysis and responsiveness were also tested.Results: Crohnbach’s α varied for all subscales between 0.88 and 0.94. The GRIX scored well for criterion-related validity on all subscales with high correlations with the EORTC QLQ-HN35 xerostomia and sticky saliva scale as well with physician-rated toxicity scoring. No significant differences were found between test and retest score and the GRIX showed good responsiveness with different time points for all subscales.Conclusion: The GRIX is a validated questionnaire which can be used in future research focusing on patient-rated xerostomia and sticky saliva during day and night in relation with the impact of emerging radiation delivery techniques aiming at reduction of xerostomia.

Implementation of hypoxia imaging into treatment planning and delivery - Corrected Proof

Daniela Thorwarth, Markus Alber — 2010-06-07

Abstract: Purpose: To review the current status of implementation of functional hypoxia imaging in radiotherapy (RT) planning and treatment delivery.Methods: Before biological imaging techniques such as positron emission tomography (PET) or magnetic resonance (MR) can be used for individual RT adaptation, three main requirements have to be fulfilled. First, tissue parameters have to be derived from the imaging data that correlate with individual therapy outcome. Then, the spatial and temporal stability of hypoxia PET images needs to be established. Finally, the dose painting (DP) concepts have to be practically feasible to be used as a basis for clinical trials.Results: A number of recent clinical studies could show the correlation of hypoxia PET imaging with different tracers and RT outcome. Most of the studies revealed a correlation between mean or maximum values and parameters assessed from the PET avid volume and treatment success, only few investigations used quantitative imaging. Multiparametric imaging seems to be very valuable. Recently, the spatial and temporal stability of hypoxia PET attracted attention. Temporal changes in the distribution of functional tumour properties were reported. Furthermore, technical feasibility of DP by contours (DPC) as well as DP by numbers (DPBN) was shown by several investigators. The challenge is now to design clinical studies in order to prove the impact of DP treatments on individual therapy success.Conclusion: A patient-specific adaptation of RT based on functional hypoxia imaging with PET is possible and promising. Conceptual feasibility could be shown for DPBN whereas to date, only DPC seems to be plausible and feasible in a clinical context.

Comparison of early quality of life in patients treated with radiotherapy following mastectomy or breast conservation therapy: A prospective study - Corrected Proof

2010-06-04

Abstract: Introduction: To compare quality of life (QOL) in breast cancer patients from a developing country after breast conservation surgery (BCS) or mastectomy and adjuvant radiotherapy (RT).Materials and methods: In a 6-month period, all consecutive early and locally advanced breast cancer patients treated with either BCS or mastectomy and treated with RT were analyzed. All patients who underwent mastectomy were treated with 45 Gray/20#/4weeks. Patients with BCS were treated with a dose of 45–50 Gray/25#/5weeks to whole breast followed by tumor bed boost (15 Gray/6#/6days with suitable energy electrons). Prospective evaluation of QOL using EORTC QLQ C30 and breast cancer specific QLQ BR23 was done before starting RT (baseline), at mid-RT and at RT conclusion for all patients.Results: One hundred and thirteen patients had mastectomy and 142 patients underwent BCS. Reliability test (Cronbach alpha) for questionnaire filling was 0.669–0.886. At pre-RT assessment, global QOL scores in mastectomy and BCS groups were 71.1 and 71.3, respectively. There was no significant difference in pre-RT EORTC QLQ C30 functional and symptom domains between mastectomy and BCS patients. However, social function domain score was higher in patients who underwent mastectomy (83 versus 73.9; p=0.018). In QLQ BR23 domains, body image and sexual functioning domains were similar between the two groups. However, sexual enjoyment (10.9 versus 47.6; p=0.006) and future perspective (7.4 versus 37.1; p=0.036) domains were significantly better in BCS arm. There was no difference between systemic side effect (BRSSE), breast symptom (BRBS) and arm symptom (BRAS) domain scores between the groups. There was no significant difference in change of QOL scores between mastectomy and BCS patients at RT completion as compared to baseline.Conclusions: There was no significant difference in quality of life in patients with BCS versus those with mastectomy. However, patients who underwent BCS had better sexual enjoyment and future perspective scores compared with mastectomy patients. There was no significant change of QOL domain scores after RT in mastectomy and BCS patients.

