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D. Ball



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    E06 - Issues in Current Multidisciplinary Practice (ID 6)

    • Event: WCLC 2013
    • Type: Educational Session
    • Track: Combined Modality
    • Presentations: 1
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      E06.2 - Staging and Early Response Assessment in Combined Modality Therapy for NSCLC (ID 399)

      14:00 - 15:30  |  Author(s): D. Ball

      • Abstract
      • Presentation
      • Slides

      Abstract
      For years radiation oncologists have dreamed of being able to dynamically adapt treatment to the response of normal and tumor tissues observed during a protracted course of radiotherapy. An obvious goal is to adjust the PTV as the GTV shrinks during treatment, which may improve dose volume metrics in the organs at risk, especially lung. Reinflation of atelectatic lung in response to tumour size reduction may require adjustment of PTV size and position to avoid geographic miss. Cone beam CT (CBCT) has revolutionised the ability to regularly image soft tissue, although it is less useful for targets within the mediastinum or those defined primarily by FDG PET. The main limiting step is the time required to develop an adaptive treatment plan without interrupting treatment. Experience suggests that tumor reduction needs to be substantial to have a meaningful impact on the dose volume metrics. The use of serial FDG PET during treatment to detect residual activity and to use this as a surrogate for persistent disease for adaptive radiotherapy is under investigation. This is however based on an unproven assumption that such FDG activity is due to tumor and not inflammation. Tumor motion adds further uncertainty, affecting both SUV and intrafraction location of the residual FDG uptake. CBCT may also detect tumor progression. This seems to be uncommon.(1) When it occurs, apart from discontinuing futile treatment to avoid unnecessary toxicity, can anything else be done? Our group has investigated the use of PET tracers to detect functional changes in tumour during treatment, including FDG and the thymidine based tracer FLT which we hypothesise images tumour proliferation. Preliminary results indicate that FLT detects functional changes in the tumour earlier than FDG, but the clinical implications of this are unknown.(2) One patient with clinical progression had increased uptake of FLT detected at 20 Gy, suggesting accelerated repopulation. The rate of treatment was accelerated with twice daily fractionation, resulting in a reduction in FLT uptake, providing anecdotal proof of principle. Accelerated repopulation has also been indirectly observed with induction chemotherapy.(3) Imaging with FLT may present an opportunity to detect altered proliferation pre-radiotherapy which may benefit from accelerated fractionation.(4) A further change that may occur during fractionated treatment is reoxygenation. We have observed changes in uptake of the hypoxia PET tracer FAZA during a course of radiotherapy,(5) indicating that hypoxia is present in some tumors pre-treatment, although surprisingly little use is made of this knowledge in clinical practice. Changes observed in normal tissue response may also present opportunities for adaptive treatment. The patient can be used as a biological dosemeter, and the occasional patient will require truncation of treatment because of esophagitis. Is this increased sensitivity a surrogate for inherently increased radiosensitivity within the tumor, indicating that a higher tumor dose is unnecessary for such patients? Our group has observed changes in normal lung during treatment using ventilation/perfusion imaging, opening up prospects of avoiding functioning (as opposed to anatomical) lung with beam redirection.(6) Conclusions: A number of tools are now available to detect tumor and normal tissue response to radiotherapy during treatment. These changes may be anatomic or functional, including changes in tumor kinetics or the micro-environment. The challenge now is to turn these observations into clinically useful patient benefits. References 1. Lim G, Bezjak A, Higgins J, Moseley D, Hope AJ, Sun A, et al. Tumor regression and positional changes in non-small cell lung cancer during radical radiotherapy. J Thorac Oncol. 2011;6:531-6. 2. Ball D, Everitt S, Hicks R, Callahan J, Plumridge N, Collins M, et al. Differential Uptake of F18-fluoro-deoxy-glucose (FDG) and F18-fluoro-deoxy-l-thymidine (FLT) Detected by Serial PET/CT Imaging During Radical Chemoradiation for Non-Small Cell Lung Cancer (NSCLC). . J Thorac Oncol 2012;7:S238. 3. El Sharouni SY, Kal HB, Battermann JJ. Accelerated regrowth of non-small-cell lung tumours after induction chemotherapy. Br J Cancer. 2003;89:2184-9. 4. Baumann M, Herrmann T, Koch R, Matthiessen W, Appold S, Wahlers B, et al. Final results of the randomized phase III CHARTWEL-trial (ARO 97-1) comparing hyperfractionated-accelerated versus conventionally fractionated radiotherapy in non-small cell lung cancer (NSCLC). Radiother Oncol. 2011;100:76-85. 5. Trinkaus ME, Blum R, Rischin D, Callahan J, Bressel M, Segard T, et al. Imaging of hypoxia with (18) F-FAZA PET in patients with locally advanced non-small cell lung cancer treated with definitive chemoradiotherapy. J Med Imaging Radiat Oncol. 2013;57:475-81. 6. Siva S, Callahan J, Hofman MS, Eu P, Martin O, Pope K, Ball D, MacManus M, Kron T, Hicks RJ. Technical considerations and preliminary experience of a pilot study of Gallium-68 VQ 4D-PET/CT in lung radiotherapy. J Thorac Oncol 2012;7: S1182.

