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To investigate the potential dosimetric and clinical benefits predicted by using four-dimensional computed tomography (4DCT) compared with 3DCT in the planning of radical radiotherapy for non-small cell lung cancer.Twenty patients were planned using free breathing 4DCT then retrospectively delineated on three-dimensional helical scan sets (3DCT). Beam arrangement and total dose (55 Gy in 20 fractions) were matched for 3D and 4D plans. Plans were compared for differences in planning target volume (PTV) geometrics and normal tissue complication probability (NTCP) for organs at risk using dose volume histograms. Tumour control probability and NTCP were modelled using the Lyman-Kutcher-Burman (LKB) model. This was compared with a predictive clinical algorithm (Maastro), which is based on patient characteristics, including: age, performance status, smoking history, lung function, tumour staging and concomitant chemotherapy, to predict survival and toxicity outcomes. Potential therapeutic gains were investigated by applying isotoxic dose escalation to both plans using constraints for mean lung dose (18 Gy), oesophageal maximum (70 Gy) and spinal cord maximum (48 Gy).4DCT based plans had lower PTV volumes, a lower dose to organs at risk and lower predicted NTCP rates on LKB modelling (P0.006). The clinical algorithm showed no difference for predicted 2-year survival and dyspnoea rates between the groups, but did predict for lower oesophageal toxicity with 4DCT plans (P = 0.001). There was no correlation between LKB modelling and the clinical algorithm for lung toxicity or survival. Dose escalation was possible in 15/20 cases, with a mean increase in dose by a factor of 1.19 (10.45 Gy) using 4DCT compared with 3DCT plans.4DCT can theoretically improve therapeutic ratio and dose escalation based on dosimetric parameters and mathematical modelling. However, when individual characteristics are incorporated, this gain may be less evident in terms of survival and dyspnoea rates. 4DCT allows potential for isotoxic dose escalation, which may lead to improved local control and better overall survival.

CORRIGENDUM: Biological consequences of nanoscale energy deposition near irradiated heavy atom nanoparticles

Background and purpose Biological dose escalation through stereotactic ablative radiotherapy (SABR) holds promise of improved patient convenience, system capacity and tumor control with decreased cost and side effects. The objectives are to report the toxicities, biochemical and pathologic outcomes of this prospective study. Materials and methods A phase I/II study was performed where low risk localized prostate cancer received SABR 35Gy in 5 fractions, once weekly on standard linear accelerators. Common Terminology Criteria for Adverse Events v3.0 and Radiation Therapy Oncology Group late morbidity scores were used to assess acute and late toxicities, respectively. Biochemical control (BC) was defined by the Phoenix definition. Results As of May 2012, 84 patients have completed treatment with a median follow-up of 55months (range 13–68months). Median age was 67years and median PSA was 5.3ng/ml. The following toxicities were observed: acute grade 3+: 0% gastrointestinal (GI), 1% genitourinary (GU), 0% fatigue; late grade 3+: 1% GI, 1% GU. Ninety-six percent were biopsy negative post-treatment. The 5-year BC was 98%. Conclusions This novel technique employing standard linear accelerators to deliver an extreme hypofractionated schedule of radiotherapy is feasible, well tolerated and shows excellent pathologic and biochemical control.

The purpose of this work was to compare the efficacy and accuracy of techniques to overcome image quality limitations of CBCT images and enable accurate treatment planning calculations using their anatomical data. Patient CBCTs that closely matched their planning CT anatomy were selected for this investigation. Three techniques were evaluated: using the default HU/ ρ e calibration curve with unmodified CBCT images, performing density overrides to limit the images to 6 discrete density values (corresponding to tissues ranging from air to dense bone) and creating a new CT image set through deformable registration of the planning CT to the CBCT (Figure (A)). Each technique was evaluated for a head and neck, lung and prostate patient treated via VMAT with dose calculation results compared to the planning CT results. Agreement was assessed using DVHs for key structures (B) and by performing 3D gamma analysis of the resultant dose distributions (C). For the lung and prostate cases, results from each of the techniques were found to closely match the planning CT dose distributions with γ _3D pass-rates >96% (2%/1 mm) and mean structure doses within 1% of the planning CT calculations. Poorer consistency was observed in the head and neck case with deformable registration identified as the more accurate technique ( γ _3D = 96.0% compared to γ _3D = 70% for the two alternative techniques). The results of this study indicate that simple techniques can be employed to accurately perform dose calculations on CBCT images. However, some limitations were identified where more robust image manipulation can improve calculation accuracy.