Dose–response relationship for radiation-induced pneumonitis after pulmonary stereotactic body radiotherapy - Corrected Proof

2010-06-04

Abstract: Purpose: To evaluate dosimetric factors predictive for radiation-induced pneumonitis (RP) after pulmonary stereotactic body radiotherapy (SBRT).Materials and methods: A retrospective analysis was performed based on 59 consecutive patients treated with cone-beam CT-based image-guided SBRT for primary NSCLC (n=21) or pulmonary metastases (n=54). The majority of patients were treated with radiosurgery of 26Gy to 80% (n=29) or three fractions of 12.5Gy to 65% (n=40). To correct for different single fraction doses, local doses were converted to 2Gy equivalent normalized total doses (NTDs) using α/β ratio of 3Gy for RP. Dose–volume parameters and incidences of RP⩾grade II SWOG were fitted using NTCP models.Results: Eleven patients developed RP grade II. With an average MLD of 10.3±5.6Gy to the ipsilateral lung, a significant dose–response relationship was observed: the MLD was 12.5±4.3Gy and 9.9±5.8Gy for patients with and without development of RP, respectively. Additionally, volumes of the lung exposed to minimum doses between 2.5 and 50Gy (V2.5–V50) were correlated with incidences of RP with a continuous decrease of the goodness of fit for higher doses.Conclusions: The MLD and V2.5–V50 of the ipsilateral lung were correlated with incidences of RP after pulmonary SBRT.

Diagnostic performance of response assessment FDG-PET/CT in patients with head and neck squamous cell carcinoma treated with high-precision definitive (chemo)radiation - Corrected Proof

2010-06-03

Abstract: Purpose: To prospectively assess diagnostic performance of response assessment fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) in patients with HNSCC treated with high-precision definitive (chemo)radiation.Methods: Fifty-seven patients treated on a prospective clinical trial having post-treatment response assessment FDG-PET/CT scans were included. Clinico-pathologic findings and follow-up information was considered as reference standard.Results: First response assessment FDG-PET/CT was done at a median of 9weeks (inter-quartile range 8–10weeks) from completion of treatment. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of first response assessment FDG-PET/CT for identifying residual disease at primary site was 50%, 91.8%, 50%, 91.8%, and 86%. The corresponding figures for the neck were 62.5%, 98%, 83.3%, 94.1%, and 93%. With a median follow-up of 26months (range 7–45months), the 3-year loco-regional control (83.9% vs 58.3%, p=0.001) and overall survival (68.8% vs 58.3%, p=0.063) was significantly better in patients with negative response assessment scans.Conclusion: The overall diagnostic accuracy of response assessment FDG-PET/CT is good, but its sensitivity and PPV is somewhat low, particularly for primary site. A negative response assessment FDG-PET/CT scan is highly suggestive of absence of viable disease that could be used to guide decision-making.

Dose–response relations for stricture in the proximal oesophagus from head and neck radiotherapy - Corrected Proof

2010-06-02

Abstract: Background and purpose: Determination of the dose–response relations for oesophageal stricture after radiotherapy of the head and neck.Material and methods: In this study 33 patients who developed oesophageal stricture and 39 patients as controls are included. The patients received radiation therapy for head and neck cancer at Karolinska University Hospital, Stockholm, Sweden. For each patient the 3D dose distribution delivered to the upper 5cm of the oesophagus was analysed. The analysis was conducted for two periods, 1992–2000 and 2001–2005, due to the different irradiation techniques used. The fitting has been done using the relative seriality model.Results: For the treatment period 1992–2005, the mean doses were 49.8 and 33.4Gy, respectively, for the cases and the controls. For the period 1992–2000, the mean doses for the cases and the controls were 49.9 and 45.9Gy and for the period 2001–2005 were 49.8 and 21.4Gy. For the period 2001–2005 the best estimates of the dose–response parameters are D50=61.5Gy (52.9–84.9Gy), γ=1.4 (0.8–2.6) and s=0.1 (0.01–0.3).Conclusions: Radiation-induced strictures were found to have a dose response relation and volume dependence (low relative seriality) for the treatment period 2001–2005. However, no dose response relation was found for the complete material.

Randomised phase II trial of hyperbaric oxygen therapy in patients with chronic arm lymphoedema after radiotherapy for cancer - Corrected Proof

2010-06-02

Abstract: Background: A non-randomised phase II study suggested a therapeutic effect of hyperbaric oxygen (HBO) therapy on arm lymphoedema following adjuvant radiotherapy for early breast cancer, justifying further investigation in a randomised trial.Methods: Fifty-eight patients with ⩾15% increase in arm volume after supraclavicular±axillary radiotherapy (axillary surgery in 52/58 patients) were randomised in a 2:1 ratio to HBO (n=38) or to best standard care (n=20). The HBO group breathed 100% oxygen at 2.4 atmospheres absolute for 100min on 30 occasions over 6weeks. Primary endpoint was ipsilateral limb volume expressed as a percentage of contralateral limb volume. Secondary endpoints included fractional removal rate of radioisotopic tracer from the arm, extracellular water content, patient self-assessments and UK SF-36 Health Survey Questionnaire.Findings: Of 53/58 (91.4%) patients with baseline assessments, 46 had 12-month assessments (86.8%). Median volume of ipsilateral limb (relative to contralateral) at baseline was 133.5% (IQR 126.0–152.3%) in the control group, and 135.5% (IQR 126.5–146.0%) in the treatment group. Twelve months after baseline the median (IQR) volume of the ipsilateral limb was 131.2% (IQR 122.7–151.5%) in the control group and 133.5% (IQR 122.3–144.9%) in the treatment group. Results for the secondary endpoints were similar between randomised groups.Interpretation: No evidence has been found of a beneficial effect of HBO in the treatment of arm lymphoedema following primary surgery and adjuvant radiotherapy for early breast cancer.

