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Background Data about factors driving accrual to radiation oncology trials are limited. In oncology, 30%-40% of trials are considered unsuccessful, many because of poor accrual. The goal of the present study was to inform the design of future trials by evaluating the effects of institutional, clinician, and patient factors on accrual rates to a randomized radiation oncology trial. Methods Investigators participating in sabr-comet (NCT01446744), a randomized phase ii trial open in Canada, Europe, and Australia that is evaluating the role of stereotactic ablative radiotherapy (sabr) in oligometastatic disease, were invited to complete a survey about factors affecting accrual. Institutional ethics approval was obtained. The primary endpoint was the annual accrual rate per institution. Univariable and multivariable linear regression analyses were used to identify factors predictive of annual accrual rates. Results On univariable linear regression analysis, off-trial availability of sabr (p = 0.014) and equipoise of the referring physician (p = 0.014) were found to be predictive of annual accrual rates. The annual accrual rates were lower when centres offered sabr for oligometastases off-trial (median: 3.7 patients vs. 8.4 patients enrolled) and when referring physicians felt that, compared with having equipoise, sabr was beneficial (median: 4.8 patients vs. 8.4 patients enrolled). Multivariable analysis identified perceived level of equipoise of the referring physician to be predictive of the annual accrual rate (p = 0.023). Conclusions The level of equipoise of referring physicians might play a key role in accrual to radiation oncology randomized controlled trials. Efforts to communicate with and educate referring physicians might therefore be beneficial for improving trial accrual rates. [ABSTRACT FROM AUTHOR]

Background Data about factors driving accrual to radiation oncology trials are limited. In oncology, 30%-40% of trials are considered unsuccessful, many because of poor accrual. The goal of the present study was to inform the design of future trials by evaluating the effects of institutional, clinician, and patient factors on accrual rates to a randomized radiation oncology trial. Methods Investigators participating in SABR-COMET (NCT01446744), a randomized phase ii trial open in Canada, Europe, and Australia that is evaluating the role of stereotactic ablative radiotherapy (sabr) in oligometastatic disease, were invited to complete a survey about factors affecting accrual. Institutional ethics approval was obtained. The primary endpoint was the annual accrual rate per institution. Univariable and multivariable linear regression analyses were used to identify factors predictive of annual accrual rates. Results On univariable linear regression analysis, off-trial availability of SABR (p = 0.014) and equipoise of the referring physician (p = 0.014) were found to be predictive of annual accrual rates. The annual accrual rates were lower when centres offered sabr for oligometastases off-trial (median: 3.7 patients vs. 8.4 patients enrolled) and when referring physicians felt that, compared with having equipoise, sabr was beneficial (median: 4.8 patients vs. 8.4 patients enrolled). Multivariable analysis identified perceived level of equipoise of the referring physician to be predictive of the annual accrual rate (p = 0.023). Conclusions The level of equipoise of referring physicians might play a key role in accrual to radiation oncology randomized controlled trials. Efforts to communicate with and educate referring physicians might therefore be beneficial for improving trial accrual rates. [ABSTRACT FROM AUTHOR]

Recent years have witnessed an explosion in genome sequencing of probiotic strains for accurate identification and characterization. Regulatory bodies are emphasizing on the need for performing phase I safety studies for probiotics. The main hypothesis of this study was to explore the feasibility of using genome databases for safety screening of strains. In this study, we attempted to develop a framework for the safety assessment of a potential probiotic strain, Lactobacillus helveticus MTCC 5463 based on genome mining for genes associated with antibiotic resistance, production of harmful metabolites, and virulence. The sequencing of MTCC 5463 was performed using GS-FLX Titanium reagents. Genes coding for antibiotic resistance and virulence were identified using Antibiotic Resistance Genes Database and Virulence Factors Database. Results indicated that MTCC 5463 carried antibiotic resistance genes associated with beta-lactam and fluoroquinolone. There is no threat of transfer of these genes to host gut commensals because the genes are not plasmid encoded. The presence of genes for adhesion, biofilm, surface proteins, and stress-related proteins provides robustness to the strain. The presence of hemolysin gene in the genome revealed a theoretical risk of virulence. The results of in silico analysis complemented the in vitro studies and human clinical trials, confirming the safety of the probiotic strain. We propose that the safety assessment of probiotic strains administered live at high doses using a genome-wide screening could be an effective and time-saving tool for identifying prognostic biomarkers of biosafety. [ABSTRACT FROM AUTHOR]