151 Background: There is a shortage of novel biomarkers in clinical use for the diagnosis and management of prostate cancer. The neutrophil-lymphocyte ratio (NLR) is a potentially useful biomarker derived from a standard full blood count from peripheral blood sampling, which is readily available and relatively inexpensive. An elevated NLR has been shown to be a poor prognostic biomarker in many advanced solid cancers, including prostate cancer (PC); however, data on NLR in non-metastatic PC have been inconsistent. The objective of this study was to evaluate baseline NLR as an independent predictor of outcome following radical radiotherapy for non-metastatic PC. Methods: Data from 477 consecutive PC patients treated with radical EBRT between 2005 and 2009 in Northern Ireland were reviewed. Outcomes included biochemical progression-free survival (bPFS; Phoenix definiton), prostate cancer-specific survival (PCSS) and overall survival (OS). A two-tailed Mann-Whitney test (significance level 5%) was used to compare NLR in each group. Results: Complete data for 409 patients were available. At a median follow-up of 75 months (range 12 – 138), 74 men (16%) had biochemical failure (BF), 12 men (3%) had died of PC, and 65 men (14%) had died of all causes. Actuarial 5-year bPFS was 91%, PCSS was 97% and OS was 89%. Median NLR was 2.42 in both the BF and non-BF groups (p = 0.78), 2.21 and 2.42 in men who died from PC and those who did not (p = 0.39) and 2.40 and 2.42 in those men who died from all causes and those men who remained alive (p = 0.83). See Table for additional data. Conclusions: In this cohort with medium- to long-term follow-up, NLR was not predictive for bPFS, PCSS or OS. Multivariate analysis of this cohort is planned. Additional prognostic biomarkers are required in PC. [Table: see text]

97 Background: Multiple randomized controlled trials (RCTs) have demonstrated the benefit of the addition of androgen deprivation therapy (ADT) to external beam radiotherapy (EBRT) in the treatment of men with localized prostate cancer (PC). Anti-androgens (AA) may have a better toxicity profile than luteinizing hormone-releasing hormone agonists (LHRHa). However, no RCT has directly compared these agents in combination with radical EBRT. We evaluated outcomes for men with localized PC treated with EBRT in conjunction with either LHRHa or AA therapy. Methods: Data from 409 consecutive patients treated in NI with radical EBRT (70-74 Gy/2Gy #) between 2005 and 2009 were reviewed. Baseline and treatment characteristics analysed comprised age at diagnosis, T stage, initial PSA (iPSA), Gleason score, age-adjusted Charlson comorbidity index (aCCI), ADT type and radiation dose. Outcomes included biochemical progression-free survival (bPFS; Phoenix), prostate cancer-specific survival (PCSS) and overall survival (OS). Cox Proportional Hazards model was used for multivariate analysis (MVA). Results: Men receiving LHRHa were significantly more likely to be older and have a higher iPSA. On MVA, factors independently associated with biochemical failure were T stage ≥ 3 and use of AA (p < 0.004 and p < 0.02 respectively). On MVA, the single independent factor for poorer OS was higher aCCI (p < 0.000015). There was a trend towards poorer OS in the LHRHa group (p = 0.087). Conclusions: An aCCI > 4 was the only independent factor for poorer OS. While there was a significantly increased rate of biochemical failure in the AA group, there was a trend towards poorer OS in the LHRHa group. This study suggests that AA may be a reasonable alternative to LHRHa therapy in men with localized PC treated with radical EBRT and ADT. [Table: see text]