Acute toxicity profile of radiotherapy in 690 children and adolescents: RiSK data - Corrected Proof

2010-06-02

Abstract: Background and purpose: The “Registry for the evaluation of side effects after radiation in childhood and adolescence” (risk) was introduced to characterize adverse effects of radiotherapy in childhood and adolescence prospectively. The aim of this analysis was to characterize the pattern of acute side effects.Materials and methods: Since 2001, patients receiving radiotherapy in one of the German pediatric therapy trials have been registered in RiSK with detailed information regarding radiation doses to organs at risk and characterization of acute toxicities.Results: From 2001 to May 2009, 690 patients have been characterized for acute toxicity in primary therapy. Acute toxicity⩾grade 1 was observed in 506 patients. In patients irradiated in their lung and liver, patients with grade 1 or 2 acute toxicities showed higher organ volumes exposed to radiation doses <20 Gray (Gy) compared to patients without toxicities. For the salivary glands, there was a positive correlation between the acute toxicity grade and the maximum radiation dose to the organ; the lower GI tract showed a similar trend. The impact of different chemotherapy regimens on these acute side effects remains unclear. Age did not have any impact on side effects.Conclusion: This analysis gives a comprehensive overview of the acute toxicities of radiotherapy in children and adolescents. With prolongation of follow-up, detailed analyses regarding late toxicities will be possible with the characterization of dose–volume–effect relationships.

Temporary sacral nerve stimulation for faecal incontinence following pelvic radiotherapy - Corrected Proof

Yasuko Maeda, Morten Høyer, Lilli Lundby, Steen Buntzen, Søren Laurberg — 2010-05-31

Abstract: Temporary sacral nerve stimulation for faecal incontinence caused by pelvic radiation injuries was successful in 7 of 13 patients (54%). The improvement of total incontinence episodes during the temporary stimulation period was a median of 83% (range 25–93%). This may be a viable treatment option for radiation-induced faecal incontinence.

The potential advantages of 18FDG PET/CT-based target volume delineation in radiotherapy planning of head and neck cancer - Corrected Proof

2010-05-31

Abstract: Purpose: This study investigated two fixed threshold methods to delineate the target volume using 18FDG PET/CT before and during a course of radical radiotherapy in locally advanced squamous cell carcinoma of the head and neck.Materials and methods: Patients were enrolled into the study between March 2006 and May 2008. 18FDG PET/CT scans were carried out 72h prior to the start of radiotherapy and then at 10, 44 and 66Gy. Functional volumes were delineated according to the SUV Cut Off (SUVCO) (2.5, 3.0, 3.5, and 4.0bwg/ml) and percentage of the SUVmax (30%, 35%, 40%, 45%, and 50%) thresholds. The background 18FDG uptake and the SUVmax within the volumes were also assessed.Results: Primary and lymph node volumes for the eight patients significantly reduced with each increase in the delineation threshold (for example 2.5–3.0bwg/ml SUVCO) compared to the baseline threshold at each imaging point. There was a significant reduction in the volume (p⩽0.0001–0.01) after 36Gy compared to the 0Gy by the SUVCO method. There was a negative correlation between the SUVmax within the primary and lymph node volumes and delivered radiation dose (p⩽0.0001–0.011) but no difference in the SUV within the background reference region. The volumes delineated by the PTSUVmax method increased with the increase in the delivered radiation dose after 36Gy because the SUVmax within the region of interest used to define the edge of the volume was equal or less than the background 18FDG uptake and the software was unable to effectively differentiate between tumour and background uptake.Conclusions: The changes in the target volumes delineated by the SUVCO method were less susceptible to background 18FDG uptake compared to those delineated by the PTSUVmax and may be more helpful in radiotherapy planning. The best method and threshold have still to be determined within institutions, both nationally and internationally.

