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Introduction: Smoking is a risk factor for the development of lung cancer and reduces life expectancy within the general population. Retrospective studies suggest that non-smokers have better outcomes after treatment for lung cancer. We used a prospective database to investigate relationships between pre-treatment smoking status and survival for a cohort of patients with stage III non-small-cell lung cancer (NSCLC) treated with curative-intent concurrent chemoradiotherapy (CRT)., Methods: All patients treated with CRT for stage III NSCLC at a major metropolitan cancer centre were prospectively registered to a database. A detailed smoking history was routinely obtained at baseline. Kaplan-Meier statistics were used to assess overall survival and progression-free survival in never versus former versus current smokers., Results: Median overall survival for 265 eligible patients was 2.21 years (95 % Confidence Interval 1.78, 2.84). It was 5.5 years (95 % CI 2.1, not reached) for 25 never-smokers versus 1.9 years (95 % CI 1.5, 2.7) for 182 former smokers and 2.2 years (95 % CI 1.3, 2.7) for 58 current smokers. Hazard ratio for death was 2.43 (95 % CI 1.32-4.50) for former smokers and 2.75 (95 % CI 1.40, 5.40) for current smokers, p = 0.006. Actionable tumour mutations (EGFR, ALK, ROS1) were present in more never smokers (14/25) than former (9/182) or current (3/58) smokers. TKI use was also higher in never smokers but this was not significantly associated with superior survival (Hazard ratio 0.71, 95 % CI 0.41, 1.26)., Conclusions: Never smokers have substantially better overall survival than former or current smokers after undergoing CRT for NSCLC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: The TROG 09.02 CHISEL trial compared conventional radiation therapy (CRT) with stereotactic body radiation therapy (SBRT) in patients with inoperable early-stage non-small cell lung cancer. Patients randomized to SBRT had less local failure and improved overall survival. This analysis reports differences in pulmonary function tests (PFTs) and the 6-minute walk test (SMWT) between patients who received SBRT and those who received CRT., Methods and Materials: We analyzed the PFTs and SMWTs of all patients recruited to the CHISEL [trial. During this trial, patients underwent serial PFTs. Linear regression models were used to compare parameters between SBRT and CRT at 3 and 12 months after treatment., Results: One hundred and one patients were enrolled; 33 patients were treated with CRT, 61 were treated with SBRT, and 7 did not receive treatment. Primary tumor size was similar between arms: SBRT 25 mm (standard deviation [SD], 9) and CRT 28 mm (SD, 9). On regression analysis, at 3 and 12 months, there was no evidence of a difference between arms in PFT decline or distance walked in the SMWT. Planning target volume size was significantly larger in the CRT arm, 142.79 cc (SD, 61.14), compared with the SBRT group, 46.15 cc (SD, 23.39). The mean biologically effective dose received by the target was significantly larger in the SBRT group, 125.92 Gy (SD, 21.58), compared with CRT, 65.49 Gy (SD, 6.32). Mean dose to the lungs minus the gross target volume incorporating motion was 8.9 Gy (SD, 2.34) in the CRT group and 4.37 Gy (SD, 1.42) in the SBRT group., Conclusions: Despite the considerably higher biologically effective doses delivered to the tumor in SBRT, there was no difference in decline in respiratory function observed between the 2 groups., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: To report stage-specific patterns of treatment and the influence of management and treatment type on survival rates for people newly diagnosed with small cell lung cancer (SCLC)., Design: Cross-sectional patterns of care study; analysis of data prospectively collected for the Victorian Lung Cancer Registry (VLCR)., Setting, Participants: All people diagnosed with SCLC in Victoria during 1 April 2011 - 18 December 2019., Main Outcome Measures: Stage-specific management and treatment of people with SCLC; median survival time., Results: During 2011-19, 1006 people were diagnosed with SCLC (10.5% of all lung cancer diagnoses in Victoria); their median age was 69 years (interquartile range [IQR], 62-77 years), 429 were women (43%), and 921 were current or former smokers (92%). Clinical stage was defined for 896 people (89%; TNM stages I-III, 268 [30%]; TNM stage IV, 628 [70%]) and ECOG performance status at diagnosis for 663 (66%; 0 or 1, 489 [49%]; 2-4, 174 [17%]). The cases of 552 patients had been discussed at multidisciplinary meetings (55%), 377 people had received supportive care screening (37%), and 388 had been referred for palliative care (39%). Active treatment was received by 891 people (89%): chemotherapy, 843 (84%); radiotherapy, 460 (46%); chemotherapy and radiotherapy, 419 (42%); surgery, 23 (2%). Treatment had commenced within fourteen days of diagnosis for 632 of 875 patients (72%). Overall median survival time from diagnosis was 8.9 months (IQR, 4.2-16 months; stage I-III: 16.3 [IQR, 9.3-30] months; stage IV: 7.2 [IQR, 3.3-12] months). Multidisciplinary meeting presentation (hazard ratio [HR], 0.66; 95% CI, 0.58-0.77), multimodality treatment (HR, 0.42; 95% CI, 0.36-0.49), and chemotherapy within fourteen days of diagnosis (HR, 0.68; 95% CI, 0.48-0.94) were each associated with lower mortality during follow-up., Conclusion: Rates of supportive care screening, multidisciplinary meeting evaluation, and palliative care referral for people with SCLC could be improved. A national registry of SCLC-specific management and outcomes data could improve the quality and safety of care., (© 2023 The Authors. Medical Journal of Australia published by John Wiley & Sons Australia, Ltd on behalf of AMPCo Pty Ltd.)