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Objective: Positron emission tomography (PET)/CT scans can improve target definition in radiotherapy for non-small cell lung cancer (NSCLC). As staging PET/CT scans are increasingly available, we evaluated different methods for co-registration of staging PET/CT data to radiotherapy simulation (RTP) scans. Methods: 10 patients underwent staging PET/CT followed by RTP PET/CT. On both scans, gross tumour volumes (GTVs) were delineated using CT (GTVCT) and PET display settings. Four PET-based contours (manual delineation, two threshold methods and a source-to-background ratio method) were delineated. The CT component of the staging scan was co-registered using both rigid and deformable techniques to the CT component of RTP PET/CT. Subsequently rigid registration and deformation warps were used to transfer PET and CT contours from the staging scan to the RTP scan. Dice's similarity coefficient (DSC) was used to assess the registration accuracy of staging-based GTVs following both registration methods with the GTVs delineated on the RTP PET/CT scan. Results: When the GTVCT delineated on the staging scan after both rigid registration and deformation was compared with the GTVCT on the RTP scan, a significant improvement in overlap (registration) using deformation was observed (mean DSC 0.66 for rigid registration and 0.82 for deformable registration, p=0.008). A similar comparison for PET contours revealed no significant improvement in overlap with the use of deformable registration. Conclusions: No consistent improvements in similarity measures were observed when deformable registration was used for transferring PET-based contours from a staging PET/CT. This suggests that currently the use of rigid registration remains the most appropriate method for RTP in NSCLC. [ABSTRACT FROM AUTHOR]

To improve the prognosis of limited stage small cell lung cancer (LS-SCLC) the addition of concurrent thoracic radiotherapy to a platinum-containing regimen is important. In the Netherlands, we initiated a multicenter, phase II study, of the combination of four cycles of carboplatin (AUC 5), paclitaxel (200 mg m(-2)) and etoposide (2 x 50 mg orally for 5 days) combined with 45 Gy (daily fractions of 1.8 Gy). The radiation was given to the involved field and concurrently with the second and third chemotherapy cycle. Patients with a partial or complete response received prophylactic cranial irradiation to a dose of 30 Gy. From January 1999 to December 2001, 37 of the 38 patients with LS-SCLC entered were eligible for toxicity analysis and response. Grade 3 and 4 haematological toxicity occurred in 57% (21/37) with febrile neutropenia in 24% (9/37). There were no treatment-related deaths or other grade 4 toxicity. Grade 3 toxicities were oesophagitis (27%), radiation pneumonitis (6%), anorexia (14%), nausea (16%), dyspnea (19%) and lethargy (22%). The objective response rate was 92% (95% confidence interval (CI) 80-98%) with a median survival time of 19.5 months (95% CI 12.8-29.2). The 1-, 2- and 5-year survival rate was 70, 47 and 27%, respectively. In field local recurrences occurred in six patients. Distant metastases were observed in 19 patients of which 13 in the brain. This study indicates that combination chemotherapy with concurrent involved-field radiation therapy is an effective treatment for LS-SCLC. Despite PCI, the brain remained the most important site of recurrence. [ABSTRACT FROM AUTHOR]

