Sir Peter MacCallum Department of Oncology - Research Publications

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    Imaging immunity in patients with cancer using positron emission tomography
    Hegi-Johnson, F ; Rudd, S ; Hicks, RJ ; De Ruysscher, D ; Trapani, JA ; John, T ; Donnelly, P ; Blyth, B ; Hanna, G ; Everitt, S ; Roselt, P ; MacManus, MP (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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    Acute 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
    Everitt, S ; Callahan, J ; Obeid, E ; Hicks, RJ ; Mac Manus, M ; Ball, D (WILEY, 2017-10-01)
    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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    Absence of a Relationship between Tumor 18F-fluorodeoxyglucose Standardized Uptake Value and Survival in Patients Treated with Definitive Radiotherapy for Non-Small-Cell Lung Cancer
    Lin, M-Y ; Wu, M ; Brennan, S ; Campeau, M-P ; Binns, DS ; MacManus, M ; Solomon, B ; Hicks, RJ ; Fisher, RJ ; Ball, DL (LIPPINCOTT WILLIAMS & WILKINS, 2014-03-01)
    INTRODUCTION: A recent meta-analysis suggested that patients with non-small-cell lung cancer (NSCLC) whose primary tumors have a higher standardized uptake value (SUV) derived from F-fluorodeoxyglucose positron emission tomography (PET) have a worse prognosis in comparison with those with tumors with lower values. However, previous analyses have had methodological weaknesses. Furthermore, the prognostic significance over the full range of SUV values in patients treated nonsurgically remains unclear. The aim of this retrospective study was to investigate the relationship between survival and maximum SUV (SUV(max)) analyzed as a continuous variable, in patients with NSCLC, staged using PET/computed tomography (CT) and treated with radiotherapy with or without chemotherapy. METHODS: Eligible patients had a histological diagnosis of NSCLC, were treated with radical radiotherapy with or without chemotherapy as their primary treatment, and had pretreatment PET/CT scans. SUV(max), defined as the maximum pixel SUV value retrieved from the primary tumor, was analyzed primarily as a continuous variable for overall survival. RESULTS: Eighty-eight patients met eligibility criteria: stage I, 19; stage II, 10; and stage III, 59. Median SUV(max) was 15.0 (range, 2.5-56). Higher stage was associated with higher SUV(max) values (p = 0.048). In univariate analysis, there was no evidence of a prognostic effect of SUV(max) (hazard ratio per doubling = 0.83; 95% confidence interval, 0.62-1.11; p = 0.22). Analyzing SUV(max) as a dichotomous variable (median cut point = 15.0), the hazard ratio (high: low) for risk of death was 0.71, with p = 0.18 (95% confidence interval, 0.44-1.15). CONCLUSIONS: In this cohort of patients, increasing SUV(max) derived from F-fluorodeoxyglucose-PET/CT was associated with increasing tumor, node, metastasis (TNM) stage. We found no evidence of an association of increasing SUV(max) with a shorter survival. Previous reports of an association between prognosis and SUV(max) may partly be the result of methodological differences between this study and previous reports and an association between stage and SUV(max).
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    Association between radiation pneumonitis and tumor response in patients with NSCLC treated with chemoradiation
    MacManus, MP ; Ball, D ; Hicks, RJ (BIOMED CENTRAL LTD, 2014-10-16)
    Dang and colleagues recently reported in the journal that tumor response to definitive chemoradiation, as assessed using the RECIST criteria, and the risk of radiation pneumonitis were positively correlated in patients with non-small cell lung cancer (NSCLC). We had previously reported similar findings in a study that used positron tomography both to measure tumor response and to assess normal tissue toxicity in patients treated with chemoradiation for NSCLC. Taken together these reports suggest that radiosensitivity of normal tissues and tumors may be strongly linked in a proportion of patients with lung cancer.
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    The utility of (18) F-FDG PET/CT for suspected recurrent breast cancer: impact and prognostic stratification
    Cochet, A ; David, S ; Moodie, K ; Drummond, E ; Dutu, G ; MacManus, M ; Chua, B ; Hicks, RJ (BMC, 2014-04-22)
    BACKGROUND: The incremental value of 18FDG PET/CT in patients with breast cancer (BC) compared to conventional imaging (CI) in clinical practice is unclear. The aim of this study was to evaluate the management impact and prognostic value of 18 F-FDG PET/CT in this setting. METHODS: Sixty-three patients who were referred to our institution for suspicion of BC relapse were retrospectively enrolled. All patients had been evaluated with CI and underwent PET/CT. At a median follow-up of 61 months, serial clinical, imaging and pathologic results were obtained to validate diagnostic findings. Overall Survival (OS) was estimated using Kaplan Meier methods and analyzed using the Cox proportional hazards regression models. RESULTS: Forty-two patients had a confirmed relapse with 37 (88%) positive on CI and 40 (95%) positive on PET/CT. When compared with CI, PET/CT had a higher negative predictive value (86% versus 54%) and positive predictive value (95% versus 70%). The management impact of PET/CT was high (change of treatment modality or intent) in 30 patients (48%) and medium (change in radiation treatment volume or dose fractionation) in 6 patients (9%). Thirty-nine patients (62%) died during follow-up. The PET/CT result was a highly significant predictor of OS (Hazard Ratio [95% Confidence Interval] =4.7 [2.0-10.9] for PET positive versus PET negative for a systemic recurrence; p = 0.0003). In a Cox multivariate analysis including other prognosis factors, PET/CT findings predicted survival (p = 0.005). In contrast, restaging by CI was not significant predictor of survival. CONCLUSION: Our study support the value of 18 F-FDG PET/CT in providing incremental information that influence patient management and refine prognostic stratification in the setting of suspected recurrent breast cancer.
