Sir Peter MacCallum Department of Oncology - Research Publications
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ItemStereotactic ablative body radiotherapy for inoperable primary kidney cancer: a prospective clinical trial(WILEY, 2017-11)OBJECTIVE: To assess the feasibility and safety of stereotactic ablative body radiotherapy (SABR) for renal cell carcinoma (RCC) in patients unsuitable for surgery. Secondary objectives were to assess oncological and functional outcomes. MATERIALS AND METHODS: This was a prospective interventional clinical trial with institutional ethics board approval. Inoperable patients were enrolled, after multidisciplinary consensus, for intervention with informed consent. Tumour response was defined using Response Evaluation Criteria In Solid Tumors v1.1. Toxicities were recorded using Common Terminology Criteria for Adverse Events v4.0. Time-to-event outcomes were described using the Kaplan-Meier method, and associations of baseline variables with tumour shrinkage was assessed using linear regression. Patients received either single fraction of 26 Gy or three fractions of 14 Gy, dependent on tumour size. RESULTS: Of 37 patients (median age 78 years), 62% had T1b, 35% had T1a and 3% had T2a disease. One patient presented with bilateral primaries. Histology was confirmed in 92%. In total, 33 patients and 34 kidneys received all prescribed SABR fractions (89% feasibility). The median follow-up was 24 months. Treatment-related grade 1-2 toxicities occurred in 26 patients (78%) and grade 3 toxicity in one patient (3%). No grade 4-5 toxicities were recorded and six patients (18%) reported no toxicity. Freedom from local progression, distant progression and overall survival rates at 2 years were 100%, 89% and 92%, respectively. The mean baseline glomerular filtration rate was 55 mL/min, which decreased to 44 mL/min at 1 and 2 years (P < 0.001). Neutrophil:lymphocyte ratio correlated to % change in tumour size at 1 year, r2 = 0.45 (P < 0.001). CONCLUSION: The study results show that SABR for primary RCC was feasible and well tolerated. We observed encouraging cancer control, functional preservation and early survival outcomes in an inoperable cohort. Baseline neutrophil:lymphocyte ratio may be predictive of immune-mediated response and warrants further investigation.
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ItemUtility of 68Ga prostate specific membrane antigen - positron emission tomography in diagnosis and response assessment of recurrent renal cell carcinoma(WILEY, 2017-06)INTRODUCTION: Prostate specific membrane antigen (PSMA) positron emission tomography (PET) is an emerging imaging modality in prostate cancer. However, 68 Ga-PSMA-PET may also have diagnostic utility in the setting of renal cell carcinoma (RCC). We investigate the differential role of 18 F-fluorodeoxyglucose (FDG) and PSMA-PET/CT scanning in patients with oligometastatic RCC. In particular, we focus on the utility of PSMA-PET for diagnostic evaluation of isolated or limited metastases planned for local surgery or radiation, as well as the potential utility of PSMA-PET for therapeutic response assessment in patients receiving stereotactic ablative body radiotherapy (SABR). METHODS: We present a retrospective series of eight patients in which comparative imaging modalities are evaluated against PSMA-PET scanning. FDG-PET and PSMA-PET scans were performed prior to definitive treatment (either surgery or SABR) of limited recurrent disease. Response assessment after SABR was performed with both PET imaging modalities at multiple time points in a subset of four patients. RESULTS: Prostate specific membrane antigen uptake is typically more intense than FDG in RCC. In all but two cases, one of which was papillary carcinoma, FDG-PET and PSMA-PET are concordant for detection of sites of disease. We demonstrate for the first time the differential kinetics of post-treatment response using PSMA and FDG-PET, with a more rapid metabolic response observed on FDG-PET. Both modalities demonstrate response earlier than morphological appearances on CT or MRI imaging. CONCLUSIONS: Our series suggests that PSMA shows early promise as a diagnostic and therapeutic response assessment tool in patients with metastatic RCC receiving definitive local therapies.
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ItemLung cancer radiation therapy in Australia and New Zealand: Patterns of practice(WILEY, 2016-10)INTRODUCTION: The RANZCR Faculty of Radiation Oncology Lung Interest Cooperative (FROLIC) surveyed patterns of lung cancer radiation therapy practice for non-small cell (NSCLC) and small cell lung cancer (SCLC) to evaluate current patterns of care and potential for improvement. METHODS: In October 2014, Radiation Oncologists (ROs) from all 62 departments in Australia and New Zealand were invited to a web-based survey directed at those treating lung cancer. Questions covered current radiation therapy practice as well as quality measures. RESULTS: Fifty-eight per cent of respondents used 4D-CT simulation. For curative treatment, 98% employed 3D-CRT and 34% intensity modulated radiotherapy (IMRT) techniques. Treatment verification was primarily performed using cone-beam CT (86%). In NSCLC, the commonest curative dose-fractionation regime was 60 Gy/30# (96%) and for palliative intent, 30 Gy/10# (76%). Forty-four per cent treated patients with stereotactic ablative body radiotherapy (SABR) and half treated central tumours with this technique. In fit patients with synchronous solitary brain metastases, 80% would give radical treatment. For curative-intent SCLC, 45-50.4 Gy/25-28# (61%) and 45 Gy/30#/1.5 Gy b.d. (48%) were used. Ninety-four per cent discussed lung cancer patients at multidisciplinary meetings. Contours were peer-reviewed by 74% and 50% for conventional fractionation and SABR respectively. CONCLUSION: A significant proportion of ROs did not have access to 4D-CT. The majority used 3D image verification and consistently prescribed evidence based doses. A significant number did not participate in peer-review of contours. Practice in IMRT and synchronous oligo-metastatic disease is variable and should be an area of future research. Utilising survey findings, FROLIC is developing consensus recommendations to guide practice.