Tirapazamine (3-amino-1,2,4-benzotriazine-1,4-di- N-oxide; SR 259075) is a selective hypoxic cell cytotoxic agent that is bioreductively activated in tumours to a reactive-drug free radical. Preclinically the agent has been shown to possess additive and synergistic anti-tumour activity in combination with radiotherapy and chemotherapy regimens. In the present study the pharmacokinetics and metabolism of tirapazamine were investigated in mice and patients as part of pre-clinical and phase I investigations. The objectives of this work were twofold; firstly, to evaluate retrospectively the utility of a pharmacokinetically guided dose-escalation (PGDE) strategy for tirapazamine, and secondly, to investigate if pharmacologically relevant plasma concentrations could be achieved at tolerable doses. Pharmacokinetic studies for PGDE were conducted in mice at four dose levels ranging from one-tenth of the LD10 to the LD50. The AUC at the LD10 (2932 μg ml-1min) was used to determine a target AUC value of 1173 μg ml-1min (equivalent to 40% of the mouse LD10 AUC) for clinical studies. A phase I study to investigate the tolerance of a single i.v. infusion of tirapazamine (once every 3 weeks) was initiated with close pharmacokinetic monitoring. The starting dose (36 mg/m2) was based on toxicity data obtained in the mouse, rat and dog. Doses were escalated by increases in the volume and duration of infusion. A retrospective analysis of the pharmacokinetic and toxicity data was then made to determine the utility of a PGDE approach. The drug exhibited a steep dose-lethality relationship in mice (LD10 294 mg/m2, LD50 303 mg/m2). The major gross toxicities were body-weight loss (15–20%), pilo-erection and hypoactivity at all dose levels. Sporadic ptosis and conjunctivitis were observed at doses of >300 mg/m2. The plasma elimination of tirapazamine fitted a monoexponential open model, with rapid elimination from the plasma ( t1/2=36±0.65 min) occuring at the LD10 dose of 294 mg/m2. A 10.3-fold increase in dose resulted in a 25.0-fold increase in AUC. Clinically, doses were escalated over the range of 36–450 mg/m2. Ototoxicity (tinnitus and reversible hearing loss) was dose-limiting at 450 mg/m2 and the MTD was 390 mg/m2 for this schedule. Pharmacokinetic analyses in patients revealed that the elimination of tirapazamine in patients was generally bi-phasic, with low inter-patient variability being found in clearance. A 12.5-fold increase in dose resulted in a 19.0-fold increase in AUC. There was good quantitative agreement in metabolite formation between mice and humans with respect to the two- and four-electron bioreductive metabolites. AUC values recorded for tirapazamine at the MTD of 390 mg/m2 (range 1035–1611 μg ml-1min) were similar to the target AUC in mice. Importantly, these levels are consistent with the levels required for radiation-dose enhancement and effective combination with cisplatin in mice. Given (a) the similarities in plasma pharmacokinetics and metabolism observed at the target AUC/MTD in mice, rats, dogs and humans, (b) the similar degree of plasma protein binding seen between species and (c) the relatively low inter-patient variability noted in drug clearance, a successful PGDE approach should have been feasible. The results also indicate that potentially therapeutic levels of tirapazamine are achievable in patients at tolerable doses. [ABSTRACT FROM AUTHOR]

A sensitive solid-phase-extraction and high-performance liquid chromatography (HPLC) method has been developed to investigate the pharmacokinetics and metabolism of the hypoxic-cell cytotoxic agent tirapazamine (1,2,4-benzotriazine-3-amine 1,4-di-N-oxide; WIN 59075, SR 4233), currently in phase I/II studies in the United Kingdom and United States. A sample extraction and concentration process was devised using strong cation-exchange Bond Elut cartridges. Tirapazamine, the mono and zero-N-oxide metabolites (WIN 64012, WIN 60109) were isocratically resolved using a microBondapak phenyl HPLC column and measured using photodiode-array detection. The minimal quantifiable level (MQL) of tirapazamine was 40 ng/ml in mouse plasma and 20 ng/ml in human plasma. Recovery was consistently greater than 80% for all compounds over the concentration range of 20 ng/ml to 20 micrograms/ml. No significant decomposition was observed following up to three freeze/thaw cycles and storage at -70 degrees C for 52 days. The assay was accurate and reproducible, with measured values lying within the limits of defined acceptance criteria. Additional studies to investigate the degree of plasma protein binding showed that tirapazamine did not bind extensively to plasma proteins (binding, 9.7% +/- 0.1% and 18.7% +/- 1.3% in mouse and human plasma, respectively). These small species differences in protein binding are unlikely to have any major impact on the extrapolation of pharmacokinetic data from mice to humans. The assay has now been successfully applied to investigate the pharmacokinetics and metabolism of tirapazamine in mice and patients as part of a pharmacokinetically guided dose-escalation strategy for phase I clinical trials. [ABSTRACT FROM AUTHOR]

