Sir Peter MacCallum Department of Oncology - Research Publications

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    Long-Term Outcomes of TROG 13.01 SAFRON II Randomized Trial of Single- Versus Multifraction Stereotactic Ablative Body Radiotherapy for Pulmonary Oligometastases
    Siva, S ; Sakyanun, P ; Mai, T ; Wong, W ; Lim, A ; Ludbrook, J ; Bettington, C ; Rezo, A ; Pryor, D ; Hardcastle, N ; Kron, T ; Higgs, B ; Le, H ; Skala, M ; Gill, S ; Eade, T ; Awad, R ; Sasso, G ; Vinod, S ; Montgomery, R ; Ball, D ; Bressel, M (LIPPINCOTT WILLIAMS & WILKINS, 2023-07-01)
    Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.In a randomized phase II clinical trial, the Trans Tasman Radiation Oncology Group compared single- versus multifraction stereotactic ablative body radiotherapy (SABR) in 90 patients with 133 oligometastases to the lung. The study found no differences in safety, efficacy, systemic immunogenicity, or survival between arms, with single-fraction SABR picked as the winner on the basis of cost-effectiveness. In this article, we report the final updated survival outcome analysis. The protocol mandated no concurrent or post-therapy systemic therapy until progression. Modified disease-free survival (mDFS) was defined as any progression not addressable by local therapy, or death. At a median follow-up of 5.4 years, the 3- and 5-year estimates for overall survival (OS) were 70% (95% CI, 59 to 78) and 51% (95% CI, 39 to 61). There were no significant differences between the multi- and single-fraction arms for OS (hazard ratio [HR], 1.1 [95% CI, 0.6 to 2.0]; P = .81). The 3- and 5-year estimates for disease-free survival were 24% (95% CI, 16 to 33) and 20% (95% CI, 13 to 29), with no differences between arms (HR, 1.0 [95% CI, 0.6 to 1.6]; P = .92). The 3- and 5-year estimates for mDFS were 39% (95% CI, 29 to 49) and 34% (95% CI, 24 to 44), with no differences between arms (HR, 1.0 [95% CI, 0.6 to 1.8]; P = .90). In this patient population, where patients receive SABR in lieu of systemic therapy, one-in-three patients are alive without disease in the long term. There were no differences in outcomes by fractionation schedule.
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    Cone-beam computed tomography for lung cancer - validation with CT and monitoring tumour response during chemo-radiation therapy
    Michienzi, A ; Kron, T ; Callahan, J ; Plumridge, N ; Ball, D ; Everitt, S (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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    Lung organ-at-risk volumes: A survey of practice and the need for a consistent definition in the 4DCT era
    Vinod, S ; Choong, C ; Vial, P ; Kron, T ; Ball, D (WILEY, 2020-02)
    INTRODUCTION: In the 4DCT era, the definition of lung organ-at-risk (OAR) volumes for dose-volume histogram (DVH) calculation is unclear, introducing potential for variability in practice. We aimed to identify definitions used clinically and evaluate the magnitude of DVH differences between these. METHODS: We surveyed Australian & New Zealand departments about lung radiotherapy protocols including lung OAR volume definition. We used these definitions to calculate lung DVHs on 10 patients prescribed lung IMRT (60-66 Gy/30-33 fractions). We calculated mean lung dose (MLD), V20 and V30 for 'Lungs - PTV', 'Lungs - CTV', 'Lungs - iGTV' (internal GTV in all respiratory phases) and 'Lungs - GTV_EX' (expiratory phase). RESULTS: The response rate was 39% (34/88). 14% and 29% of departments did not have a departmental protocol for OAR and tumour volume delineation, respectively. All permutations for lung OAR volumes were used with no clear preference. For conventional radiotherapy (n = 27), this included Lungs alone (n = 1), Lungs - PTV (n = 6), Lungs - CTV (n = 2), Lungs - iGTV (n = 6), Lungs - GTV in single phase (n = 5) and individual clinician preference (n = 7). The different lung OAR volumes resulted in MLD difference ranging from 0.9 to 4.15 Gy, V20 from 1.5% to 6.6% and V30 from 1.34% to 7.11%. The largest differences between subtraction of GTV_EX and iGTV were 0.32 Gy, 0.43% and 0.46% for MLD, V20 and V30, respectively. CONCLUSION: A significant number of departments lacked lung cancer radiotherapy contouring protocols. Lung OAR volume definition was variable between and within departments. Potentially clinically significant differences in lung DVH parameters were seen according to the volume used.