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    Spleen Volume Variation in Patients with Locally Advanced Non-Small Cell Lung Cancer Receiving Platinum-Based Chemo-Radiotherapy
    Wen, SW ; Everitt, SJ ; Bedo, J ; Chabrot, M ; Ball, DL ; Solomon, B ; MacManus, M ; Hicks, RJ ; Moeller, A ; Leimgruber, A ; St-Pierre, Y (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.
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    Durable Complete Remission and Long-Term Survival in FDG-PET Staged Patients with Stage III Follicular Lymphoma, Treated with Wide-Field Radiation Therapy
    MacManus, MP ; Hicks, RJ ; Bressel, M ; Campbell, BA ; Wirth, A ; Ryan, G ; Prince, HM ; Wolf, M ; Brown, R ; Seymour, JF (MDPI, 2020-04-01)
    Advanced-stage follicular lymphoma (FL) is generally considered incurable with conventional systemic therapies, but historic series describe long-term disease-free survival in stage III disease treated with wide-field radiation therapy (WFRT), encompassing all known disease sites. We report outcomes for patients staged with 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) and treated with CT-planned WFRT, given as either comprehensive lymphatic irradiation (CLI) or total nodal irradiation (TNI). This analysis of a prospective cohort includes PET-staged patients given curative-intent WFRT as a component of initial therapy, or as sole treatment for stage III FL. Thirty-three PET-staged patients with stage III FL received WFRT to 24-30Gy between 1999 and 2017. Fifteen patients also received planned systemic therapy (containing rituximab in 11 cases) as part of their primary treatment. At 10 years, overall survival and freedom from progression (FFP) were 100% and 75%, respectively. None of the 11 rituximab-treated patients have relapsed. Nine relapses occurred; seven patients required treatment, and all responded to salvage therapies. A single death occurred at 16 years. The principal acute toxicity was transient hematologic; one patient had residual grade two toxicity at one year. With FDG-PET staging, most patients with stage III FL experience prolonged FFP after WFRT, especially when combined with rituximab.
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    Nodal metabolic tumour volume on baseline F-18-FDG PET/CT and overall survival in stage II and III NSCLC patients undergoing curative-intent chemoradiotherapy/radiotherapy
    Alipour, R ; Bucknell, N ; Bressel, M ; Everitt, S ; MacManus, M ; Siva, S ; Hofman, MS ; Akhurst, T ; Hicks, RJ ; Iravani, A (WILEY, 2021-07-28)
    INTRODUCTION: This study aims to investigate whether nodal metabolic tumour volume (nMTV) and nodal total lesion glycolysis (nTLG) on Fluorine-18 fluoro-deoxy-glucose positron emission tomography-computed tomography (18 F-FDG PET/CT) in inoperable node-positive stage II and III non-small cell lung cancer (NSCLC) are independent predictors of overall survival (OS) in patients undergoing curative-intent chemoradiotherapy/radiotherapy (CRT/RT). METHODS: Data from two prospective trials between 2004 and 2016 were analysed retrospectively. Primary, nodal and total metabolic tumour volume and total lesion glycolysis (pMTV, nMTV, tMTV, pTLG, nTLG and tTLG, respectively) were derived from baseline 18 F-FDG PET/CT. Cox regressions were used to model OS by 18 F-FDG PET/CT parameters adjusting for overall stage. RESULTS: 89 patients with stage II (8%) and stage III (92%) were included. The median age at diagnosis was 67 years; 62% were male. The median follow-up was 6.9 years; the median OS was 2.2 years (95% CI 1.7-3.1). The median pMTV, nMTV and tMTV were 14 mL (range 0-360), 8 mL (range 0-250) and 34 mL (range 3-384), respectively. In 3 patients, the primary lesion could not be delineated from the central hilar mass. There was no association between nMTV (adjusted HR 1.04, 95% CI 0.95-1.15, P-value 0.43), pMTV (adjusted HR 1.0, 95% CI 0.96-1.04, P-value 0.92), tMTV (adjusted HR 1.0, 95% CI 0.97-1.04, P-value 0.88), nTLG, pTLG or tTLG and OS. Consistent results were noted when patients with central hilar lesions were excluded from analysis. CONCLUSION: In node-positive stage II and III NSCLC patients who underwent 18 F-FDG PET/CT-guided target delineation curative-intent concurrent CRT/RT, metabolic parameters did not appear to provide independent prognostication.
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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.