Purpose The goal of this project was to see if using IMRT to deliver elective pelvic nodal irradiation (EPNI) for prostate cancer reduced acute treatment toxicity. Methods Two hundred and thirty patients were enrolled into prospective trials delivering EPNI with a concomitant hypofractionated IMRT boost to the prostate. During accrual, the method of EPNI delivery changed as new literature emerged. Three methods were used (1) 4FB, (2) IMRT with 2 cm CTV margins around the pelvic vessels as suggested by Shih et al. (2005) [7] (IMRT-Shih), and (3) IMRT with nodal volumes suggested by the RTOG (IMRT-RTOG). Initially patients were treated with an empty bladder, with the remainder treated with bladder full. Results Patients in the 4FB group had higher rates of grade 2 acute GI toxicities compared to the IMRT-Shih and IMRT-RTOG groups (31.9% vs 20.8% vs 7.2%, p = 0.0009). Patients in the 4FB group had higher rates of grade 3 urinary frequency compared to the two IMRT groups (8.5% vs 0% vs 0%, p = 0.027). However, multivariate analysis suggested the factor that most influenced toxicity was bladder filling followed by IMRT. Conclusions Bladder filling appeared to be the dominant factor which predicted for acute toxicity, followed by the use of IMRT.

Gold nanoparticles are emerging as promising agents for cancer therapy and are being investigated as drug carriers, photothermal agents, contrast agents and radiosensitisers. This review introduces the field of nanotechnology with a focus on recent gold nanoparticle research which has led to early-phase clinical trials. In particular, the pre-clinical evidence for gold nanoparticles as sensitisers with ionising radiation in vitro and in vivo at kilovoltage and megavoltage energies is discussed.

Background and purpose The addition of gold nanoparticles (GNPs) to tumours leads to an increase in dose due to their high density and energy absorption coefficient, making it a potential radiosensitiser. However, experiments have observed radiosensitisations significantly larger than the increase in dose alone, including at megavoltage energies where gold's relative energy absorption is lowest. This work investigates whether GNPs create dose inhomogeneities on a sub-cellular scale which combine with non-linear dose dependence of cell survival to be the source of radiosensitisation at megavoltage energies. Materials and methods Monte Carlo simulations were carried out to calculate dose in the vicinity of a single GNP on the nanoscale. The effect of this nanoscale dose distribution was then modelled for MDA-MB-231 cells exposed to 2nm GNPs, and compared to experimental results. Results Dramatic dose inhomogeneities occur around GNPs exposed to megavoltage radiation. When analysed using the Local Effect Model, these inhomogeneities lead to significant radiosensitisation, in agreement with experimental results. Conclusions This work suggests that GNP radiosensitisation is driven by inhomogeneities in dose on the nanoscale, rather than changes in dose over the entire cell, which may contribute to the similar radiosensitisation observed in megavoltage and kilovoltage experiments. The short range of these inhomogeneities and the variation in enhancement in different cells suggests sub-cellular localisation is important in determining GNP radiosensitisation.

Gold nanoparticles (GNPs) are being proposed as contrast agents to enhance X-ray imaging and radiotherapy, seeking to take advantage of the increased X-ray absorption of gold compared to soft tissue. However, there is a great discrepancy between physically predicted increases in X-ray energy deposition and experimentally observed increases in cell killing. In this work, we present the first calculations which take into account the structure of energy deposition in the nanoscale vicinity of GNPs and relate this to biological outcomes, and show for the first time good agreement with experimentally observed cell killing by the combination of X-rays and GNPs. These results are not only relevant to radiotherapy, but also have implications for applications of heavy atom nanoparticles in biological settings or where human exposure is possible because the localised energy deposition high-lighted by these results may cause complex DNA damage, leading to mutation and carcinogenesis.

