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M. Macmanus



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    MO17 - Radiotherapy I: Stereotactic Ablative Body Radiotherapy (ID 106)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 1
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      MO17.01 - Response assessment of Stereotactic Ablative Body Radiotherapy (SABR) for pulmonary metastases: utility of 4D-FDG-PET and CT perfusion (ID 2225)

      16:15 - 17:45  |  Author(s): M. Macmanus

      • Abstract
      • Presentation
      • Slides

      Background
      Response assessment using conventional RECIST criteria after SABR of lung targets can be confounded by fibrotic response. The purpose of this study was to evaluate the utility of 4D-FDG-PET/CT and CT perfusion scans in the response assessment of single fraction SABR for inoperable pulmonary oligometastases.

      Methods
      This is a prospective ethics approved clinical study of patients undergoing single fraction SABR with 26Gy for pulmonary metastases. Eligible patients had 1-2 metastases with no extrathoracic disease on staging FDG-PET. Serial 3D / 4D-FDG-PET and CT perfusion studies were performed at baseline, 14 days and 70 days after therapy. Two radiologists independently reported CT perfusion scans.

      Results
      At a median follow-up of 16 months (range 3-27), 10 patients with 13 metastases received SABR. A further 7 patients (41%) were screened from the study due to interval progression of disease between the time of the original FDG-PET and trial 4D-FDG-PET / perfusion CT. The mean time between the original FDG-PET and trial scans was 62 days. No patient progressed locally, 7/10 patients progressed distantly of which 2/7 received subsequent SABR. At the end of study period, 5/10 patients are alive without disease. The median progression free survival was 14 months. The change in SUVmax from baseline was higher on 3D than 4D-PET by a mean of 20.6% (range 0.2%-47.2%) at 14 days and 14.8% (range 0-37.8%) at 70 days. Overall, the SUVmax increased at 14 days (mean 104.9%, p<0.01) and decreased at 70 days (mean=55.5%, p<0.01), despite persistent morphological lesions on the concurrent late timepoint CT. There was strong level of inter-observer agreement of CT perfusion interpretation with a median intraclass correlation coefficient of 89% (range 57%-98%). Perfusion parameters of Time to Peak Blood Flow and Blood Volume showed a median increase of 18.8% and 23.0% at 2 weeks post-therapy and decreased below baseline by a median 7.0% and 14.0% at 70 days (non-significant).

      Conclusion
      High rates of interval progression between staging scans indicates a need to expedite management of oligometastases in a timely fashion. Increased tumour perfusion and FDG-PET intensity at 2 weeks post-RT is likely due to an inflammatory response to large single dose SABR. Late PET response was associated with tumour control despite CT apparent morphological lesions. Conventional 3D PET may overestimate change in PET intensity post SABR as compared to 4D PET. These findings, in particular CT perfusion findings, require a larger patient cohort for validation.

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    MO23 - Radiotherapy II: Lung Toxicity, Target Definition and Quality Assurance (ID 107)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 1
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      MO23.01 - Four-dimensional Gallium-68 perfusion PET/CT scans can improve radiotherapy planning through functional avoidance of lung (ID 2490)

      10:30 - 12:00  |  Author(s): M. Macmanus

      • Abstract
      • Presentation
      • Slides

      Background
      [68]Ga-macroaggregated-albumin ([68]Ga-MAA) perfusion PET/CT is a novel molecular imaging technique for the assessment of functional lung volumes. This prospective study aims to investigate the utility of four-dimensional (4D) [68]Ga-perfusion PET/CT for functional adaptation of radiation therapy (RT) planning in patients with non-small cell lung cancer (NSCLC).

      Methods
      An interim analysis was performed of a prospective clinical study of patients with NSCLC who underwent 4D-perfusion PET/CT scanning prior to curative intent RT. All patients were planned to 60Gy in 30fx with or without concurrent chemotherapy based on conventional anatomical lung volumes. Subsequently, a single nuclear medicine physician in conjunction with a single radiation oncologist contoured the functional ‘perfused’ lung using a visually adapted threshold. Functional lung was defined as lung parenchyma with Ga-MAA uptake. A second volume labeled as ‘high-perfused’ lung was created based on a visually adapted 30% max SUV threshold (figure 1). A single RT planner optimised the 3D conformal radiotherapy plan to spare the functionally ‘perfused’ and ‘high-perfused’ lung volumes respectively. Dose volumetrics were compared using mean lung dose (MLD), V5, V10, V20, V30, V40, V50 and V60 parameters. Figure 1 figure 1 - RT Plans optimised to each of the conventional, 'perfused' and 'high perfused' lung volumes.

