Sir Peter MacCallum Department of Oncology - Research Publications
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ItemNo Preview AvailableLong-Term Outcomes of TROG 13.01 SAFRON II Randomized Trial of Single- Versus Multifraction Stereotactic Ablative Body Radiotherapy for Pulmonary Oligometastases(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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ItemNo Preview AvailableEarly circulating tumor DNA dynamics at the commencement of curative-intent radiotherapy or chemoradiotherapy for NSCLC(ELSEVIER IRELAND LTD, 2023-11)BACKGROUND: The kinetics of circulating tumor DNA (ctDNA) release following commencement of radiotherapy or chemoradiotherapy may reflect early tumour cell killing. We hypothesised that an increase in ctDNA may be observed after the first fraction of radiotherapy and that this could have clinical significance. MATERIALS AND METHODS: ctDNA analysis was performed as part of a prospective, observational clinical biomarker study of non-small cell lung cancer (NSCLC) patients, treated with curative-intent radiotherapy or chemoradiotherapy. Blood was collected at predefined intervals before, during (including 24 h after fraction 1 of radiotherapy) and after radiotherapy/chemoradiotherapy. Mutation-specific droplet digital PCR assays used to track ctDNA levels during and after treatment. RESULTS: Sequential ctDNA results are available for 14 patients with known tumor-based mutations, including in EGFR, KRAS and TP53, with a median follow-up of 723 days (range 152 to 1110). Treatments delivered were fractionated radiotherapy/chemoradiotherapy, in 2-2.75 Gy fractions (n = 12), or stereotactic ablative body radiotherapy (SABR, n = 2). An increase in ctDNA was observed after fraction 1 in 3/12 patients treated with fractionated radiotherapy with a complete set of results, including in 2 cases where ctDNA was initially undetectable. Neither SABR patient had detectable ctDNA immediately before or after radiotherapy, but one of these later relapsed systemically with a high detected ctDNA concentration. CONCLUSIONS: A rapid increase in ctDNA levels was observed after one fraction of fractionated radiotherapy in three cases. Further molecular characterization will be required to understand if a "spike" in ctDNA levels could represent rapid initial tumor cell destruction and could have clinical value as a surrogate for early treatment response and/or as a means of enriching ctDNA for mutational profiling.
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ItemNo Preview AvailableRisk-Directed Ambulatory Thromboprophylaxis in Lung and Gastrointestinal Cancers The TARGET-TP Randomized Clinical Trial(American Medical Association, 2023-11)IMPORTANCE: Thromboprophylaxis for individuals receiving systemic anticancer therapies has proven to be effective. Potential to maximize benefits relies on improved risk-directed strategies, but existing risk models underperform in cohorts with lung and gastrointestinal cancers. OBJECTIVE: To assess clinical benefits and safety of biomarker-driven thromboprophylaxis and to externally validate a biomarker thrombosis risk assessment model for individuals with lung and gastrointestinal cancers. DESIGN, SETTING, AND PARTICIPANTS: This open-label, phase 3 randomized clinical trial (Targeted Thromboprophylaxis in Ambulatory Patients Receiving Anticancer Therapies [TARGET-TP]) conducted from June 2018 to July 2021 (with 6-month primary follow-up) included adults aged 18 years or older commencing systemic anticancer therapies for lung or gastrointestinal cancers at 1 metropolitan and 4 regional hospitals in Australia. Thromboembolism risk assessment based on fibrinogen and d-dimer levels stratified individuals into low-risk (observation) and high-risk (randomized) cohorts. INTERVENTIONS: High-risk patients were randomized 1:1 to receive enoxaparin, 40 mg, subcutaneously daily for 90 days (extending up to 180 days according to ongoing risk) or no thromboprophylaxis (control). MAIN OUTCOMES AND MEASURES: The primary outcome was objectively confirmed thromboembolism at 180 days. Key secondary outcomes included bleeding, survival, and risk model validation. RESULTS: Of 782 eligible adults, 328 (42%) were enrolled in the trial (median age, 65 years [range, 30-88 years]; 176 male [54%]). Of these participants, 201 (61%) had gastrointestinal cancer, 127 (39%) had lung cancer, and 132 (40%) had metastatic disease; 200 (61%) were high risk (100 in each group), and 128 (39%) were low risk. In the high-risk cohort, thromboembolism occurred in 8 individuals randomized to enoxaparin (8%) and 23 control individuals (23%) (hazard ratio [HR], 0.31; 95% CI, 0.15-0.70; P = .005; number needed to treat, 6.7). Thromboembolism occurred in 10 low-risk individuals (8%) (high-risk control vs low risk: HR, 3.33; 95% CI, 1.58-6.99; P = .002). Risk model sensitivity was 70%, and specificity was 61%. The rate of major bleeding was low, occurring in 1 participant randomized to enoxaparin (1%), 2 in the high-risk control group (2%), and 3 in the low-risk group (2%) (P = .88). Six-month mortality was 13% in the enoxaparin group vs 26% in the high-risk control group (HR, 0.48; 95% CI, 0.24-0.93; P = .03) and 7% in the low-risk group (vs high-risk control: HR, 4.71; 95% CI, 2.13-10.42; P < .001). CONCLUSIONS AND RELEVANCE: In this randomized clinical trial of individuals with lung and gastrointestinal cancers who were stratified by risk score according to thrombosis risk, risk-directed thromboprophylaxis reduced thromboembolism with a desirable number needed to treat, without safety concerns, and with reduced mortality. Individuals at low risk avoided unnecessary intervention. The findings suggest that biomarker-driven, risk-directed primary thromboprophylaxis is an appropriate approach in this population. TRIAL REGISTRATION: ANZCTR Identifier: ACTRN12618000811202.