Delivering sufficient dose to tumours while sparing surrounding tissue is one of the primary challenges of radiotherapy, and in common practice this is typically achieved by using highly penetrating MV photon beams and spatially shaping dose. However, there has been a recent increase in interest in the possibility of using contrast agents with high atomic number to enhance the dose deposited in tumours when used in conjunction with kV x-rays, which see a significant increase in absorption due to the heavy element's high-photoelectric cross-section at such energies. Unfortunately, the introduction of such contrast agents significantly complicates the comparison of different source types for treatment efficacy, as the dose deposited now depends very strongly on the exact composition of the spectrum, making traditional metrics such as beam quality less valuable. To address this, a 'figure of merit' is proposed, which yields a value which enables the direct comparison of different source types for tumours at different depths inside a patient. This figure of merit is evaluated for a 15 MV LINAC source and two 150 kVp sources (both of which make use of a tungsten target, one with conventional aluminium filtration, while the other uses a more aggressive thorium filter) through analytical methods as well as numerical models, considering tissue treated with a realistic concentration and uptake ratio of gold nanoparticle contrast agents (10 mg ml (-1) concentration in 'tumour' volume, 10:1 uptake ratio). Finally, a test case of human neck phantom is considered with a similar contrast agent to compare the abstract figure to a more realistic treatment situation. Good agreement was found both between the different approaches to calculate the figure of merit, and between the figure of merit and the effectiveness in a more realistic patient scenario. Together, these observations suggest that there is the potential for contrast-enhanced kilovoltage radiation to be a useful therapeutic tool for a number of classes of tumour on dosimetric considerations alone, and they point to the need for further research in this area.

Introduction: Next generation sequencing (NGS) has identified genomic aberrations causing DNA repair defects in sporadic metastatic castration resistant prostate cancer (mCRPC). We hypothesized that single agent olaparib would have antitumor activity in a sub-population of mCRPC patients (pts) and that exome and transcriptome studies would identify this population. Methods: TOPARP is an open-label, investigator-initiated phase II trial with a novel multi-step adaptive design (CRUK/11/029). The first part of the study (TOPARP-A) has a two-stage design evaluating the antitumor activity of single agent olaparib in unselected mCRPC pts (p0 = 0.05; p1 = 0.20; α = 0.02; β = 0.10) with a preplanned analysis to identify a biomarker defined sensitive subgroup. Primary endpoint, response rate (RR), was defined as objective response by RECIST 1.1 and/or PSA fall ≥50% and/or confirmed circulating tumor cell (CTC) count falls from ≥5 to Results: Fifty pts were enrolled from 7 UK centers; all had had prior docetaxel, 48 (96%) prior abiraterone and 29 (58%) prior cabazitaxel. Overall, 16 of 49 evaluable pts experienced a response (RR 32.7%, 95% CI: 20.0 to 47.5), with 11 and 4 pts having been on treatment for >6 and >12 months respectively at data cut-off. NGS identified homozygous deletions and/or putatively deleterious mutations in DNA repair genes in 15/49 (30.6%) evaluable pts. While a majority of these genomic aberrations occurred in BRCA2 and ATM, biallelic loss of other relevant genes, including members of the Fanconi Anemia complementation group and CHEK2, were also observed. Among these fifteen pts, 13 (86.7%) responded to olaparib. All seven pts with BRCA2 loss (somatic [4/7] or germline [3/7]) and 4/5 pts with ATM truncating mutations responded to olaparib. The specificity of the biomarker suite was 94% in this population. Conversely, PTEN loss and ERG rearrangements were not associated with response. Finally, consistent with previous studies of olaparib, anemia (10/50, 20%) and fatigue (6/50, 12%) were the most common grade>3 adverse events, with 13 (26%) pts requiring a dose reduction. Conclusions: Olaparib has durable antitumor activity in heavily pre-treated pts with sporadic mCRPC with a 32.7% overall response rate. Genomic defects in DNA repair genes associate with olaparib sensitivity in sporadic mCRPC, offering a possibility for the very first molecular treatment stratification of advanced prostate cancer. Citation Format: Joaquin Mateo, Shahneen Sandhu, Susana Miranda, Suzanne Carreira, Suneil Jain, Christy Ralph, Andrew Protheroe, Syed Hussain, Robert Jones, Tony Elliot, Ursula McGovern, Alexa Gillman, Claire Paulding, Helen Mossop, Nuria Porta, Diletta Bianchini, Zafeiris Zafeiriou, Gunther Boysen, Daniel Nava Rodrigues, Penelope Flohr, George Seed, Jane Goodall, Ines Figueiredo, Raquel Perez-Lopez, Nina Tunariu, Aurelius Omlin, Roberta Ferraldeschi, Lakshmi P. Kunju, Rosalind Eeles, Gerhardt Attard, Dan Robinson, Arul Chinnaiyan, Emma Hall, Johann S. de Bono. DNA repair defects and antitumor activity with PARP inhibition: TOPARP, a phase II trial of olaparib in metastatic castration resistant prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT322. doi:10.1158/1538-7445.AM2015-CT322

