Sir Peter MacCallum Department of Oncology - Research Publications
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ItemImaging immunity in patients with cancer using positron emission tomography(NATURE PORTFOLIO, 2022-04-07)Immune checkpoint inhibitors and related molecules can achieve tumour regression, and even prolonged survival, for a subset of cancer patients with an otherwise dire prognosis. However, it remains unclear why some patients respond to immunotherapy and others do not. PET imaging has the potential to characterise the spatial and temporal heterogeneity of both immunotherapy target molecules and the tumor immune microenvironment, suggesting a tantalising vision of personally-adapted immunomodulatory treatment regimens. Personalised combinations of immunotherapy with local therapies and other systemic therapies, would be informed by immune imaging and subsequently modified in accordance with therapeutically induced immune environmental changes. An ideal PET imaging biomarker would facilitate the choice of initial therapy and would permit sequential imaging in time-frames that could provide actionable information to guide subsequent therapy. Such imaging should provide either prognostic or predictive measures of responsiveness relevant to key immunotherapy types but, most importantly, guide key decisions on initiation, continuation, change or cessation of treatment to reduce the cost and morbidity of treatment while enhancing survival outcomes. We survey the current literature, focusing on clinically relevant immune checkpoint immunotherapies, for which novel PET tracers are being developed, and discuss what steps are needed to make this vision a reality.
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ItemBlood-Derived Extracellular Vesicle-Associated miR-3182 Detects Non-Small Cell Lung Cancer Patients(MDPI, 2022-01)With five-year survival rates as low as 3%, lung cancer is the most common cause of cancer-related mortality worldwide. The severity of the disease at presentation is accredited to the lack of early detection capacities, resulting in the reliance on low-throughput diagnostic measures, such as tissue biopsy and imaging. Interest in the development and use of liquid biopsies has risen, due to non-invasive sample collection, and the depth of information it can provide on a disease. Small extracellular vesicles (sEVs) as viable liquid biopsies are of particular interest due to their potential as cancer biomarkers. To validate the use of sEVs as cancer biomarkers, we characterised cancer sEVs using miRNA sequencing analysis. We found that miRNA-3182 was highly enriched in sEVs derived from the blood of patients with invasive breast carcinoma and NSCLC. The enrichment of sEV miR-3182 was confirmed in oncogenic, transformed lung cells in comparison to isogenic, untransformed lung cells. Most importantly, miR-3182 can successfully distinguish early-stage NSCLC patients from those with benign lung conditions. Therefore, miR-3182 provides potential to be used for the detection of NSCLC in blood samples, which could result in earlier therapy and thus improved outcomes and survival for patients.
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ItemImproving radiation therapy for non-small cell lung cancer: molecular imaging and a team-based approach.(Department of Biomedical Imaging, University of Malaya, Malaysia, 2007-01)The successful integration of molecular imaging and radiation therapy has been shown to significantly impact the management of patients with non-small cell lung cancer (NSCLC). The collaboration of multidisciplinary team members, including radiation oncologists, radiation therapists, nuclear medicine physicians and physicists, has enabled PET/CT to be utilised for routine use throughout the radiotherapy treatment trajectory. Applications include disease diagnosis and staging, target volume definition for radiation therapy and monitoring tumour response to treatment. Not only has the adoption of this technology demonstrated benefits for our current patients, it is also opening doors for significant research in the future.
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ItemPlease Place Your Seat in the Full Upright Position: A Technical Framework for Landing Upright Radiation Therapy in the 21st Century(FRONTIERS MEDIA SA, 2022-03-03)Delivering radiotherapy to patients in an upright position can allow for increased patient comfort, reduction in normal tissue irradiation, or reduction of machine size and complexity. This paper gives an overview of the requirements for the delivery of contemporary arc and modulated radiation therapy to upright patients. We explore i) patient positioning and immobilization, ii) simulation imaging, iii) treatment planning and iv) online setup and image guidance. Treatment chairs have been designed to reproducibly position seated patients for treatment and can be augmented by several existing immobilisation systems or promising emerging technologies such as soft robotics. There are few solutions for acquiring CT images for upright patients, however, cone beam computed tomography (CBCT) scans of upright patients can be produced using the imaging capabilities of standard Linacs combined with an additional patient rotation device. While these images will require corrections to make them appropriate for treatment planning, several methods indicate the viability of this approach. Treatment planning is largely unchanged apart from translating gantry rotation to patient rotation, allowing for a fixed beam with a patient rotating relative to it. Rotation can be provided by a turntable during treatment delivery. Imaging the patient with the same machinery as used in treatment could be advantageous for online plan adaption. While the current focus is using clinical linacs in existing facilities, developments in this area could also extend to lower-cost and mobile linacs and heavy ion therapy.