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    O27 - Clinical Trials and Practice (ID 142)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Other Topics
    • Presentations: 1
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      O27.01 - Thromboembolism in lung cancer - an area of urgent unmet need (ID 2096)

      16:15 - 17:45  |  Author(s): D. Ball

      • Abstract
      • Presentation
      • Slides

      Background
      Current management of lung cancer (LC) (chemotherapy - CHT, radiotherapy – RT, and biological therapies) occurs predominantly in the ambulatory care (AC) setting. Post-surgery hospital admission is becoming progressively shorter due to advances in technique and greater reliance on home recovery.[1,2]As such, LC management occurs outside the scope of current thromboprophylaxis (TP) guidelines.[2-8] Recommendations for TP strategies in these high thromboembolism (TE) risk patients are lacking.[9] The aim of this study was to profile TE incidence in LC patients receiving anti-cancer therapy, exploring patient-, disease- and treatment-related risk factors associated with higher thrombotic rates. This could identify high-risk populations, disease features and/or treatment periods that warrant strong recommendations for targeted preventative strategies to reduce LC-associated TE, and in particular consideration of pharmacological-TP (P-TP).

      Methods
      Retrospective review of LC patients referred to Peter MacCallum Cancer Centre, a tertiary dedicated cancer centre, between 01/07/11 - 30/06/12 for anti-cancer therapy. Data were collected from medical, pharmacy, pathology and diagnostic imaging electronic records. Follow up was defined as time from study entry (referral date) to first occurring event; TE, death, loss to follow-up or study end. Hazard ratios were calculated using Cox proportional hazards model.

      Results
      222 patients were followed for a median 10 months from time of first hospital registration. The cohort was predominantly newly diagnosed (77%), with advanced disease (71%), NSCLC (92%). Among NSCLC adenocarcinoma was the predominant histological subtype (77%). 30% of patients received multiple lines of therapy within the study period; 49% received CHT (alone or combination chemoradiotherapy, CRT), 73% RT (alone or CRT), 19% biologic therapy and 19% surgical intervention. 10.8% of patients had radiologically confirmed TE, giving an incidence rate of 131 events per 1000 person-years (95%CI 87-195). 83% (20/24) of events occurred in the AC setting; 71% symptomatic, 29% asymptomatic. 16 events were pulmonary embolism (PE) (5 fatal), 4 deep vein thrombosis (DVT), 1 combination DVT/PE, 1 atrial and 2 arterial thrombosis. TE occurred frequently in both NSCLC and SCLC (10.8% and 10.5% respectively), and more frequently among patients with adenocarcinoma compared to squamous cell histology (14.7% and 5.3% respectively). Presence of more advanced or metastatic disease, prior history of TE and comorbidity score>2 were associated with higher rates of TE. More than a third (38%) of TE events occurred during the CHT period, 13% post-surgery, 8% during RT and biologic therapy respectively. CHT demonstrated more than five-fold increased TE risk compared to no CHT (HR 5.7 95% CI 2.2-14.8) with a similar finding for RT (HR 5.2 95%CI 2.0-13.2). Importantly, P-TP was not routinely or systematically prescribed for ambulant LC patients during any treatment phase, at this institution.

      Conclusion
      LC patients are at high risk of preventable and potentially life-threatening thrombotic events. TE events occur frequently in the AC setting and consideration of P-TP is warranted, but not used routinely due to a lack of high quality data. There is a demand for appropriate risk-stratification and directed preventative strategies. Prospective data and the development of dynamic risk profiles which can direct clinical practice are needed.