93 Background: To evaluate the spatial pattern of permanent prostate brachytherapy (PBT) learning curve using post-implant multi-sector dosimetric analysis. Methods: Two hundred patients treated with I-125 PBT at a single institution were assessed. A 12 sector analysis of post-implant CT was created for each case by dividing the prostate base, mid gland and apex into 4 sectors each. Dosimetric analysis was evaluated for whole prostate and individual sectors assessing: minimum dose to 90% of prostate (D90) and dose to 0.1 cm3 of the rectum (D0.1cc). Linear regression analysis and Pearson’s correlation co-efficient were used to investigate changes in D90with case number. Results: Global prostate analysis demonstrated a post-implant learning curve with significant improvement in D90 (p90 with case number (r2=0.19, p=0.0001) at a rate of 0.11 Gy/case. Sector analysis demonstrated greatest improvement in base sectors with increasing case number with an improvement of 0.16 Gy/case (Table; p=0.049 when compared to global D90). Further, D90 in posterior mid-gland reduced with case number and correlated with reduced rectal D0.1cc. Conclusions: Sector analysis demonstrated increased spatial information on the PBT learning curve which may enable on-going improvements in implant quality. [Table: see text]

178 Background: To evaluate outcomes and treatment history of low risk (LR) prostate cancer patients(pts) diagnosed between 2006-2008 in a single academic institute. Methods: Treatment and toxicity details were retrieved through retrospective chart review,apart from surgery where toxicity data was not available in detail.Biochemical RFS following primary and salvage treatments and CSS were computed.Pts who underwent salvage treatment for local failure and subsequently remained under biochemical control were censored as disease free for the salvage bRFS. Results: 594 pts were eligible for this study. Treatment options were active surveillance (AS=178 pts), low dose rate brachytherapy (LDR=192 pts, I-125 implant), stereotactic ablative body radiotherapy (SABR =84 pts; 35Gy in 5 weekly fractions), external beam radiation (EBRT=81 pts; 76Gy ) and radical prostatectomy (RP=59 pts). Median follow was > 70 months in all cohorts. 17.9% on AS protocol underwent active treatment. Biochemical failures were detected in 9 (5%), 10 (5.2%), 3 (3.5%), 6 (7.4%) and 9 (15.3%) pts respectively. Out of these, 4 pts in AS cohort, 2 in SABR group, and 7 in RP underwent local/salvage treatment. The 7-year bRFS was 94.4%, 93.6%, 95.8%, 90.1% and 89.5% for primary treatment and 95.7%, 93.6%, 98.7%, 90.1% and 98.3% following salvage treatment. 1 pt in AS, 2 in LDR, 1 pt in SABR and EBRT group developed metastatic disease. The 6 year CSS was 100% in all groups apart from LDR (99.4%) and EBRT (98.8%). Significant dysuria (20.8%) and hematochezia (7.4%) were noticed in EBRT cohort (Table). One grade 4 toxicity was noted in LDR, SABR and EBRT pts. Conclusions: AS has CSS comparable to other treatment options in LR prostate cancer setting with minimal toxicity. In the primary setting all treatment modalities apart from RP and EBRT have 7-year bRFS >93%. Differences in bRFS following salvage treatment might be due to pt and treatment selection. [Table: see text]