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    Single-arm prospective interventional study assessing feasibility of using gallium-68 ventilation and perfusion PET/CT to avoid functional lung in patients with stage III non-small cell lung cancer
    Bucknell, N ; Hardcastle, N ; Jackson, P ; Hofman, M ; Callahan, J ; Eu, P ; Iravani, A ; Lawrence, R ; Martin, O ; Bressel, M ; Woon, B ; Blyth, B ; MacManus, M ; Byrne, K ; Steinfort, D ; Kron, T ; Hanna, G ; Ball, D ; Siva, S (BMJ PUBLISHING GROUP, 2020)
    BACKGROUND: In the curative-intent treatment of locally advanced lung cancer, significant morbidity and mortality can result from thoracic radiation therapy. Symptomatic radiation pneumonitis occurs in one in three patients and can lead to radiation-induced fibrosis. Local failure occurs in one in three patients due to the lungs being a dose-limiting organ, conventionally restricting tumour doses to around 60 Gy. Functional lung imaging using positron emission tomography (PET)/CT provides a geographic map of regional lung function and preclinical studies suggest this enables personalised lung radiotherapy. This map of lung function can be integrated into Volumetric Modulated Arc Therapy (VMAT) radiotherapy planning systems, enabling conformal avoidance of highly functioning regions of lung, thereby facilitating increased doses to tumour while reducing normal tissue doses. METHODS AND ANALYSIS: This prospective interventional study will investigate the use of ventilation and perfusion PET/CT to identify highly functioning lung volumes and avoidance of these using VMAT planning. This single-arm trial will be conducted across two large public teaching hospitals in Australia. Twenty patients with stage III non-small cell lung cancer will be recruited. All patients enrolled will receive dose-escalated (69 Gy) functional avoidance radiation therapy. The primary endpoint is feasibility with this achieved if ≥15 out of 20 patients meet pre-defined feasibility criteria. Patients will be followed for 12 months post-treatment with serial imaging, biomarkers, toxicity assessment and quality of life assessment. DISCUSSION: Using advanced techniques such as VMAT functionally adapted radiation therapy may enable safe moderate dose escalation with an aim of improving local control and concurrently decreasing treatment related toxicity. If this technique is proven feasible, it will inform the design of a prospective randomised trial to assess the clinical benefits of functional lung avoidance radiation therapy. ETHICS AND DISSEMINATION: This study was approved by the Peter MacCallum Human Research Ethics Committee. All participants will provide written informed consent. Results will be disseminated via publications. TRIALS REGISTRATION NUMBER: NCT03569072; Pre-results.