      Results
      14 consecutive patients had RT plans adapted to functional lung volumes based on perfusion PET/CT. This patient cohort consisted of ex-smokers with pre-existing airways disease, with a mean FEV1 of 1.87L (0.83L-2.82L) and DLCO of 54% (27%-87%). The average MLD of the original treatment plans was 11.44Gy using conventional anatomical lung measurements. When considering the functional ‘perfused’ lung and ‘high perfused’ lung, the original plan produced an average MLD of 11.12Gy and 12.41Gy respectively. Plans optimized for ‘perfused’ lung only showed significant improvement of the V60 dose parameter (median 1.00Gy, p=0.04). However, plans optimized for ‘high perfused’ lung improved MLD, V30, V40, V50 and V60 (all p-values <0.05). The MLD was improved by a median of 0.86Gy, p<0.01. The largest improvement was found in the V30 parameter, with a median difference of 1.76Gy.

      Conclusion
      This is the first study of [68]Ga perfusion PET/CT for planning the treatment of lung cancer patients. RT plans adapted to ‘high perfused’ but not ‘perfused’ functional lung volumes allows for significant technical improvement of conventional RT for NSCLC patients. The clinical impact of this improvement in planning technique should be validated in the context of a prospective study measuring patient toxicity outcomes.

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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): M. Macmanus

      • 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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    P2.06 - Poster Session 2 - Prognostic and Predictive Biomarkers (ID 165)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.06-036 - DNA Damage Response during Curative Radiotherapy of Non-Small Cell Lung Cancer: In-Vivo Biodosimetry with Peripheral Blood Lymphocytes and Systemic Effects Measured in Hair Follicles (ID 2652)

      09:30 - 16:30  |  Author(s): M. Macmanus

      • Abstract

      Background
      The interactions between radiation dose, toxicity and systemic responses are poorly understood during radiotherapy of patients with NSCLC). The purpose of this study was to monitor DNA damage using the gamma-H2AX assay in tissues inside and outside irradiated volumes of patients with NSCLC.

      Methods
      This prospective ethics approved study assessed 12 patients receiving radiotherapy was planned to 60 Gy in 30 fractions over 6 weeks. Six patients receive concurrent platinum doublet chemotherapy (chemoRT), and six patients had radiotherapy alone. The number, distribution and kinetics of gamma-H2AX foci were compared with the irradiated volume. Lymphocytes and eyebrow hairs were processed for gamma-H2AX staining and microscopy at each of 5 time-points; baseline, 1 and 24 hours post-first fraction, 4 weeks into radiotherapy, and 3 months after treatment completion.

      Results
      The mean irradiated target volume was 384 cm[3] (range 87-1137 cm[3]). We observed the presence of a small subpopulation of lymphocytes with multiple (>5) gamma-H2AX foci at 1-hour post-first fraction. There was no difference in this subpopulation between patients receiving chemoradiotherapy or radiotherapy alone at baseline (p=0.26) nor at 1-hour (p=0.24) There was a strong correlation between the size of this subpopulation and irradiated volume (r=0.84, p<0.01), indicating direct radiation exposure. This suggests potential utility of the gamma-H2AX assay as a human in-vivo biodosimeter. This subpopulation was not detected at 24 hours due to DNA damage repair. A trend for reduction of this subpopulation and the average number of foci in lymphocytes analysed at 4 weeks of radiotherapy suggests an impaired radiation response after multiple radiotherapy fractions. By contrast, the mean number of observed hair follicle gamma-H2AX foci was not different from baseline to 1-hour post first-fraction (p=0.42), elevated at 24 hrs (p=0.10) and 4 weeks (p=<0.01) but was not different from baseline at 3 months (p=0.31). The scattered dose at the eyebrow was recorded at <0.01 Gy per fraction and was insufficient to directly induce the observed gamma-H2AX signal Figure 1 Figure 1 - a brisk DNA damage response in out-of-field eyebrow hair 24-hours post radiation (gamma-H2AX foci in green)

      Conclusion
      The Gamma-H2AX assay on peripheral blood at 1-hour may be a useful as a human in-vivo biodosimeter. To our knowledge, this study is the first report of abscopal DNA damage response in hair follicles associated with radiotherapy in cancer patients. Further validation of our findings on a larger patient cohort is warranted.

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

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 1
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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): M. Macmanus

      • 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.