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ItemThe VAMPIRE challenge: A multi-institutional validation study of CT ventilation imaging(WILEY, 2019-03)PURPOSE: CT ventilation imaging (CTVI) is being used to achieve functional avoidance lung cancer radiation therapy in three clinical trials (NCT02528942, NCT02308709, NCT02843568). To address the need for common CTVI validation tools, we have built the Ventilation And Medical Pulmonary Image Registration Evaluation (VAMPIRE) Dataset, and present the results of the first VAMPIRE Challenge to compare relative ventilation distributions between different CTVI algorithms and other established ventilation imaging modalities. METHODS: The VAMPIRE Dataset includes 50 pairs of 4DCT scans and corresponding clinical or experimental ventilation scans, referred to as reference ventilation images (RefVIs). The dataset includes 25 humans imaged with Galligas 4DPET/CT, 21 humans imaged with DTPA-SPECT, and 4 sheep imaged with Xenon-CT. For the VAMPIRE Challenge, 16 subjects were allocated to a training group (with RefVI provided) and 34 subjects were allocated to a validation group (with RefVI blinded). Seven research groups downloaded the Challenge dataset and uploaded CTVIs based on deformable image registration (DIR) between the 4DCT inhale/exhale phases. Participants used DIR methods broadly classified into B-splines, Free-form, Diffeomorphisms, or Biomechanical modeling, with CT ventilation metrics based on the DIR evaluation of volume change, Hounsfield Unit change, or various hybrid approaches. All CTVIs were evaluated against the corresponding RefVI using the voxel-wise Spearman coefficient rS , and Dice similarity coefficients evaluated for low function lung ( DSClow ) and high function lung ( DSChigh ). RESULTS: A total of 37 unique combinations of DIR method and CT ventilation metric were either submitted by participants directly or derived from participant-submitted DIR motion fields using the in-house software, VESPIR. The rS and DSC results reveal a high degree of inter-algorithm and intersubject variability among the validation subjects, with algorithm rankings changing by up to ten positions depending on the choice of evaluation metric. The algorithm with the highest overall cross-modality correlations used a biomechanical model-based DIR with a hybrid ventilation metric, achieving a median (range) of 0.49 (0.27-0.73) for rS , 0.52 (0.36-0.67) for DSClow , and 0.45 (0.28-0.62) for DSChigh . All other algorithms exhibited at least one negative rS value, and/or one DSC value less than 0.5. CONCLUSIONS: The VAMPIRE Challenge results demonstrate that the cross-modality correlation between CTVIs and the RefVIs varies not only with the choice of CTVI algorithm but also with the choice of RefVI modality, imaging subject, and the evaluation metric used to compare relative ventilation distributions. This variability may arise from the fact that each of the different CTVI algorithms and RefVI modalities provides a distinct physiologic measurement. Ultimately this variability, coupled with the lack of a "gold standard," highlights the ongoing importance of further validation studies before CTVI can be widely translated from academic centers to the clinic. It is hoped that the information gleaned from the VAMPIRE Challenge can help inform future validation efforts.
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ItemRadiotherapy and immunotherapy: a synergistic effect in cancer care(WILEY, 2019-01-14)Radiotherapy is an effective treatment modality commonly used in efforts to cure many localised cancers and in the palliation of symptoms in metastatic cancers. Immunotherapy has revolutionised cancer care by increasing the disease control and overall survival of patients in several cancer types; however, the majority of patients do not respond to currently available therapies based on immune checkpoint inhibitors (ICIs). The benefit of those agents is limited to patients who have a pre-existing active immune microenvironment that can be reactivated by ICIs. It is now recognised that radiotherapy does not only directly kill tumour cells but it also changes the tumour microenvironment, enhancing tumour cell recognition by the immune system and, therefore, acting as an in situ vaccine. Radiotherapy increases expression of tumour-associated antigens, causes the release of cytokines, stimulates recruitment of dendritic cells and, most importantly, stimulates the proliferation and priming of cytotoxic CD8+ T cells in the tumour microenvironment. This immunological cascade specifically generates activated T cells able to induce immunogenic cell death directed against cancer cells bearing those antigens. By its ability to overcome some tumour immune escape mechanisms, radiation provides a non-pharmacological and cost-effective approach to potentially improve the systemic response to immune checkpoints inhibitors.