EORTC radiation proctitis-specific quality of life module – Pretesting in four European countries - Corrected Proof

2010-05-06

Abstract: Background and purpose: Radiation proctitis is a side effect which can occur after pelvic radiation therapy. Currently available questionnaires do not comprehensively assess the range of problems, nor impact on quality of life associated with proctitis. This article reports on the cultural testing phase of an EORTC module (QLQ-PRT21) developed to assess radiation proctitis specific issues and designed to be used in conjunction with the EORTC core quality of life questionnaire (QLQ-C30).Methods: The previously developed 21-item module, pre-tested in Australia, was translated into Norwegian, German, French and Italian. Patients completed the EORTC QLQ-C30 and module questionnaires towards the end of their radical pelvic radiation treatment to target acute side effects. Patients experiencing chronic proctitis were also surveyed. Patients also participated in structured interviews to determine issues of comprehensibility, coverage and relevance. Results were compared with Australian data.Results: Questionnaires were completed by 64 European patients. The module was found to be relevant and culturally acceptable to participants. Feedback has led to minor translation modifications and the inclusion of two additional questions.Conclusion: This module is ready for Phase IV testing which will consist of large scale field testing with the aim to perform psychometric analysis and finalise a module that will be suitable in the assessment of radiation induced proctitis.

Test of association between variant tgβ1 alleles and late adverse effects of breast radiotherapy - Corrected Proof

2010-05-03

Abstract: Purpose: To test for association between single nucleotide polymorphisms at the TGFβ1 locus and the risk of late normal tissue injury following whole breast radiotherapy.Methods: A retrospective study compared the number of variant alleles at −509 and codons 10 and 25 of the TGFβ1 locus in women followed up in two prospective clinical trials who developed either marked radiotherapy adverse effects or no adverse effects after matching on fractionation schedule, breast size, surgical deficit, chemotherapy and length of follow up.Results: Median follow up in the two trials was 7.4 (maximum 15) years and 5.3 (maximum 5.3) years. 1237/1716 (72%) women with photographic assessments of radiotherapy adverse effects were alive and well, and 147/1237 (12%) potential cases with the most marked change in photographic change in breast appearance were matched to potential controls recording no change. In an unmatched analysis of 82 cases and 108 controls, no significant difference in the number of genetic variants was observed.Conclusions: No association was detected between sequence variations at the TGFβ1 locus and the risk of late adverse effects of breast radiotherapy.

A prospective, comparative study on the early effects of local and remote radiation therapy on carotid intima–media thickness and vascular cellular adhesion molecule-1 in patients with head and neck and prostate tumors - Corrected Proof

2010-05-03

Abstract: Background and purpose: To investigate early vascular changes related to carotid atherosclerotic injury post-radiation therapy (RT), we studied carotid intima–media thickness (IMT) and vascular cellular adhesion molecule (VCAM)-1 at two time-points after RT and compared local and remote irradiation effects in patients with head and neck (HNC) and prostate cancer (PC), respectively.Material and methods: We prospectively studied patients beginning RT for HNC or PC, performing carotid ultrasound before RT, early after and six months after treatment to measure carotid IMT. Blood samples were simultaneously collected to study VCAM-1 by ELISA.Results: We studied 19 patients with HNC and 24 with PC. Patients with HNC were younger (55±10years) than PC patients (68±8years). Early post-RT only HNC patients had an increase in IMT compared to baseline measurements (0.73±0.04mm vs. 0.80±0.05mm, p=0.029). On the other hand, VCAM-1 levels decreased in PC patients, remaining unchanged in HNC patients. Late post-RT (six months from previous assessment), neither IMT nor VCAM-1 values changed in both groups.Conclusion: Local and remote RT seem to exert differential early effects regarding vascular-related changes: (1) local RT seems to affect vascular structure and increase IMT and (2) RT for PC is associated with reduction in VCAM levels, suggesting systemic modulation of cancer-related factors.

Synergistic induction of profibrotic PAI-1 by TGF-β and radiation depends on p53 - Corrected Proof

2010-05-03

Abstract: Radiation-induced fibrosis is a severe side effect of radiotherapy. TGF-β and radiation synergistically induce expression of the profibrotic PAI-1 gene and this cooperation potentially involves p53. Here, we demonstrate that p53 is both indispensable and sufficient for the radiation effect inducing synergistic activation of PAI-1 by radiation and TGF-β.

Characterization of FDG-PET images after stereotactic body radiation therapy for lung cancer - Corrected Proof

2010-04-30

Abstract: Background and purpose: The purpose was to characterize 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) findings after stereotactic body radiation therapy (SBRT) for lung cancer.Materials and methods: This was a retrospective review of 32 FDG-PET scans from 23 patients who underwent SBRT for lung cancer and who showed no evidence of local recurrence. The FDG uptake by lesions was assessed visually using a 3-point scale (0, none or faint; 1, mild; or 2, moderate to intense), and the demarcation (ill- or well-defined) was evaluated. For semi-quantitative analysis, the maximum standardized uptake value (SUVmax) was calculated.Results: Grade 2 intensity was observed in 70%, 33%, 30%, and 0% of PET scans performed <6, 6–12, 12–24, and >24months, respectively, after SBRT; well-defined demarcation was observed in 80%, 33%, 40%, and 17%, respectively, and the respective means of the SUVmax were 4.9, 2.6, 3.0, and 2.3. The SUVmax was significantly higher for scans performed at <6months than at 6–12 or >24months.Conclusions: FDG uptake tended to be intense and well-defined at early times after SBRT, especially within 6months, and was faint and ill-defined at later periods. Moderate to intense FDG uptake observed soon after SBRT does not always indicate a residual tumour.