Introduction: SABR is an established curative treatment for early stage non-small cell lung cancer (NSCLC) in patients considered to be at high risk for surgery or refuse an operation. Several studies report long-term local control rates >90% with SABR in biological equivalent doses of 100Gy. In this study we retrospectively analyzed potential causes for local failure. Materials: In an institutional database containing 729 patients treated with SABR for early stage NSCLC, all patients with suspicious tumor growth on imaging, even in the absence of histological proof, were coded as having a local recurrence. Kaplan-Meier and Cox-regression analysis was used to identify prognostic factors for local failure. In addition we retrospectively reviewed the successive steps from target definition to treatment delivery, in order to evaluate a possible cause for local relapse. This included the quality of planning 4-dimensional CT-scans, accuracy of target contouring, target mobility, proximity of organs at risk, dosimetric target coverage and image-guidance in patients treated using cone-beam CT-based localization. Results: The 3-year actuarial local failure rate was 8.4%, with a local recurrence identified in 32 patients at a median interval of 14.9 months. Recurrences were histologically confirmed in 38%, diagnosed on a combination of CT- and FDG-PET-scans in 28%, and CT-scans only in 31% of patients. A single patient was suspected of having a local recurrence based on X-ray only. In 22/32 patients (69%) local failure was the first site of recurrence. Multivariate analysis revealed TNM-stage as a prognostic factor for local failure, with 3-year local failure rates for T1a of 8.2%, T1b of 5.1%, T2a of 10.1% and T2b of 13.9%, respectively (p=0.012). In 18/32 (56%) of patients, the tumor was located immediately adjacent to the chest wall, and in retrospect target contouring was judged to be (too) tight in 5/18 patients. As only 6/32 patients (19%) exhibited tumor motion >1cm, geographical misses caused by mobility are an unlikely cause of failure. In a single patient, unnoticed artifacts in the planning 4DCT-scan possibly led to inadequate target definition. In 53% of patients, no apparent explanation for local recurrence could be identified. Conclusions: TNM-stage is a prognostic factor for local recurrence. A potential explanation for local failure could only be identified in a minority of patients. However, a tumor location immediately adjacent to the chest wall in more than half of patients with a local recurrences cautions against unduly tight contouring in fear of chest wall toxicity. Disclosure: No significant relationships. [ABSTRACT FROM AUTHOR]

Purpose: After stereotactic ablative radiotherapy (SABR) for early-stage non-small cell lung cancer, benign CT changes due to radiation-induced lung injury (RILI) are common, and difficult to differentiate from recurrence. The goal of this study was to measure the utility of CT image feature analysis in differentiating RILI from recurrence at different time points post-treatment. Methods: A total of 22 patients treated with SABR were selected, with a total of 24 lesions (n=11 with recurrence [73% biopsy proven], n=13 without recurrence but with substantial benign RILI). Two regions of interest were manually contoured on each follow-up CT scan: consolidative changes and ground glass opacity (GGO). RECIST measures were also taken for the consolidative areas. For each lesion, contoured regions were analyzed for the mean and variation in Hounsfield unit (HU) density (basic texture analysis), 3D volume, and RECIST over the course of follow-up. As a preliminary study of the utility of the measures, classification of this dataset using a linear Bayes normal classifier and leave-one-out cross validation was performed. Results: A total of 136 CT scans were reviewed, and the median duration of imaging follow-up was 26 months. Patients with recurrence had significantly denser consolidative changes (p=.046) and increased variability of CT densities within the GGO regions (p=.0078) detected at nine months post-SABR, compared to patients without recurrence. Restricting the analysis to the GGO in the peritumoral region only (within 4 mm) variability of CT density remained significant at nine months post-SABR (p=.0499). Standard metrics, such as 3D volume and RECIST were significant predictors, but only after 15 months post-SABR: (p=.030 and p=.028 respectively). Based on our preliminary study of classification accuracy, texture analysis within the GGO regions was the best predictor, with a cross validation error of 26.1%. Based on classification as the positive prediction of patients with recurrence, the false negative and false positive rates were 27.3% and 25% respectively. Conclusions: Changes in mean CT density and textural analysis in the GGO have the potential to differentiate benign RILI from tumour recurrence at 9 months post-SABR. With further refinement and incorporation of further texture metrics, this approach may lead to development of a clinically useful tool. If validated, this approach has the potential for earlier detection and salvage of recurrence, and could result in fewer investigations of patients exhibiting benign RILI. Disclosure: No significant relationships. [ABSTRACT FROM AUTHOR]