Despite significant therapeutic advances, lung cancer remains the leading cause of cancer-related death worldwide 1 . Non-small cell lung cancer (NSCLC) patients have a very poor overall five-year survival rate of only 10-20%. Currently, TNM staging is the gold standard for predicting overall survival and selecting optimal initial treatment options for NSCLC patients, including those with curable stages of disease. However, many patients with locoregionally-confined NSCLC relapse and die despite curative-intent interventions, indicating a need for intensified, individualised therapies. Epithelial-to-mesenchymal transition (EMT), the phenotypic depolarisation of epithelial cells to elongated, mesenchymal cells, is associated with metastatic and treatment-refractive cancer. We demonstrate here that EMT-induced protein changes in small extracellular vesicles are detectable in NSCLC patients and have prognostic significance. Overall, this work describes a novel prognostic biomarker signature that identifies potentially-curable NSCLC patients at risk of developing metastatic NSCLC, thereby enabling implementation of personalised treatment decisions., (© 2023. The Author(s).)

Purpose: Medical operability is prognostic for survival after SABR in primary malignancies. This study investigated the prognostic significance of medical operability and total versus subtotal ablation of all oligometastatic disease sites., Methods and Materials: Consecutive patients with 1 to 5 sites of active extracranial oligometastases had medical operability status and presence of subtotal versus total metastatic ablation recorded prospectively in an institutional database. We retrospectively compared overall survival (OS) and progression-free survival (PFS) for medically operable or inoperable patients and patients undergoing total or subtotal metastatic ablation. Secondary endpoints were patterns of failure, high-grade treatment toxic effects (Common Terminology Criteria for Adverse Events version 4.0), and freedom from systemic therapy. The threshold dose per fraction considered ablative was 8 Gy., Results: A total of 401 patients with 530 treated oligometastases were included, with a median follow-up of 3 years. Three hundred and two and 99 patients had metachronous and synchronous presentations of oligometastatic disease, respectively. Common histologies included prostate (24%), lung (18%), gastrointestinal (19%), and breast (11%). More than 90% of doses delivered were Biologically Effective Dose [BED 10 ] ≥60 Gy. Cumulative incidence at 5 years of local-only failure was 6%, local and distant 2%, and distant-only 58%. The 3- and 5-year OS [95% confidence intervals {CIs}] were 68% [62-73] and 54% [47-61], and PFS was 20% [15-25] and 14% [10-20]. The 3- and 5-year freedom from systemic therapy [95% CIs] were 40% [34-46] and 31% [24-37], respectively. Seventy-six patients were inoperable and 325 were operable. Operability status was not prognostic for OS (adjusted hazard ratio [HR], 1.0; 95% CI, 0.6-1.7; P = .9) or for PFS (adjusted HR, 1.1; 95% CI, 0.8-1.6; P = .5). Total metastatic ablation was prognostic for OS (adjusted HR, 0.8; 95% CI, 0.4-0.9; P = .032) and for PFS (adjusted HR, 0.6; 95% CI, 0.4-0.8; P = .003)., Conclusions: Medical operability was not prognostic in patients with oligometastatic disease treated with SABR. Total metastatic ablation was associated with superior OS and PFS compared with subtotal metastatic ablation. Our data support ablation of all sites of oligometastases wherever feasible., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: ImmunoPET is a multicentre, single arm, phase 0-1 study that aims to establish if 89 Zr-durvalumab PET/CT can be used to interrogate the expression of PD-L1 in larger, multicentre clinical trials., Methods: The phase 0 study recruited 5 PD-L1+ patients with metastatic non-small cell lung cancer (NSCLC). Patients received 60MBq/70 kg 89 Zr-durva up to a maximum of 74 MBq, with scan acquisition at days 0, 1, 3 or 5±1 day. Data on (1) Percentage of injected 89 Zr-durva dose found in organs of interest (2) Absorbed organ doses (µSv/MBq of administered 89 Zr-durva) and (3) whole-body dose expressed as mSv/100MBq of administered dose was collected to characterise biodistribution.The