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ItemPredicting muscle loss during lung cancer treatment (PREDICT): protocol for a mixed methods prospective study(BMJ PUBLISHING GROUP, 2021-09)INTRODUCTION: Low muscle mass and low muscle attenuation (radiodensity), reflecting increased muscle adiposity, are prevalent muscle abnormalities in people with lung cancer receiving curative intent chemoradiation therapy (CRT) or radiation therapy (RT). Currently, there is a limited understanding of the magnitude, determinants and clinical significance of these muscle abnormalities in the lung cancer CRT/RT population. The primary objective of this study is to identify the predictors of muscle abnormalities (low muscle mass and muscle attenuation) and their depletion over time in people with lung cancer receiving CRT/RT. Secondary objectives are to assess the magnitude of change in these parameters and their association with health-related quality of life, treatment completion, toxicities and survival. METHODS AND ANALYSIS: Patients diagnosed with lung cancer and planned for treatment with CRT/RT are invited to participate in this prospective observational study, with a target of 120 participants. The impact and predictors of muscle abnormalities (assessed via CT at the third lumbar vertebra) prior to and 2 months post CRT/RT on the severity of treatment toxicities, treatment completion and survival will be assessed by examining the following variables: demographic and clinical factors, weight loss, malnutrition, muscle strength, physical performance, energy and protein intake, physical activity and sedentary time, risk of sarcopenia (Strength, Assistance in walking, Rise from a chair, Climb stairs, Falls history (SARC-F) score alone and with calf-circumference) and systemic inflammation. A sample of purposively selected participants with muscle abnormalities will be invited to take part in semistructured interviews to understand their ability to cope with treatment and explore preference for treatment strategies focused on nutrition and exercise. ETHICS AND DISSEMINATION: The PREDICT study received ethics approval from the Human Research Ethics Committee at Peter MacCallum Cancer Centre (HREC/53147/PMCC-2019) and Deakin University (2019-320). Findings will be disseminated through peer review publications and conference presentations.
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ItemAcute radiation oesophagitis associated with 2-deoxy-2-[18F]fluoro-d-glucose uptake on positron emission tomography/CT during chemo-radiation therapy in patients with non-small-cell lung cancer(WILEY, 2017-10)INTRODUCTION: Acute radiation oesophagitis (ARO) is frequently experienced by patients receiving concurrent chemo-radiation therapy (cCRT) for non-small-cell lung cancer (NSCLC). We investigated ARO symptoms (CTCAE v3.0), radiation dose and oesophageal FDG PET/CT uptake. METHOD: Candidates received cCRT (60 Gy, 2 Gy/fx) and sequential FDG PET/CT (baseline FDG0 , FDGwk2 and FDGwk4 ). Mean and maximum standardized uptake value (SUVmean and SUVmax) and radiation dose (Omean and Omax ) were calculated within the whole oesophagus and seven sub-regions (5-60 Gy). RESULTS: Forty-four patients underwent FDG0 and FDGwk2 , and 41 (93%) received FDGwk4 , resulting in 129 PET/CT scans for analysis. Of 29 (66%) patients with ≥ grade 2 ARO, SUVmax (mean ± SD) increased from FDG0 to FDGwk4 (3.06 ± 0.69 to 3.83 ± 1.27, P = 0.0019) and FDGwk2 to FDGwk4 (3.10 ± 0.75 to 3.83 ± 1.27, P = 0.0046). Radiation dose (mean ± SD) was higher in grade ≥2 patients; Omean (47.5 ± 20 vs 53.9 ± 10.2, P = 0.0061), Omax (13.7 ± 9.6 vs 20.1 ± 10.6, P = 0.0009) and V40 Gy (8.0 ± 8.2 vs 11.9 ± 7.3, P = 0.0185). CONCLUSIONS: FDGwk4 SUVmax and radiation dose were associated with ≥ grade 2 ARO. Compared to subjective assessments, future interim FDG PET/CT acquired for disease response assessment may also be utilized to objectively characterize ARO severity and image-guided oesophageal dose constraints.