The clinical characteristics and non-steroidal treatment for radiation-induced bronchiolitis obliterans organizing pneumonia syndrome after breast-conserving therapy - Corrected Proof

2010-04-12

Abstract: Purpose: A rare and unique occurrence of radiation-induced pulmonary injury was observed outside the tangential field for early breast cancer treatment. The findings appeared to be idiopathic and were termed radiation-induced bronchiolitis obliterans organizing pneumonia (BOOP) syndrome. The goal of this study was to report and determine the incidence, analyze the characteristics of the pulmonary lesions on the images and also investigate the treatment methods.Materials and methods: A retrospective analysis was conducted of 616 consecutive patients that underwent breast-conserving therapy (BCT) from January 1992 to December 2008. The patients were observed at least one year after radiotherapy for BCT. Radiotherapy was administered by 4 MV photons in all patients. The patients underwent chest X-rays periodically. If the BOOP syndrome was found, chest computed tomography (CT) were conducted to identify the characteristics of the pulmonary lesion outside the radiation field.Results: The incidence of the radiation-induced BOOP syndrome was 12 patients (1.9%). Six of them had fever and cough, 6 had no symptoms. The pulmonary lesions were classified into four patterns on chest CT. Progression of the pulmonary lesions observed on chest X-ray were classified into three patterns. BOOP syndrome appeared within 5.6months after radiotherapy and completely disappeared within 12months after its onset. Their clinical conditions were not severe and these pulmonary lesions disappeared gradually without use of steroids in our institution. There was no death caused by BOOP syndrome.Conclusions: Although the incidence of BOOP syndrome and its associated prognosis are not significant, this clinical condition must be carefully followed using diagnositic imaging in order to not over administer steroids.

ErbB2 expression through heterodimerization with erbB1 is necessary for ionizing radiation- but not EGF-induced activation of Akt survival pathway - Corrected Proof

2010-03-29

Abstract: Purpose: ErbB1-dependent Akt phosphorylation improves post-irradiation cellular survival. In the present study, we investigated the contribution of erbB2 as a heterodimerization partner of erbB1 in activation of Akt survival signaling after irradiation or EGF treatment.Materials and methods: Pattern of receptor dimerization and protein phosphorylation were investigated by Western and immunoblotting as well as immunoprecipitation techniques. Residual DNA double-strand breaks (DNA-DSB) and clonogenic activity were analyzed by γH2AX and standard clonogenic assay. To knocked erbB2 expression siRNA was used.Results: In lung carcinoma cell lines A549 and H661, the erbB1-tyrosine kinase (TK) inhibitor erlotinib blocked EGF as well as ionizing radiation (IR)-induced Akt and DNA-PKcs phosphorylation. Targeting Akt and erbB1 induced cellular radiation sensitivity while, the erbB2-TK inhibitor AG825 neither affected phosphorylation of Akt and DNA-PKcs nor induced radiosensitization. ErbB2-siRNA and the anti-erbB2 antibody trastuzumab blocked IR-induced, but not EGF-stimulated Akt phosphorylation and impaired the repair of DNA-DSB. Likewise, IR but not EGF enhanced erbB1/erbB2 heterodimerization and resulted in the release of phosphorylated erbB2 cleavage products p135 and p95. Trastuzumab prevented radiation-induced formation of an active erbB1/erbB2 heterodimer and increased cellular radiation sensitivity. ErbB1- but not erbB2-TK inhibition stabilized erbB2 (p185) through preventing its cleavage.Conclusions: The data indicates that ErbB2 through heterodimerization with erbB1 is necessary for the activation of Akt signaling following irradiation but not following EGF treatment.