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    Development of a multicentre automated model to reduce planning variability in radiotherapy of prostate cancer
    Panettieri, V ; Ball, D ; Chapman, A ; Cristofaro, N ; Gawthrop, J ; Griffin, P ; Herath, S ; Hoyle, S ; Jukes, L ; Kron, T ; Markham, C ; Marr, L ; Moloney, P ; Nelli, F ; Ramachandran, P ; Smith, A ; Hornby, CJ (ELSEVIER, 2019-07)
    BACKGROUND AND PURPOSE: Inter-institutional studies highlighted correlation between consistent radiotherapy quality and improved overall patient survival. In treatment planning automation has the potential to address differences due to user-experience and training, promoting standardisation. The aim of this study was to evaluate implementation and clinical effect of a multicentre collaboratively-developed automated planning model for Intensity-Modulated Radiation Therapy/Volumetric-Modulated Arc Therapy of prostate. The model was built using a variety of public institutions' clinical plans, incorporating different contouring and dose protocols, aiming at minimising their variation. METHODS AND MATERIALS: A model using 110 clinically approved and treated prostate plans provided by different radiotherapy centres was built with RapidPlan (RP), for use on intact and post-prostatectomy prostate cases. The model was validated, distributed and introduced into clinical practice in all institutions. To investigate its impact a total of 126 patients, originally manually inverse planned (OP), were replanned using RP without additional planner manual intervention. Target and organ-at-risk (OAR) metrics were statistically compared between original and automated plans. RESULTS: For all centres combined and individually, RP provided plans comparable or superior to OP for all dose metrics. Statistically significant reductions with RP were found in bladder (V40Gy) and rectal (V50Gy) low doses (within 2.3% and 3.4% for combined and 4% and 10% individually). No clinically significant changes were seen for the PTV, independently of seminal vesicle inclusion. CONCLUSION: This project showed it is feasible to develop, share and implement RP models created with plans from different institutions treated with a variety of techniques and dose protocols, with the potential of improving treatment planning results and/or efficiency despite the original variability.
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    Systematic endobronchial ultrasound-guided transbronchial needle aspiration improves radiotherapy planning in non-small cell lung cancer
    Cole, AJ ; Hardcastle, N ; Turgeon, G-A ; Thomas, R ; Irving, LB ; Jennings, BR ; Ball, D ; Kron, T ; Steinfort, DP ; Siva, S (European Respiratory Society, 2019-07)
    Objectives: Patients suitable for radical chemoradiotherapy for lung cancer routinely have radiotherapy (planning) volumes based on positron emission tomography (PET)-computed tomography (CT) imaging alone. Endobronchial ultrasound (EBUS)-guided transbronchial needle aspiration (TBNA) can identify PET-occult malignancy and benign PET-avid regions. We investigated the impact of EBUS-TBNA on curative-intent radiotherapy in non-small cell lung cancer (NSCLC). Methods: A prospective multicentre trial was undertaken, investigating the impact of systematic EBUS-TBNA in addition to PET-CT for patients considered for radical chemoradiotherapy with NSCLC. A subset analysis of patients with discordant findings between PET-CT and EBUS-TBNA was performed. Radiotherapy plans investigated tumour coverage and dose to critical organs at risk (OARs) using PET-CT alone in comparison to PET-CT and EBUS-TBNA. Results: Of 30 patients enrolled, 10 had discordant findings between PET-CT and EBUS-TBNA. EBUS-TBNA-derived plans allowed for reduction in dose to OARs in patients downstaged by EBUS-TBNA, and reduced the risk of geographic miss in treating PET-occult disease in four patients where EBUS-TBNA identified malignant involvement of PET-negative lymphadenopathy. With the addition of EBUS-TBNA to radiotherapy planning, reductions were noted of 5.7%, 3.7% and 12.5% for the risks of symptomatic pneumonitis, mean heart dose and mean oesophageal dose, respectively. Conclusions: This study demonstrates for the first time that systematic EBUS-TBNA prior to radical-intent radiotherapy significantly improves coverage of subclinical disease through detection of PET-occult metastases. Identification of false-positive lymph node involvement in highly selected cases may reduce radiation dose to critical structures, and risk of organ toxicity.