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ItemCone-beam computed tomography for lung cancer - validation with CT and monitoring tumour response during chemo-radiation therapy(WILEY, 2017-04)INTRODUCTION: Cone-beam computed tomography (CBCT) is a valuable image-guidance tool in radiation therapy (RT). This study was initiated to assess the accuracy of CBCT for quantifying non-small cell lung cancer (NSCLC) tumour volumes compared to the anatomical 'gold standard', CT. Tumour regression or progression on CBCT was also analysed. METHODS: Patients with Stage I-III NSCLC, prescribed 60 Gy in 30 fractions RT with concurrent platinum-based chemotherapy, routine CBCT and enrolled in a prospective study of serial PET/CT (baseline, weeks two and four) were eligible. Time-matched CBCT and CT gross tumour volumes (GTVs) were manually delineated by a single observer on MIM software, and were analysed descriptively and using Pearson's correlation coefficient (r) and linear regression (R2 ). RESULTS: Of 94 CT/CBCT pairs, 30 patients were eligible for inclusion. The mean (± SD) CT GTV vs CBCT GTV on the four time-matched pairs were 95 (±182) vs 98.8 (±160.3), 73.6 (±132.4) vs 70.7 (±96.6), 54.7 (±92.9) vs 61.0 (±98.8) and 61.3 (±53.3) vs 62.1 (±47.9) respectively. Pearson's correlation coefficient (r) was 0.98 (95% CI 0.97-0.99, ρ < 0.001). The mean (±SD) CT/CBCT Dice's similarity coefficient was 0.66 (±0.16). Of 289 CBCT scans, tumours in 27 (90%) patients regressed by a mean (±SD) rate of 1.5% (±0.75) per fraction. The mean (±SD) GTV regression was 43.1% (±23.1) from the first to final CBCT. CONCLUSION: Primary lung tumour volumes observed on CBCT and time-matched CT are highly correlated (although not identical), thereby validating observations of GTV regression on CBCT in NSCLC.
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ItemA Deep Learning Model to Automate Skeletal Muscle Area Measurement on Computed Tomography Images(FRONTIERS MEDIA SA, 2021-05-07)BACKGROUND: Muscle wasting (Sarcopenia) is associated with poor outcomes in cancer patients. Early identification of sarcopenia can facilitate nutritional and exercise intervention. Cross-sectional skeletal muscle (SM) area at the third lumbar vertebra (L3) slice of a computed tomography (CT) image is increasingly used to assess body composition and calculate SM index (SMI), a validated surrogate marker for sarcopenia in cancer. Manual segmentation of SM requires multiple steps, which limits use in routine clinical practice. This project aims to develop an automatic method to segment L3 muscle in CT scans. METHODS: Attenuation correction CTs from full body PET-CT scans from patients enrolled in two prospective trials were used. The training set consisted of 66 non-small cell lung cancer (NSCLC) patients who underwent curative intent radiotherapy. An additional 42 NSCLC patients prescribed curative intent chemo-radiotherapy from a second trial were used for testing. Each patient had multiple CT scans taken at different time points prior to and post- treatment (147 CTs in the training and validation set and 116 CTs in the independent testing set). Skeletal muscle at L3 vertebra was manually segmented by two observers, according to the Alberta protocol to serve as ground truth labels. This included 40 images segmented by both observers to measure inter-observer variation. An ensemble of 2.5D fully convolutional neural networks (U-Nets) was used to perform the segmentation. The final layer of U-Net produced the binary classification of the pixels into muscle and non-muscle area. The model performance was calculated using Dice score and absolute percentage error (APE) in skeletal muscle area between manual and automated contours. RESULTS: We trained five 2.5D U-Nets using 5-fold cross validation and used them to predict the contours in the testing set. The model achieved a mean Dice score of 0.92 and an APE of 3.1% on the independent testing set. This was similar to inter-observer variation of 0.96 and 2.9% for mean Dice and APE respectively. We further quantified the performance of sarcopenia classification using computer generated skeletal muscle area. To meet a clinical diagnosis of sarcopenia based on Alberta protocol the model achieved a sensitivity of 84% and a specificity of 95%. CONCLUSIONS: This work demonstrates an automated method for accurate and reproducible segmentation of skeletal muscle area at L3. This is an efficient tool for large scale or routine computation of skeletal muscle area in cancer patients which may have applications on low quality CTs acquired as part of PET/CT studies for staging and surveillance of patients with cancer.