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    P1.08 - Poster Session 1 - Radiotherapy (ID 195)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 1
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      P1.08-012 - Significant association between radiation induced oesophagitis, neutropenia and V20 in patients with non-small cell lung cancer (ID 1518)

      09:30 - 16:30  |  Author(s): D. Ball

      • Abstract

      Background
      Radiation induced oesophagitis (RIO) is frequently associated with high dose thoracic radiation therapy (RT). Although RIO is uncommonly life threatening, it is a distressing toxicity associated with pain, decreased oral intake and can significantly impact on patient’s quality of life. The aim of this retrospective analysis was to assess the rates of acute and late RIO and investigate the association of RIO with radiation dosimetrics and neutropenia.

      Methods
      Criteria for inclusion of patient data included a pathological confirmation of non-small cell lung cancer (NSCLC), treatment with concurrent chemotherapy and radical or high dose palliative RT at our centre between 03/04 and 08/07. Exclusion criteria included previous thoracic RT, RT alone, treatment breaks of > five days, inconsistent radiation dose per fraction and hyper-fractionated RT. Acute and late RIO and neutropenia were scored using the Common Toxicity Criteria for Adverse Events (CTCAE v3.0) criteria. Using Focal (Computerized Medical Systems CMS, St Louis, MO, USA), the outer muscular border of the oesophagus was delineated from the cricoid (superior border) to the gastro-oesophageal junction (inferior border) on CT derived images, using pre-defined soft-tissue window/level settings. Dosimetric data was derived from Xio (CMS) plans (three-dimensional conformal RT (3DCRT) with 6MV photons), including the oesophageal length and volume, maximum and mean doses, percentage of oesophagus receiving 20 to 60 Gy (in 5 Gy increments) and percentage length of oesophagus (whole and partial circumference) receiving 20 to 60 Gy (10 Gy increments). Assessment of potential prognostic factors with respect to acute oesophagitis was done using Wilcoxon rank sum test and Spearman’s correlation. Acute oesophagitis and acute neutropenia reaction were dichotomised as grade 0+1 vs. grade 2+3+4. The association of acute oesophagitis with acute neutropenia was examined using Barnard’s test.

      Results
      The data of 54 patients were eligible for inclusion in this trial. 48 (89%) patients had acute RIO of at least grade 1 (95% CI [78% to 95%]) and five patients (9%) had late RIO of at least grade 1 (95% CI [4% to 20%]). There was a statistically significant correlation between the grade of acute RIO, oesophagus V20 (r=0.303, p=0.026) and length oesophagus receiving 20Gy (whole circumference) (r=0.319, p=0.019). The mean (SD) maximum dose to the oesophagus was 50.2 Gy (18) (r=0.143, p=0.302) and the mean (SD) mean oesophageal dose was 20.8 Gy (10.8) (r=0.269, p=0.049). The maximum grade of acute oesophagitis was significantly associated with acute neutropenia (p=0.035).

      Conclusion
      Acute neutropenia, mean oesophageal dose and the volume and length of oesophagus receiving low radiation doses were significantly associated with acute RIO in our patient cohort. No association was demonstrated between RIO and maximum radiation dose.

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    P2.24 - Poster Session 2 - Supportive Care (ID 157)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Supportive Care
    • Presentations: 1
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      P2.24-045 - Enhancing psychological services for people with lung cancer (ID 2656)

      09:30 - 16:30  |  Author(s): D. Ball

      • Abstract

      Background
      Background: Lung cancer patients have a higher level of disease burden, higher unmet psychosocial needs and lower uptake of psychological services compared with other cancer groups. The Department of Clinical Psychology, in collaboration with the lung cancer service at PeterMac, revised the model of psychological care to optimise access and improve psychosocial well-being.

      Methods
      Method: This revised model of care involved realigning the Psychology Outpatient Clinic to run in parallel with the Lung Outpatient Clinic. The aims were to: 1) provide a timely and early intervention service; 2) increase patient access to psychology services; 3) reduce the burden of accessing psychology services; and 4) assess psychological needs of patients and provide appropriate psychological interventions. Patient demographics, uptake, referral information and session data were collected for a three month period and compared to data from the same period in the previous year.