First report on the patient database for the identification of the genetic pathways involved in patients over-reacting to radiotherapy: GENEPI-II - Corrected Proof

2010-03-25

Abstract: Background: Identifying the most radiosensitive patient group would have huge clinical implications.Methods: A tissue bank containing skin fibroblasts, whole blood, lymphocytes, plasma and lymphoblastoid cell lines from clinically radiation hypersensitive patients was established from patients in Europe and Canada. Over-reacting individuals had CTCAE3.0 severe acute side effects grade 2 or more occurring at very low radiation doses where these side effects are unexpected or grade 3–4 lasting more than 4weeks after the end of radiotherapy and/or requiring surgical intervention at any time or severe late side effects grade 3–4.Results: Eleven patients have been identified with a mean age of 61.6±8.5years (range 49–74). Two patients were male, 9 female. One patient had non-small cell lung cancer, 6 breast cancer, 2 head and neck cancer, one lymphoma and one meningioma. The mean follow-up time after radiotherapy was 1658±1048days (range 84–3752).Conclusions: The establishment of an international tissue bank of the rare group of patients with extreme hypersensitivity to radiotherapy was proven to be feasible and should enable in-depth molecular studies.

Is 18F-FDG a surrogate tracer to measure tumor hypoxia? Comparison with the hypoxic tracer 14C-EF3 in animal tumor models - Corrected Proof

2010-03-22

Abstract: Introduction: Fluorodeoxyglucose (FDG) has been reported as a surrogate tracer to measure tumor hypoxia with positron emission tomography (PET). The hypothesis is that there is an increased uptake of FDG under hypoxic conditions secondary to enhanced glycolysis, compensating the hypoxia-induced loss of cellular energy production. Several studies have already addressed this issue, some with conflicting results. This study aimed to compare the tracers 14C-EF3 and 18F-FDG to detect hypoxia in mouse tumor models.Materials and methods: C3H, tumor-bearing mice (FSAII and SCCVII tumors) were injected iv with 14C-EF3, and 1h later with 18F-FDG. Using a specifically designed immobilization device with fiducial markers, PET (Mosaic®, Philips) images were acquired 1h after the FDG injection. After imaging, the device containing mouse was frozen, transversally sliced and imaged with autoradiography (AR) (FLA-5100, Fujifilm) to obtain high resolution images of the 18F-FDG distribution within the tumor area. After a 48-h delay allowing for 18F decay a second AR was performed to image 14C-EF3 distribution. AR images were aligned to reconstruct the full 3D tumor volume, and were compared with the PET images. Image segmentation with threshold-based methods was applied on both AR and PET images to derive various tracer activity volumes. The matching index DSI (dice similarity index) was then computed. The comparison was performed under normoxic (ambient air, FSAII: n=4, SCCVII, n=5) and under hypoxic conditions (10% O2 breathing, SCCVII: n=4).Results: On AR, under both ambient air and hypoxic conditions, there was a decreasing similarity between 14C-EF3 and FDG with higher activity sub-volumes. Under normoxic conditions, when comparing the 10% of tumor voxels with the highest 18F-FDG or 14C-EF3 activity, a DSI of 0.24 and 0.20 was found for FSAII and SCCVII, respectively. Under hypoxic conditions, a DSI of 0.36 was observed for SCCVII tumors. When comparing the 14C-EF3 distribution in AR with the corresponding 18F-FDG-PET images, the DSI reached values of 0.26, 0.22 and 0.21 for FSAII and SCCVII under normoxia and SCCVII under hypoxia, respectively.Conclusion: This study showed that FDG is not a good surrogate tracer for tumor hypoxia under either ambient or hypoxic conditions. Only specific hypoxia tracers should be used to measure tumor hypoxia.

Predictors of acute bowel toxicity in patients treated with IMRT whole pelvis irradiation after prostatectomy - Corrected Proof

2010-03-22

Abstract: Purpose/objective: Whole pelvis irradiation with IMRT (WPRT–IMRT) after prostatectomy is efficient in reducing acute toxicity: however, a number of patients still experience moderate acute bowel toxicity.Materials and methods: Ninety-six patients treated with WPRT–IMRT after prostatectomy with adjuvant or salvage intent were analysed. A number of parameters were individually recovered, including the DVHs of the intestinal cavity outside PTV and of the loops referred to both the WPRT phase and the whole treatment. Correlation between clinical-dosimetric parameters and acute bowel toxicity was investigated by logistic analyses. Best predictive cut-off values for continuous variables were assessed by ROC curves.Results: 15/96 (15.6%) Patients experienced grade 2 toxicity (no grade 3). Best dose–volume predictors were the fraction of loops receiving more than 45, 50 and 55Gy (respectively, V45TL⩾50cc, V50TL⩾13cc, V55TL⩾3cc; p-values ranging from 0.005 to 0.027). Age, GU acute toxicity, rectal acute toxicity and time between prostatectomy and IMRT were also predictors of acute bowel toxicity. Multivariate analysis showed that the most predictive independent parameters were age (OR: 1.13; 95%CI: 1.02–1.25; p=0.021) and V50TL (⩾13cc, OR: 8.2; 95%CI: 1.7–40; p=0.009).Conclusions: The risk of moderate acute uGI toxicity during WPRT–IMRT for post-operatively treated patients increases with age; the risk is substantially reduced in patients with small overlap between PTV and loops.