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ItemGeographic miss of lung tumours due to respiratory motion: a comparison of 3D vs 4D PET/CT defined target volumes(BMC, 2014-12-16)BACKGROUND: PET/CT scans acquired in the radiotherapy treatment position are typically performed without compensating for respiratory motion. The purpose of this study was to investigate geographic miss of lung tumours due to respiratory motion for target volumes defined on a standard 3D-PET/CT. METHODS: 29 patients staged for pulmonary malignancy who completed both a 3D-PET/CT and 4D-PET/CT were included. A 3D-Gross Tumour Volume (GTV) was defined on the standard whole body PET/CT scan. Subsequently a 4D-GTV was defined on a 4D-PET/CT MIP. A 5 mm, 10 mm, 15 mm symmetrical and 15×10 mm asymmetrical Planning Target Volume (PTV) was created by expanding the 3D-GTV and 4D-GTV's. A 3D conformal plan was generated and calculated to cover the 3D-PTV. The 3D plan was transferred to the 4D-PTV and analysed for geographic miss. Three types of miss were measured. Type 1: any part of the 4D-GTV outside the 3D-PTV. Type 2: any part of the 4D-PTV outside the 3D-PTV. Type 3: any part of the 4D-PTV receiving less than 95% of the prescribed dose. The lesion motion was measured to look at the association between lesion motion and geographic miss. RESULTS: When a standard 15 mm or asymmetrical PTV margin was used there were 1/29 (3%) Type 1 misses. This increased 7/29 (24%) for the 10 mm margin and 23/29 (79%) for a 5 mm margin. All patients for all margins had a Type 2 geographic miss. There was a Type 3 miss in 25 out of 29 cases in the 5, 10, and 15 mm PTV margin groups. The asymmetrical margin had one additional Type 3 miss. Pearson analysis showed a correlation (p < 0.01) between lesion motion and the severity of the different types of geographic miss. CONCLUSION: Without any form of motion suppression, the current standard of a 3D- PET/CT and 15 mm PTV margin employed for lung lesions has an increasing risk of significant geographic miss when tumour motion increases. Use of smaller asymmetric margins in the cranio-caudal direction does not comprise tumour coverage. Reducing PTV margins for volumes defined on 3D-PET/CT will greatly increase the chance and severity of a geometric miss due to respiratory motion. 4D-imaging reduces the risk of geographic miss across the population of tumour sizes and magnitude of motion investigated in the study.
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ItemSpleen Volume Variation in Patients with Locally Advanced Non-Small Cell Lung Cancer Receiving Platinum-Based Chemo-Radiotherapy(PUBLIC LIBRARY SCIENCE, 2015-11-24)There is renewed interest in the immune regulatory role of the spleen in oncology. To date, very few studies have examined macroscopic variations of splenic volume in the setting of cancer, prior to or during therapy, especially in humans. Changes in splenic volume may be associated with changes in splenic function. The purpose of this study was to investigate variations in spleen volume in NSCLC patients during chemo-radiotherapy. Sixty patients with stage I-IIIB NSCLC underwent radiotherapy (60 Gy/30 fractions) for six weeks with concomitant carboplatin/paclitaxel (Ca/P; n = 32) or cisplatin/etoposide (Ci/E; n = 28). A baseline PET/CT scan was performed within 2 weeks prior to treatment and during Weeks 2 and 4 of chemo-radiotherapy. Spleen volume was measured by contouring all CT slices. Significant macroscopic changes in splenic volume occurred early after the commencement of treatment. A significant decrease in spleen volume was observed for 66% of Ca/P and 79% of Ci/E patients between baseline and Week 2. Spleen volume was decreased by 14.2% for Ca/P (p<0.001) and 19.3% for Ci/E (p<0.001) patients. By Week 4, spleen volume was still significantly decreased for Ca/P patients compared to baseline, while for Ci/E patients, spleen volume returned to above baseline levels. This is the first report demonstrating macroscopic changes in the spleen in NSCLC patients undergoing radical chemo-radiotherapy that can be visualized by non-invasive imaging.