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ItemThe therapeutic relevance of a BRCA2 mutation in a patient with recurrent thymoma: a case report.(AME Publishing Company, 2022)BACKGROUND: Thymomas are characterized by a low tumor mutation burden and a paucity of actionable mutations. Clinical behavior can vary from relatively indolent to very aggressive and impact survival. Platinum-based chemotherapy is the primary treatment modality for inoperable disease and is palliative in intent. Patients with advanced thymoma frequently experience disease recurrence after frontline therapy. Treatment options for relapsed thymoma are relatively limited. A case of recurrent thymoma harboring a breast cancer gene 2 (BRCA2) mutation was presented for multidisciplinary discussion at the International Thymic Malignancy Interest Group (ITMIG) Tumor Board meeting. CASE DESCRIPTION: A 63-year-old female presented with Tumor Node Metastasis (TNM) stage I, World Health Organization (WHO) subtype B1 thymoma at diagnosis and underwent surgical resection. First recurrence occurred in the left costophrenic recess and was treated with preoperative external beam radiotherapy (EBRT), surgical excision, and post-operative chemotherapy. Histology was consistent with WHO subtype B2 thymoma and genomic analysis of the resected tumor detected a BRCA2 mutation. Second recurrence occurred in the mediastinum and bilateral pleurae. Mediastinal disease was treated with EBRT, and the pleural deposits were observed initially. However, upon further progression, the case was discussed at the ITMIG tumor board meeting to determine optimal second line therapy for this patient. CONCLUSIONS: A potential role of poly (ADP-ribose) polymerase (PARP) inhibitors versus cytotoxic chemotherapy for treatment of BRCA2-mutated recurrent thymoma merits discussion. However, due to the absence of data to support the functional and therapeutic significance of BRCA2 mutations in patients with thymoma, the potential for severe toxicity associated with PARP inhibitors, and availability of other safe and effective alternatives, other treatment options should be considered. PARP inhibitors can be considered for treatment of BRCA2-mutated thymomas as part of a clinical trial or when other treatment options have been exhausted.
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ItemA phase III study of radiotherapy with and without continuous-infusion fluorouracil as palliation for non-small-cell lung cancer(NATURE PUBLISHING GROUP, 1997)This study assesses the effect of adding continuous-infusion fluorouracil to palliative thoracic radiation therapy (RT) on the rate and duration of symptom relief in patients with advanced non-small-cell lung cancer (NSCLC). Two hundred eligible patients with NSCLC were randomized to receive either 20 Gy in five daily fractions as palliation for intrathoracic disease or the same RT with concurrent continuous infusion of 1 g m(-2) day(-1) fluorouracil for 5 days. Survival, response and rates of symptom relief in the two groups were compared according to treatment intent, and toxicities were compared according to treatment received. The overall response rate was higher in patients randomized to the combination (29%) than in patients randomized to RT alone (16%) (P = 0.035). However, there were no significant differences between the treatment arms in terms of overall or progression-free survival or in palliation of symptoms. Patients treated with RT plus fluorouracil had significantly more acute toxicity, including nausea and vomiting (P = 0.01), oesophagitis (P = 0.0003), stomatitis (P = 0.0005) and skin reaction (P = 0.003). This study suggests for the first time an interaction between RT and infusional fluorouracil in NSCLC. Although RT plus fluorouracil resulted in a significantly higher response rate than achieved with RT alone, this did not translate into more effective palliation. Because the combination produced significantly more toxicity than RT alone, it is not recommended for the palliative treatment of NSCLC. Nevertheless, these results suggest that opportunities may exist for exploitation of the observed enhancement of antitumour effect in the setting of high-dose radical RT for NSCLC.
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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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ItemPatterns of health services utilization in the last two weeks of life among cancer patients: Experience in an Australian academic cancer center(WILEY, 2017-12)AIM: To report the trend in end-of-life health services (HS) utilization among cancer patients treated in a large Australian academic cancer center over a 12-year period. METHODS: This is a retrospective study of cancer patients treated at the Peter MacCallum Cancer Centre (PMCC), who had documented death between January 2002 and December 2013. Using administrative and billing database, we report on the utilization of different categories of HS within two weeks of death: diagnostic investigations (pathology and radiology), inpatient and outpatient services, and potentially futile interventions (PFI, which include radiotherapy, chemotherapy and surgery). RESULTS: Of the 27 926 "active" cancer patients in the study (i.e. those with medical contact at PMCC in the last year of life), 6368 (23%) had documented HS utilization within two weeks of death. 11% and 9% had pathology and radiology investigations respectively, 14% had outpatient clinic appointments, and 7% had hospital admissions. There were 2654 patients (10%) who had PFI within two weeks of death - 2198 (8%) had radiotherapy, 287 (1%) chemotherapy and 267 (1%) surgery. We observed peak HS and PFI utilization in 2004, which then dropped to its lowest in 2009/2010. CONCLUSION: Experience in an Australian cancer center suggests approximately one in four "active" cancer patients had HS utilization, and one in ten had PFI, within two weeks of death. The implementation of palliative care guidelines may reduce some of these potentially wasteful and futile interventions.
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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.