      Results
      Results: Our sample included a total of 37 patients with lung cancer. The results indicated that the revised model of service delivery led to: a 21% increase in new lung patient referrals for psychology services; an almost 100% uptake of services; and a 186% increase in the number of scheduled sessions attended by lung patients. The main reasons that patients attended sessions were to address mood fluctuations, loss and grief issues, relationship and existential concerns.

      Conclusion
      Conclusion: The revised model made a significant impact on meeting the previously unmet needs of this patient group through providing timely assessments and interventions. This highlights the potential effectiveness of integrating psychology services within medical cancer streams. We received no funding and there was no duality or conflict of interest

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    P3.08 - Poster Session 3 - Radiotherapy (ID 199)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 3
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      P3.08-019 - Visual assessment of the presence of central photopenia on FDG-PET imaging in non-small cell lung cancer (NSCLC) and its prognostic influence on survival in patients treated with radiotherapy. A subset analysis of TROG 99.05. (ID 2513)

      09:30 - 16:30  |  Author(s): D. Ball

      • Abstract

      Background
      Cavitation in NSCLC has anecdotally been associated with worse prognosis and survival. It has been postulated that rapid tumour growth and disordered angiogenesis leads to necrosis, cavitation and central hypoxia, with associated reduction in tumour radiosensitivity. This study investigated central photopenia on FDG-PET imaging (indicating reduced metabolic activity in necrotic areas) as an independent prognostic factor in patients with NSCLC treated by definitive radiotherapy.

      Methods
      Pre-treatment PET images for 172 patients (single institution, enrolled in multicentre prospective observational study TROG 99.05) with pathologically proven stage I-III NSCLC planned for definitive radiotherapy (minimum 50 Gy in 20 fractions) or chemoradiotherapy (93.4%) were independently analysed by two investigators at two time points one month apart. The presence and percent of tumour demonstrating central photopenia were scored using visual assessment. Central photopenia was defined as a non-peripheral volume within the primary tumour with an SUV <40% of the SUVmax. Survival was adjusted for known prognostic factors including performance status, T and N stage.

      Results
      Inter-observer agreement for the presence (Kappa=0.822, p<0.001) and proportion (intraclass correlation coefficient (ICC)=0.913 with 95% CI, 0.862-0.946, p<0.001) of photopenia and were good. Intra-observer reassessment showed fair agreement (Kappa=0.600, p<0.001 and ICC=0.752 with 95% CI, 0.634-0.836, p<0.001). Photopenia, present in 43% of the tumours was associated with larger tumour volumes (mean volume 197.3cm[3 ]vs 56.2cm[3 ]in solid tumours, p<0.001) and weight loss (51% of patients vs 31%, p=0.029). Median survival was shorter in the presence of photopenia but there was no significant difference in overall survival (OS) on univariate (HR=1.25, 95% CI, 0.89-1.77, p=0.200) or multivariate analysis (HR=1.14, 95% CI, 0.80-1.61, p=0.465) after adjusting for stage and performance status. Correlations of OS and the percent of photopenia were not statistically significant. Figure 1

      Conclusion
      The presence and proportion of photopenia on FDG-PET imaging can be reproducibly measured using visual analysis without requiring specialist workstation software. Central photopenia was associated with larger tumours, weight loss, and shorter median survival, but there was no statistically significant effect on overall survival after adjusting for known prognostic factors.

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      P3.08-021 - Patient Specific Quality Assurance for Lung Cancer Stereotactic Ablative Body Radiotherapy (ID 2559)

      09:30 - 16:30  |  Author(s): D. Ball

      • Abstract

      Background
      Hypofractionated image guided radiotherapy of extracranial targets has become increasingly popular as a treatment modality for inoperable patients with one or more small lesions, often referred to as Stereotactic Ablative Body Radiotherapy (SABR). Our institution is using SABR for lung, liver, spine and kidney tumours and is the lead in a multicentre clinical trial of radical SABR for early stage lung cancer. Current and future trends in patient safety and quality assurance (QA) programs are towards ensuring patient safety using the most efficient methods. There is limited published work on patient specific QA for lung SABR treatments on which to base risk management QA programs. Thus, we have performed a review of the first two years of lung SABR patient specific QA process with the aims of highlighting specific areas of uncertainty in lung SABR delivery with the aims of improving efficiency and effectiveness of our QA program. This presentation will detail the results of the review and the evolution of the QA program to a risk-management based approach.