163 Background: To document the long-term outcomes of intermediate risk (IR) prostate cancer patients managed on active surveillance (AS) protocol in a single institute. Methods: Patients(pts) with PSA >10ng/ml or Gleason score 7 or clinical stage T2b/2c were identified from a prospectively collected database of 945 patients managed on AS between 1995 and 2013. Intervention was offered to those pts with a PSA doubling time of < 3 years, Gleason score or clinical progression.Overall survival (OS), cause-specific survival (CSS) for IR and low risk (LR) pts were analyzed as well as metastasis free survival (MFS) and treatment-free survival (TFS) for IR pts. Results: 237 (23.9%) pts had IR disease, with a median follow up of 6.9 years (IQR 3.89, 10.85) .708 pts had LR cancer with a median follow up of 6.4 years (IQR 3.76, 9.03). 61.2% of the IR cohort was older than 70 years. 86 IR pts (36.3%) received treatment (mainly radiation). The median treatment free interval for IR pts was 12.3 years (range 10.1 - 19.8). 33 IR patients developed biochemical failure and 17 developed metastatic disease [11 IR pts(4.6%) and 6 LR pts(0.8%)].The 10 and 15year OS was 68.4% and 50.3% for IR pts;83.6% and 68.8% for LR pts (p value

the oral cavity, oropharynx, nasopharynx, hypopharynx, and larynx, often managed with a combination of surgery, chemotherapy, and radiation therapy. Prognostic factors affecting treatment outcomes in the elderly have not been clearly defined in the literature. Patient-specific factors may be important when considering treatment options for this population in order to maximize patient survival and post-treatment quality of life (QOL). This study aims to explore and clarify the role of key prognostic factors on outcomes in HNC patients over the age of 80 years treated with radiation therapy at the Odette Cancer Centre (OCC). Methods and Materials: From a database of 933 HNC patients treated at OCC between Jan 2007 and December 2012, a sample of 40 eligible patients will be randomly selected. Prognostic factors identified from the literature will be extracted from relevant patient records and recorded in a database in three key categories: disease-related, treatment-related and patient-specific. Patient outcome datadoverall survival and rates of recurrence, treatment completion, and radiation toxicitydwill also be retrieved and recorded. Univariate analysis will be employed to determine which of the patient, disease, and treatment factors significantly predict for outcomes in this population. Results: 92.5% of patients successfully completed their treatment as prescribed. Though palliative patients (mean age 89, median 91) were likely to be older than radical patients (mean age 84.7, median 84), no connection was found between age and outcome measures. Dose, fractionation, and stage were not found to significantly impact outcomes in this sample. Mortality status was unavailable for 25% of patients. Further data collection is ongoing to confirm these and other findings. Conclusions: Preliminary results suggest that choice of treatment regime may be tailored to patient convenience without compromising outcome, and that many older patients are able to successfully complete even aggressive radical therapy. The results of this study and the database from which the sample was drawn may be useful in further studies to inform practices in the HN site group at OCC. Prognostic data may also be utilized to create a medical nomogram, in the form of a visual tool useful in facilitating patient-specific education during the informed consent procedure.

e16101 Background: Treatment with Abiraterone acetate (AA) combined with prednisolone has proven benefit in overall survival compared with prednisolone alone in men with metastatic castration resis...