Mammary fat necrosis following radiotherapy in the conservative management of localized breast cancer: Does it matter? - Corrected Proof

Mark Trombetta, Vladimir Valakh, Thomas B. Julian, E. Day Werts, David Parda — 2010-03-15

Abstract: Purpose: Fat necrosis is a well-described and relatively common complication arising from post-lumpectomy irradiation of the breast, most commonly breast brachytherapy. We wish to assess the clinical significance of fat necrosis resulting from post-lumpectomy breast irradiation.Methods: We reviewed the literature to determine the overall incidence and significance of fat necrosis to determine whether or not fat necrosis poses a significant clinical problem.Results: Fat necrosis occurs in up to one-quarter of patients following post-lumpectomy breast irradiation. Only rarely is invasive intervention required however, it does significantly degrade the quality of all modalities of breast imaging.Conclusions: Fat necrosis is a common complication of radiotherapy which rarely requires therapeutic intervention. However, post-therapeutic clinical imaging such as mammography, ultrasound and magnetic resonance imaging are affected which may result in additional diagnostic procedures up to and including biopsy.

Radiotherapy on the neck nodes predicts severe weight loss in patients with early stage laryngeal cancer - Corrected Proof

2010-03-11

Abstract: Background and purpose: Although patients with early stage (T1/T2) laryngeal cancer (LC) are thought to have a low incidence of malnutrition, severe weight loss is observed in a subgroup of these patients during radiotherapy (RT). The objective of this study was to evaluate weight loss and nutrition-related symptoms in patients with T1/T2 LC during RT and to select predictive factors for early identification of malnourished patients.Methods: Of all patients with T1/T2 LC, who received primary RT between 1999 and 2007, the following characteristics were recorded: sex, age, TNM classification, tumour location, radiation schedule, performance status, quality of life, weight loss, and nutrition-related symptoms. The association between baseline characteristics and malnutrition (>5% weight loss during RT) was investigated by Cox regression analysis.Results: The study population consisted of 238 patients. During RT, 44% of patients developed malnutrition. Tumour location, TNM classification, RT on the neck nodes, RT dose, nausea/vomiting, pain, swallowing, senses problems, trouble with social eating, dry mouth and the use of painkillers were all significantly associated with malnutrition. In the multivariate analysis, RTs on both the neck nodes (HR 4.16, 95% CI 2.62–6.60) and dry mouth (HR 1.72, 95% CI 1.14–2.60) remained predictive. Nevertheless, RT on the neck nodes alone resulted in the best predictive model for malnutrition scores.Conclusions: Patients with early stage laryngeal cancer are at risk of malnutrition during radiotherapy. Radiotherapy on the neck nodes is the best predictor of malnutrition during radiotherapy. Therefore, we suggest to offer nutritional counselling to all the patients who receive nodal irradiation.

Quality of life as predictor of survival: A prospective study on patients treated with combined surgery and radiotherapy for advanced oral and oropharyngeal cancer - Corrected Proof

2010-03-02

Abstract: Background and purpose: The relation between health-related quality of life (HRQOL) and survival was investigated at baseline and 6months in 80 patients with advanced oral or oropharyngeal cancer after microvascular reconstructive surgery and (almost all) adjuvant radiotherapy.Materials and methods: Multivariate Cox regression analyses of overall and disease-specific survival were performed including sociodemographic (age, gender, marital status, comorbidity), and clinical (tumor stage and site, radical surgical, metastasis, radiotherapy) parameters, and HRQOL (EORTC QLQ-C30 global quality of life scale).Results: Before treatment, younger age and having a partner were predictors of disease-specific survival; younger age predicted overall survival. At 6months post-treatment, disease-specific and overall survival was predicted by (deterioration of) global quality of life solely. Global health-related quality of life after treatment was mainly influenced by emotional functioning.Conclusion: Deterioration of global quality of life after treatment is an independent predictor of survival in patients with advanced oral or oropharyngeal cancer.