      Methods
      SABR involves one or few fractions of high radiation dose typically delivered in many small fields or arcs. Tight margins are often applied to mobile targets through heterogeneous tissue density with non-coplanar beams. We have conducted thorough QA for individual patients similar to the more common IMRT QA with particular reference to motion management. Individual patient QA was performed in a Perspex phantom (Modus Medical) using a point dose verification and radiochromic film for verification of the dose distribution. The results for the first 33 plans were analysed with the aim of revising QA procedures for future lung SABR plans. The results from these plans were then used to highlight particular areas of delivery uncertainty which require attention during patient specific QA.

      Results
      While individual beams could vary by up to 7%, the total dose in the target was found to be within ±2% of the prescribed dose for all 33 plans. The QA process verified all aspects of the plan delivery including non-coplanar geometry, isocentre accuracy under couch rotation and internal target volume construction. The QA process highlighted the importance of accounting for couch transmission and demonstrated the need for accurate motion management strategies. The review of the first 33 plans lead to the creation of a risk-management based approach to QA of subsequent treatment plans. Particular emphasis is now placed on verification of small field dosimetry and motion management strategies for lesions with large motion.

      Conclusion
      QA is essential for complex radiotherapy deliveries such as SABR. We found individual patient QA helpful in setting up the technique and understanding weak points in the process chain. Ongoing review of the patient specific QA results has lead to improvements in efficiency in the process, facilitating a risk-management based approach to patient specific QA for SABR.

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      P3.08-024 - Preliminary experience in bronchoscopic placement and in-treatment imaging of two different fiducial markers for guidance of lung cancer radiation. (ID 2758)

      09:30 - 16:30  |  Author(s): D. Ball

      • Abstract

      Background
      During conventional radiation therapy, treatment image guidance is largely indirect relying on slow acquisition 3D volumetric imaging or the use of bony surrogates. Fiducial marker placement within/adjacent to lung tumours facilitates image guided radiation therapy by …….. Marker placement has been attempted percutaneously but is associated with pneumothorax in up to 45%, with frequent use of chest drain tubes. Furthermore, in-treatment imaging protocols are not standardized, and the impact of marker characteristics on accuracy of in-treatment imaging has not previously been reported. We describe our preliminary experience in bronchoscopic implantation and in-treatment tracking/imaging of two different types of lung fiducial marker.

      Methods
      Study design: Prospective observational case series of NSCLC patients undergoing radical radiation treatment . Bronchoscopic implantation: performed under conscious sedation using radial probe endobronchial ultrasound and fluoroscopic guidance to achieve tumour localization and placement within/adjacent to peripheral tumours. Post-implantation/ in-treatment imaging: Time-resolved 4D CT (Philips Brilliance+bellows system) for treatment planning and after completion of treatment to investigate marker movement. Throughout treatment delivery MV electronic portal images (EPI) were acquired plus kV planar and Cone Beam CT (CBCT) (Varian Medical System) images.

      Results
      Four patients with T1N0 NSCLC underwent bronchoscopic implantation of fiducial markers (two using Visicoil[TM] linear fiducial 10x0.75mm, two using SuperDimension® superLock™ 2-band 13x0.9mm markers. Confirmation of tumour localization was achieved with EBUS in all four patients. Two markers were placed in adjacent airways in one patient, and the remainder had a single marker placed within/adjacent to their peripheral tumour. No complications related to bronchoscopy or marker implantation were observed. No marker migration was observed over the treatment time for both marker types. Visibility of the markers in EPI was only possibly in selected beam directions though they were easily discernible in kV planar images (Figure 1a). While diagnostic CT scanning was able to demonstrate the markers in great clarity (Figure 1b), they caused significant image artefacts in CBCT. Figure 1 Figure 1: Image-guided radiotherapy images demonstrating: a) 4DCT image showing visicoil fiducial on maximum intensity projection images, tumour+motion contoured in red, & b) kV orthogonal image showing superLock™ 2-band marker.

      Conclusion
      Our preliminary experience indicates bronchoscopic implantation of fiducial markers is safe, and is achievable with a high degree of accuracy on initial imaging, and stability on subsequent in-treatment imaging. There is a fine balance of marker size minimising CBCT artefacts while allowing visualisation in EPI imaging which would be an ideal tool to verify gated radiotherapy delivery.