262 Background: To use sector based pre- and postimplant dosimetric analysis to evaluate the effect of changes in implant technique in a developing I-125 permanent prostate brachytherapy program (PPB). Methods: 109 men treated with PPB were divided into two groups by implant technique. The first 50 patients (group 1) had needle-by-needle seed deposition under axial ultrasound (USS) guidance and subsequent 59 patients (group 2) having needle placement row-by-row then seed deposition under sagittal USS guidance. Twelve sector dose volume analysis of pre-implant ultrasound (USpre) and postimplant CT (CTpost) study was performed in all cases. Individual sectors were created by dividing the cranio-caudal prostate into three equal lengths creating prostate base, midgland and apex. Each of these volumes was then divided into four axial sectors (right and left anterior, right and left posterior). The difference in the minimum dose delivered to 90% of prostate volume (D90) and the prostate volume receiving 100%, 150%, and 200% of the prescribed dose (V100, V150, and V200) was compared between both groups. Results: In both groups, the volume of prostate in sectors one through six (entire base and anterior midgland) were significantly larger on CTpost when compared to equivalent sectors in USpre (p < 0.001), conversely the volumes in sectors 11 and 12 (posterior apex) were significantly smaller (p =0.001). When comparing dosimetric parameters of all equivalent sectors in CTpost of both groups, it was found that D90 of sector seven and eight (posterior midgland) in Group 1 received increased dose leading to elevated dose to the rectum but was significantly reduced in Group 2 (p < 0.01), which resulted in achieving the dose as planned in USpre. Prostate implant dosimetry was significantly improved in group 2 with a trend to increased equivalent dose between CTpost and USpre to each sectors and significant decrease in V150 and V200 in majority of the sectors. Conclusions: The row-by-row technique under sagittal USS guidance significantly improved our post implant dosimetric parameters when compared to single needle source placement under axial USS guidance as assessed by 12 sector analysis.

1 Background: Active surveillance (AS) is an accepted management strategy for localized prostate cancer. However, the rate of pathological upgrading has not been well described in mature study cohorts. Furthermore, concern exists over the possibility of prostate cancer dedifferentiation with time in patients on AS. Methods: Patients in our prospectively collected AS database with at least one repeat prostate biopsy were included. Linear regression analysis was used to estimate the proportion of patients upgraded (Gleason 6 to 3+4 or higher, Gleason 3+4 to 4+3 or higher) with time from diagnostic biopsy. Results: 593 of 862 patients in our cohort had at least one repeat biopsy. Median follow-up was 6.4 years (max. 20.2 years). The total number of biopsies ranged from 2 to 6. 20% of patients were intermediate risk, 0.3 % high risk, all others low risk. 31.2% of patients were upgraded during active surveillance. The proportion of patients upgraded increased with time, suggesting prostate cancer dedifferentiation occurred at a rate of 1.0%/year (95%CI -0.12 to 2.16%/year). The estimated rate of increase was 2.5 times higher in patients with intermediate risk disease at diagnosis (rate 1.9%/year, 95%CI -0.7-4.6) compared with those with low risk disease (rate 0.75%/year, 95%CI -0.5-2.0). Further analysis is underway. 62% of upgraded patients (n=114) went on to have active treatment. Patients who were upgraded and treated had significantly greater PSA velocities (median 1.2 ng/ml/y vs 0.42 ng/ml/y, p=0.01) and significantly higher Gleason scores when upgraded, than those who remained on surveillance (21.8% vs 2.8% Gleason 8-10, p

69 Background: To deliver elective pelvic nodal irradiation (EPNI), a 4-field box (4FB) has been a common technique. More recently, there are increasing reports of using IMRT to deliver EPNI. Even though studies show a clear dosimetric benefit to bowel and bladder, there is a lack of good data demonstrating decreased toxicity with the use of IMRT in this setting. Methods: From 2004-2010, 230 patients with localized high risk prostate cancer were enrolled into 3 sequential prospective phase I/II trials of delivering EPNI (45 Gy) along with a concomitant hypofractionated IMRT boost to the prostate (67.5 Gy total) in 25 fractions over 5 weeks time. All patients were to receive 3 years of adjuvant androgen deprivation. During the accrual period, the method used to deliver the EPNI portion of the treatment changed as new literature emerged about target volumes for EPNI. The 3 methods used to deliver EPNI in this large cohort were 1) 4FB, 2) IMRT with 2cm CTV margins around the pelvic vessels as suggested by Shih et al (IMRT-Shih), and 3) IMRT with nodal volumes as suggested by RTOG (IMRT-RTOG). Common Terminology Criteria for Adverse Events v3.0 was used to assess acute toxicity prospectively during treatment and then at 3 months. Results: For EPNI, 94 patients were treated with a 4FB, 53 were treated with IMRT-Shih, and 83 were treated with IMRT-RTOG. There were no acute grade 3 GI toxicities. Patients in the 4FB group had higher rates of acute grade ≥ 2 proctitis compared to the IMRT-Shih and IMRT-RTOG groups (16.0% vs 2.0% vs 2.4%, p=0.0009). The 4FB group also had higher rates of grade ≥ 2 flatulence compared to the 2 other IMRT groups (17.0% vs 7.6% vs 0%, p Conclusions: In this non-randomized comparison, IMRT resulted in statistically significant decreases in acute proctitis, flatulence, and urinary frequency when compared to a 4FB technique to deliver EPNI in localized high risk prostate cancer. Analysis for possible confounding factors will be performed.