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    Safety, Efficacy, and Patterns of Failure After Single-Fraction Stereotactic Body Radiation Therapy (SBRT) for Oligometastases
    Sogono, P ; Bressel, M ; David, S ; Shaw, M ; Chander, S ; Chu, J ; Plumridge, N ; Byrne, K ; Hardcastle, N ; Kron, T ; Wheeler, G ; Hanna, GG ; MacManus, M ; Ball, D ; Siva, S (ELSEVIER SCIENCE INC, 2021-03-01)
    PURPOSE: Fewer attendances for radiation therapy results in increased efficiency and less foot traffic within a radiation therapy department. We investigated outcomes after single-fraction (SF) stereotactic body radiation therapy (SBRT) in patients with oligometastatic disease. METHODS AND MATERIALS: Between February 2010 and June 2019, patients who received SF SBRT to 1 to 5 sites of oligometastatic disease were included in this retrospective study. The primary objective was to describe patterns of first failure after SBRT. Secondary objectives included overall survival (OS), progression-free survival (PFS), high-grade treatment-related toxicity (Common Terminology Criteria for Adverse Events grade ≥3), and freedom from systemic therapy (FFST). RESULTS: In total, 371 patients with 494 extracranial oligometastases received SF SBRT ranging from 16 Gy to 28 Gy. The most common primary malignancies were prostate (n = 107), lung (n = 63), kidney (n = 52), gastrointestinal (n = 51), and breast cancers (n = 42). The median follow-up was 3.1 years. The 1-, 3-, and 5-year OS was 93%, 69%, and 55%, respectively; PFS was 48%, 19%, and 14%, respectively; and FFST was 70%, 43%, and 35%, respectively. Twelve patients (3%) developed grade 3 to 4 treatment-related toxicity, with no grade 5 toxicity. As the first site of failure, the cumulative incidence of local failure (irrespective of other failures) at 1, 3 and 5 years was 4%, 8%, and 8%, respectively; locoregional relapse at the primary was 10%, 18%, and 18%, respectively; and distant failure was 45%, 66%, and 70%, respectively. CONCLUSIONS: SF SBRT is safe and effective, and a significant proportion of patients remain FFST for several years after therapy. This approach could be considered in resource-constrained or bundled-payment environments. Locoregional failure of the primary site is the second most common pattern of failure, suggesting a role for optimization of primary control during metastasis-directed therapy.
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    Monitoring DNA Damage and Repair in Peripheral Blood Mononuclear Cells of Lung Cancer Radiotherapy Patients
    Lobachevsky, PN ; Bucknell, NW ; Mason, J ; Russo, D ; Yin, X ; Selbie, L ; Ball, DL ; Kron, T ; Hofman, M ; Siva, S ; Martin, OA (MDPI, 2020-09)
    Thoracic radiotherapy (RT) is required for the curative management of inoperable lung cancer, however, treatment delivery is limited by normal tissue toxicity. Prior studies suggest that using radiation-induced DNA damage response (DDR) in peripheral blood mononuclear cells (PBMC) has potential to predict RT-associated toxicities. We collected PBMC from 38 patients enrolled on a prospective clinical trial who received definitive fractionated RT for non-small cell lung cancer. DDR was measured by automated counting of nuclear γ-H2AX foci in immunofluorescence images. Analysis of samples collected before, during and after RT demonstrated the induction of DNA damage in PBMC collected shortly after RT commenced, however, this damage repaired later. Radiation dose to the tumour and lung contributed to the in vivo induction of γ-H2AX foci. Aliquots of PBMC collected before treatment were also irradiated ex vivo, and γ-H2AX kinetics were analyzed. A trend for increasing of fraction of irreparable DNA damage in patients with higher toxicity grades was revealed. Slow DNA repair in three patients was associated with a combined dysphagia/cough toxicity and was confirmed by elevated in vivo RT-generated irreparable DNA damage. These results warrant inclusion of an assessment of DDR in PBMC in a panel of predictive biomarkers that would identify patients at a higher risk of toxicity.