Discontinuous induction of X-linked inhibitor of apoptosis in EA.hy.926 endothelial cells is linked to NF-κB activation and mediates the anti-inflammatory properties of low-dose ionising-radiation - Corrected Proof

2010-02-19

Abstract: Background and purpose: This study aimed to characterize a link between X-linked inhibitor of apoptosis protein (XIAP) expression, apoptosis induction, Nuclear Factor kappa B (NF-κB) activity and the anti-inflammatory properties of low-dose ionising-radiation (LD-RT).Material and methods: EA.hy.926 endothelial cells (ECs) were irradiated with doses ranging from 0.3 to 3Gy, and subsequently stimulated by TNF-α, and XIAP expression was either detected by immunoblotting or TaqMan-PCR. Apoptosis was quantified by AnnexinV staining or by caspase 3/7 activity assays. NF-κB transcriptional activity was analysed by a luciferase reporter assay, secretion of Transforming Growth Factor beta 1 (TGF-β1) and adhesion of peripheral blood mononuclear cells (PBMC) to EC were quantified using ELISA and adhesion assays.Results: LD-RT of the activated EA.Hy.926 EC induces XIAP expression in a discontinuous manner with a relative maximum at 0.5Gy and 3Gy which parallels a discontinuity in apoptosis induction and caspase 3/7 activity. siRNA-mediated attenuation of XIAP resulted in an increased rate of apoptosis, a hampered NF-κB transcriptional activity and a diminished secretion of TGF-β1. As compared to control-siRNA treated cells, adhesion of PBMC to EC was increased in XIAP depleted EA.Hy.926 EC.Conclusion: The modulation of apoptosis, NF-κB activity and TGF-β1 by XIAP in irradiated and subsequent stimulated EC contributes to an impaired PBMC/EC adhesion and to the anti-inflammatory properties of LD-RT.

Association of single nucleotide polymorphisms in ATM, GSTP1, SOD2, TGFB1, XPD and XRCC1 with clinical and cellular radiosensitivity - Corrected Proof

2010-02-19

Abstract: Purpose: To examine the association of polymorphisms in ATM (codon 158), GSTP1 (codon 105), SOD2 (codon 16), TGFB1 (position -509), XPD (codon 751), and XRCC1 (codon 399) with fibrosis and also individual radiosensitivity.Methods and materials: Retrospective analysis with 69 breast cancer patients treated with breast-conserving radiotherapy; total dose delivered was restricted to vary between 54 and 55Gy. Fibrosis was evaluated according to LENT/SOMA score. DNA was extracted from blood samples; cellular radiosensitivity was measured using the G0 assay and polymorphisms by PCR–RFLP and MALDI-TOF, respectively.Results: Twenty-five percent of all patients developed fibrosis of grade 2 or 3. This proportion tends to be higher in patients being polymorphic in TGFB1 or XRCC1 when compared to patients with wildtype genotype, whereas for ATM, GSTP1, SOD2 and XPD the polymorphic genotype appears to be associated with a lower risk of fibrosis. However, none of these associations are significant. In contrast, when a risk score is calculated based on all risk alleles, there was significant association with an increased risk of fibrosis (per risk allele odds ratio (ORs)=2.09, 95% confidence interval (CI): 1.32–3.55, p=0.0005). All six polymorphisms were found to have no significant effect on cellular radiosensitivity.Conclusions: It is most likely that risk for radiation-induced fibrosis can be assessed by a combination of risk alleles. This finding needs to be replicated in further studies.

No association between SNPs regulating TGF-β1 secretion and late radiotherapy toxicity to the breast: Results from the RAPPER study - Corrected Proof

2010-01-25

Abstract: Background and purpose: Several small studies have reported associations between TGFB1 single nucleotide polymorphisms (SNPs), considered to increase secretion of TGF-β1, and greater than 3-fold increases in incidence of fibrosis – an indicator of late toxicity after radiotherapy in breast cancer patients.Materials and methods: Two SNPs in TGFB1, C-509T (rs1800469) and L10P (rs1800470), were genotyped in 778 breast cancer patients who had received radiotherapy to the breast. Late radiotherapy toxicity was assessed two years after radiotherapy using a validated photographic technique, clinical assessment and patient questionnaires.Results: On photographic assessment, 210 (27%) patients showed some degree of breast shrinkage, whilst 45 (6%) patients showed marked breast shrinkage. There was no significant association of genotype at either of the TGFB1 SNPs with any measure of late radiation toxicity.Conclusion: This adequately powered trial failed to confirm previously reported increases in fibrosis with TGFB1 genotype – any increase greater than 1.36 can be excluded with 95% confidence. Similar frequent failures to replicate associations with candidate genes have been resolved using genome-wide association scans: this methodology detects common, low risk alleles but requires even larger patient numbers for adequate statistical power.

REMOVED: Boron neutron capture therapy (BNCT) for glioblastoma multiforme: A phase 2 study evaluating a prolonged high dose of boronophenylalanine (BPA) - Corrected Proof

2006-05-24

This article has been removed consistent with Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). The Publisher apologizes for any inconvenience this may cause.

REMOVED: Boron neutron capture therapy in the treatment of glioblastoma: As effective, more effective or less effective than photon irradiation? - Corrected Proof

Rolf F. Barth, Heikki Joensuu — 2006-05-09

This article has been removed, consistent with Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). The Publisher apologizes for any inconvenience this may cause.