186 Background: Biological dose escalation through hypofractionated image-guided radiotherapy (H-IGRT) holds the promise of improved patient outcomes, system capacity but decreased cost. In 2006 we initiated a prospective trial of H-IGRT of patients with low risk localized prostate cancer. In this report, we report the toxicities, quality of life (QOL), biochemical and pathologic outcomes of this cohort with more mature follow-up. Methods: A phase I/II study in which patients with T1-2b, Gleason≤6, and PSA≤10 ng/ml prostate cancer received 35 Gy in 5 fractions, once a week over 29 days. No patients received hormone therapy. Treatment was delivered with intensity modulated radiotherapy (IMRT) on standard linear accelerators, with daily image guidance using gold seed fiducials, and a 4 mm CTV-PTV margin. CTCAE v3.0 and RTOG late morbidity scores were used to assess acute and late toxicities, respectively. QOL was assessed by the Expanded Prostate Cancer Index Composite (EPIC). Biochemical control (BC) was defined by the Phoenix definition, adjusted for benign bounce. Results: As of September 2011, 83 patients have completed treatment with a median follow-up of 42 months (range 12–60 months). Median age was 67y (42 – 82y). 78 patients (92%) were T1a-c; all had Gleason 6 cancers; median PSA was 5.3 (0.8 – 9.9 ng/ml). 82 (99%) had BC; the remaining patient had a negative biopsy and a history of chronic prostatitis. The median PSA on last visit was 0.69 ng/ml (.02 – 2.6 ng/ml). Of 59 patients who have had a biopsy to date, 2 (3%) were positive but both are under BC. The following toxicities were observed: acute grade 3+: 0% GI, 1% GU, 0% fatigue; late grade 3+: 1% GI, 1% GU. Median transformed QOL scores at baseline (0.5 SD) and 36mo follow-up are: urinary – 95% (4.1), 93%; bowel – 96% (4.8), 96%; sexual – 65% (13.7), 51%; and hormonal – 95% (5.3), 95%. Conclusions: This novel technique employing standard linear accelerators to deliver an extreme hypofractionated schedule of radiotherapy is feasible, well tolerated and shows excellent pathologic and biochemical control. A randomized study versus standard fractionation should be performed.

High atomic number (Z) materials such as gold preferentially absorb kilovoltage x-rays compared to soft tissue and may be used to achieve local dose enhancement in tumours during treatment with ionizing radiation. Gold nanoparticles have been demonstrated as radiation dose enhancing agents in vivo and in vitro. In the present study, we used multiple endpoints to characterize the cellular cytotoxic response of a range of cell lines to 1.9 nm gold particles and measured dose modifying effects following transient exposure at low concentrations. Gold nanoparticles caused significant levels of cell type specific cytotoxicity, apoptosis and increased oxidative stress. When used as dose modifying agents, dose enhancement factors varied between the cell lines investigated with the highest enhancement being 1.9 in AGO-1522B cells at a nanoparticle concentration of 100 microg ml(-1). This study shows exposure to 1.9 nm gold particles to induce a range of cell line specific responses including decreased clonogenic survival, increased apoptosis and induction of DNA damage which may be mediated through the production of reactive oxygen species. This is the first study involving 1.9 nm nanometre sized particles to report multiple cellular responses which impact on the radiation dose modifying effect. The findings highlight the need for extensive characterization of responses to gold nanoparticles when assessing dose enhancing potential in cancer therapy.