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ItemThe Emerging Role of Stereotactic Ablative Radiotherapy for Primary Renal Cell Carcinoma: A Systematic Review and Meta-Analysis(ELSEVIER, 2019-11)CONTEXT: Stereotactic ablative radiotherapy (SABR) is an emerging treatment option for primary renal cell carcinoma (RCC). OBJECTIVE: To systematically review the literature on SABR for primary RCC and perform a meta-analysis evaluating local control (LC), toxicity, and renal function. EVIDENCE ACQUISITION: A PROSPERO-registered (#115573), Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA)-based systematic review of the literature was conducted (1995-2019). Studies of SABR targeting primary RCC tumors were included, while those targeting only metastases were excluded. The primary outcome was LC defined as tumor size reduction and/or absence of local progression. Secondary outcomes included toxicity (Common Terminology Criteria for Adverse Events) and renal function (change in estimated glomerular filtration rate [eGFR]). Weighted random-effect meta-analyses using the DerSimonian and Laird method were conducted for primary and secondary outcomes. The I2 statistic and Cochran's Q test were used to assess heterogeneity. EVIDENCE SYNTHESIS: From 2386 PubMed entries and 924 meeting abstracts, 26 studies were identified (11 prospective trials), including 383 tumors in 372 patients, most of whom were deemed inoperable. Weighted averages (ranges) of median follow-up, median age, and mean tumor size were 28.0 (5.8-79.2)mo, 70.4 (62-83)yr, and 4.6 (2.3-9.5)cm, respectively. RCC histology was confirmed in 78.9% of patients who underwent pretreatment biopsy. Dose fractionation varied, but 26Gy in one fraction and 40Gy in five fractions were most common. The random-effect estimates for LC, grade 3-4 toxicity, and post-SABR eGFR change were 97.2% (95% confidence interval [CI]: 93.9-99.5%, I2=20%), 1.5% (95% CI: 0-4.3%, I2=0%), and -7.7ml/min (95% CI: -12.5 to -2.8, I2=2%), respectively, and heterogeneity was minimal. Six patients with pre-existing renal dysfunction (2.9%) required dialysis. CONCLUSIONS: Renal SABR is locally effective and associated with low toxicity rates for primary RCC, despite treatment of larger tumors in older, mostly medically inoperable patients. PATIENT SUMMARY: Stereotactic ablative radiotherapy is a high-precision, noninvasive radiation treatment requiring few outpatient visits, and represents a safe and effective management option for primary renal cell carcinoma.
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ItemDiffusion weighted and dynamic contrast enhanced MRI as an imaging biomarker for stereotactic ablative body radiotherapy (SABR) of primary renal cell carcinoma(PUBLIC LIBRARY SCIENCE, 2018-08-16)PURPOSE: To explore the utility of diffusion and perfusion changes in primary renal cell carcinoma (RCC) after stereotactic ablative body radiotherapy (SABR) as an early biomarker of treatment response, using diffusion weighted (DWI) and dynamic contrast enhanced (DCE) MRI. METHODS: Patients enrolled in a prospective pilot clinical trial received SABR for primary RCC, and had DWI and DCE MRI scheduled at baseline, 14 days and 70 days after SABR. Tumours <5cm diameter received a single fraction of 26 Gy and larger tumours received three fractions of 14 Gy. Apparent diffusion coefficient (ADC) maps were computed from DWI data and parametric and pharmacokinetic maps were fitted to the DCE data. Tumour volumes were contoured and statistics extracted. Spearman's rank correlation coefficients were computed between MRI parameter changes versus the percentage tumour volume change from CT at 6, 12 and 24 months and the last follow-up relative to baseline CT. RESULTS: Twelve patients were eligible for DWI analysis, and a subset of ten patients for DCE MRI analysis. DCE MRI from the second follow-up MRI scan showed correlations between the change in percentage voxels with washout contrast enhancement behaviour and the change in tumour volume (ρ = 0.84, p = 0.004 at 12 month CT, ρ = 0.81, p = 0.02 at 24 month CT, and ρ = 0.89, p = 0.001 at last follow-up CT). The change in mean initial rate of enhancement and mean Ktrans at the second follow-up MRI scan were positively correlated with percent tumour volume change at the 12 month CT onwards (ρ = 0.65, p = 0.05 and ρ = 0.66, p = 0.04 at 12 month CT respectively). Changes in ADC kurtosis from histogram analysis at the first follow-up MRI scan also showed positive correlations with the percentage tumour volume change (ρ = 0.66, p = 0.02 at 12 month CT, ρ = 0.69, p = 0.02 at last follow-up CT), but these results are possibly confounded by inflammation. CONCLUSION: DWI and DCE MRI parameters show potential as early response biomarkers after SABR for primary RCC. Further prospective validation using larger patient cohorts is warranted.
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ItemNo Preview AvailableSystematic endobronchial ultrasound-guided transbronchial needle aspiration improves radiotherapy planning in non-small cell lung cancer(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.