Introduction: The AJCC staging system has recently updated the staging of multiple lung lesions located in one lobe (T3), in different lobes on ipsilateral side (T4) and bilateral lesions (M1a) in order to better reflect on the outcome of these patients. ESMO guidelines have stated that synchronously detected lesions should be treated as synchronous primary tumors, and a curative approach for both lesions may improve survival. The majority of patients with synchronous double lung tumors are elderly and exhibits multiple co-morbidities, rendering them unit for surgery of both lesions. We analyzed the clinical outcome in such patients who were treated with SABR as a single modality for both lesions (N=57) or in combination with surgery for the second lesion (N=6). Methods: SABR was performed in 63 patients with synchronous early stage double tumors at the VUmc from 2003 - 2012. All patients were discussed in a multi-disciplinary tumor board, and staging FDG-PET scans were available for all patients. A pathological diagnosis was available for both lesions in only 5%, and in one of both lesions in 49%. SABR was delivered to a total dose of 54-60 Gy in 3-12 fractions for all lesions. Clinical outcome, including survival, patterns of relapse and toxicity (CTC v4.0) was evaluated. A sub-analysis was performed for ipsilateral and bilateral synchronous lesions. Results: Median overall survival of the 63 patients was 31 months, with an actuarial survival rate of 40% at 3 years. Overall lesional local control was 79% after 3 years. Local control correlated significantly with tumor size (p=0.005), number of fractions (p=0.013) and with location of lesions (p=0.004). Lesional control at 3 years for bilateral lesions was 92% versus 62% for ipsilateral lesions (p=0.009). Regional- and distant failures were observed in 17% and 46% at three years, respectively. No physician-reported grade =3 early toxicity was observed. Late grade 3 toxicity was reported in 3 patients (5%), and consisted of pneumonitis (n=1), rib fracture(n=1) and pain of the thoracic wall(n=1). No grade 4 or 5 late toxicity was reported. Conclusion: Curative treatment using SABR for both lesions (or combined with surgery) offers the chance of long-term survival. Severe toxicity of SABR for synchronous double tumors was uncommon, and not different from that reported for single lesions. The disappointing local control rate observed after SABR for ipsilateral double lesions was independent from SABR fractionation scheme, and will be investigated in more detail. Disclosure: No significant relationships. [ABSTRACT FROM AUTHOR]

Purpose: To compare lesional stereotactic radiosurgery to whole brain (WBRT) radiotherapy with simultaneous infield boost for brain metastases in terms of overall survival. Methods: A retrospective review was performed on two institutional databases of 500 patients diagnosed with brain metastatic disease who received either stereotactic radiosurgery (SRS, n=381) or whole brain with simultaneous in-field boost radiotherapy (SIB, n=119), between 2002-2011. Propensity score matching was utilized to obtain two groups with similar known prognostic factor characteristics. Kaplan-Meier and univariable/multivariable Cox modeling was conducted to assess the treatment impact on overall survival (OS). Results: Propensity score matching created a matched cohort of 178 patients (89 SRS/SIB) with similar baseline characteristics. Multivariable analysis demonstrated that presence/absence of systemic metastases, patient age, tumour volume, and presence/absence of active primary were found to be more predictive of OS than treatment assignment (p=0.38). SIB was associated with reduced intracranial failure likely due to the WBRT component of the treatment (HR 0.36, p<0.001). Conclusions: Adjusting for other predictive factors, treatment with either SRS or SIB did not result in any statistically significant difference in OS; however, observed intracranial failure was different due to the use of WBRT in the SIB cohort. Disclosure: No significant relationships. [ABSTRACT FROM AUTHOR]

Background: A phase III multi-centre randomised trial (ROSEL) has been initiated to establish the role of stereotactic radiotherapy in patients with operable stage IA lung cancer. Due to rapid changes in radiotherapy technology and evolving techniques for image-guided delivery, guidelines had to be developed in order to ensure uniformity in implementation of stereotactic radiotherapy in this multi-centre study.Methods/design: A Quality Assurance Working Party was formed by radiation oncologists and clinical physicists from both academic as well as non-academic hospitals that had already implemented stereotactic radiotherapy for lung cancer. A literature survey was conducted and consensus meetings were held in which both the knowledge from the literature and clinical experience were pooled. In addition, a planning study was performed in 26 stage I patients, of which 22 were stage 1A, in order to develop and evaluate the planning guidelines. Plans were optimised according to parameters adopted from RTOG trials using both an algorithm with a simple homogeneity correction (Type A) and a more advanced algorithm (Type B). Dose conformity requirements were then formulated based on these results.Conclusion: Based on current literature and expert experience, guidelines were formulated for this phase III study of stereotactic radiotherapy versus surgery. These guidelines can serve to facilitate the design of future multi-centre clinical trials of stereotactic radiotherapy in other patient groups and aid a more uniform implementation of this technique outside clinical trials. [ABSTRACT FROM AUTHOR]

A response to a letter to the editor about his article concerning the safety of using involved-field irradiation in treating limited-stage small-cell lung cancer is presented.