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    A prospective observational study of Gallium-68 ventilation and perfusion PET/CT during and after radiotherapy in patients with non-small cell lung cancer
    Siva, S ; Callahan, J ; Kron, T ; Martin, OA ; MacManus, MP ; Ball, DL ; Hicks, RJ ; Hofman, MS (BMC, 2014-10-02)
    BACKGROUND: Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancers, and is the leading cause of cancer deaths. Radiation therapy (RT), alone or in combination with chemotherapy, is the standard of care for curative intent treatment of patients with locally advanced or inoperable NSCLC. The ability to intensify treatment to achieve a better chance for cure is limited by the risk of injury to the surrounding lung. METHODS/DESIGN: This is a prospective observational study of 60 patients with NSCLC receiving curative intent RT. Independent human ethics board approval was received from the Peter MacCallum Cancer Centre ethics committee. In this research, Galligas and Gallium-68 macroaggregated albumin (MAA) positron emission tomography (PET) imaging will be used to measure ventilation (V) and perfusion (Q) in the lungs. This is combined with computed tomography (CT) and both performed with a four dimensional (4D) technique that tracks respiratory motion. This state-of-the-art scan has superior resolution, accuracy and quantitative ability than previous techniques. The primary objective of this research is to observe changes in ventilation and perfusion secondary to RT as measured by 4D V/Q PET/CT. Additionally, we plan to model personalised RT plans based on an individual's lung capacity. Increasing radiation delivery through areas of poorly functioning lung may enable delivery of larger, more effective doses to tumours without increasing toxicity. By performing a second 4D V/Q PET/CT scan during treatment, we plan to simulate biologically adapted RT depending on the individual's accumulated radiation injury. Tertiary aims of the study are assess the prognostic significance of a novel combination of clinical, imaging and serum biomarkers in predicting for the risk of lung toxicity. These biomarkers include spirometry, (18)F-Fluorodeoxyglucose PET/CT, gamma-H2AX signals in hair and lymphocytes, as well as assessment of blood cytokines. DISCUSSION: By correlating these biomarkers to toxicity outcomes, we aim to identify those patients early who will not tolerate RT intensification during treatment. This research is an essential step leading towards the design of future biologically adapted radiotherapy strategies to mitigate the risk of lung injury during dose escalation for patients with locally advanced lung cancer. TRIALS REGISTRATION: Universal Trial Number (UTN) U1111-1138-4421.
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    A Pattern of Early Radiation-Induced Inflammatory Cytokine Expression Is Associated with Lung Toxicity in Patients with Non-Small Cell Lung Cancer
    Siva, S ; MacManus, M ; Kron, T ; Best, N ; Smith, J ; Lobachevsky, P ; Ball, D ; Martin, O ; LEE, YJ (PUBLIC LIBRARY SCIENCE, 2014-10-07)
    PURPOSE: Lung inflammation leading to pulmonary toxicity after radiotherapy (RT) can occur in patients with non-small cell lung cancer (NSCLC). We investigated the kinetics of RT induced plasma inflammatory cytokines in these patients in order to identify clinical predictors of toxicity. EXPERIMENTAL DESIGN: In 12 NSCLC patients, RT to 60 Gy (30 fractions over 6 weeks) was delivered; 6 received concurrent chemoradiation (chemoRT) and 6 received RT alone. Blood samples were taken before therapy, at 1 and 24 hours after delivery of the 1st fraction, 4 weeks into RT, and 12 weeks after completion of treatment, for analysis of a panel of 22 plasma cytokines. The severity of respiratory toxicities were recorded using common terminology criteria for adverse events (CTCAE) v4.0. RESULTS: Twelve cytokines were detected in response to RT, of which ten demonstrated significant temporal changes in plasma concentration. For Eotaxin, IL-33, IL-6, MDC, MIP-1α and VEGF, plasma concentrations were dependent upon treatment group (chemoRT vs RT alone, all p-values <0.05), whilst concentrations of MCP-1, IP-10, MCP-3, MIP-1β, TIMP-1 and TNF-α were not. Mean lung radiation dose correlated with a reduction at 1 hour in plasma levels of IP-10 (r2 = 0.858, p<0.01), MCP-1 (r2 = 0.653, p<0.01), MCP-3 (r2 = 0.721, p<0.01), and IL-6 (r2 = 0.531, p = 0.02). Patients who sustained pulmonary toxicity demonstrated significantly different levels of IP-10 and MCP-1 at 1 hour, and Eotaxin, IL-6 and TIMP-1 concentration at 24 hours (all p-values <0.05) when compared to patients without respiratory toxicity. CONCLUSIONS: Inflammatory cytokines were induced in NSCLC patients during and after RT. Early changes in levels of IP-10, MCP-1, Eotaxin, IL-6 and TIMP-1 were associated with higher grade toxicity. Measurement of cytokine concentrations during RT could help predict lung toxicity and lead to new therapeutic strategies.