phase 1 study will recruit 20 patients undergoing concurrent chemoradiotherapy for stage III NSCLC. Patients will have 89 Zr-durva and FDG-PET/CT before, during and after chemoradiation. In order to establish the feasibility of 89 Zr-durva PET/CT for larger multicentre trials, we will collect both imaging and toxicity data. Feasibility will be deemed to have been met if more than 80% of patients are able complete all trial requirements with no significant toxicity., Ethics and Dissemination: This phase 0 study has ethics approval (HREC/65450/PMCC 20/100) and is registered on the Australian Clinical Trials Network (ACTRN12621000171819). The protocol, technical and clinical data will be disseminated by conference presentations and publications. Any modifications to the protocol will be formally documented by administrative letters and must be submitted to the approving HREC for review and approval., Trial Registration Number: Australian Clinical Trials Network ACTRN12621000171819., Competing Interests: Competing interests: FH-J has clinical trial funding, has received honoraria and participated in advisory boards for Astra Zeneca. She has received payments and honoria from BeiGene and MSD for lectures and presentations. Her work is supported by the Peter Mac Foundation and the Victorian Cancer Agency. SER and PSD are inventors on intellectual property relating to the use of DFOSq that have been licensed from the University of Melbourne to Telix Pharmaceuticals. TJ has received payments and honoraria from BMS and Astra Zeneca for lectures and presentations, and sits on Data Safety and Monitoring Boards or Advisory boards for Roche, BMS, Astra Zeneca, Novartis, Amgen, Puma, MSD and Merck. SF has received payments and honoraria from Astra Zeneca, Roche, Amgen, Novartis, Bayer, GSK, BMS, MSD and Janssen for lectures and presentations. KB has received payments and honoraria from Bayer and Abbvie for lectures and presentations and participates on Data Safety and Monitoring boards for Novartis., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: The aim of this study was to evaluate the diagnostic accuracy of 18 -fluorodeoxyglucose-positron emission tomography ( 18 F-FDG PET) and PET/computed tomography (PET/CT) in imaging primary and metastatic lesions in Ewing sarcoma (ES)., Methods: PubMed, Cochrane, Scopus, and Web of Science were searched for relevant studies. Data concerning 18 F-FDG PET/CT diagnostic accuracy were extracted and then analyzed using Open Meta-analyst software. Reported diagnostic accuracy outcomes included sensitivity, specificity, negative likelihood ratio (NLR), positive likelihood ratio (PLR), and diagnostic odds ratio., Results: Thirty-one studies with a total of 735 patients were included in this meta-analysis. The sensitivity and specificity of 18 F-FDG PET/CT were: 92.6% and 74.1% for total ES lesions, 96.7% and 68.3% for ES primary lesions, 76.1% and 92.4% for lung metastasis, 83.9% and 93.2% for bone metastasis, and 89.9% and 92.6% for ES recurrence, respectively., Conclusion: 18 F-FDG PET/CT is sensitive and accurate in diagnosing, staging, and detecting the recurrence of ES compared with non-PET imaging. It has high accuracy for diagnosing recurrence of ES in bone metastases; however, CT remains a superior diagnostic method for detecting lung metastasis., (© 2021 Wiley Periodicals LLC.)

Competing Interests: FH-J has received clinical trial funding from AstraZeneca. MM declares no competing interests.

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., (© 2021 The Royal Australian and New Zealand College of Radiologists.)

Aims: At diagnosis, <1% of patients with non-small cell lung cancer (NSCLC) have synchronous solitary brain metastasis (SSBM). In prior cohorts without 18-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) staging, definitive treatment to intracranial and intrathoracic disease showed a 5-year overall survival (OS) of 11-21%. We investigated the long-term survival outcomes for patients with SSBM NSCLC, diagnosed in the FDG-PET/CT era and treated definitively with local therapies to both intracranial and intrathoracic sites of disease., Materials and Methods: This retrospective study assessed patients staged with FDG-PET/CT who received definitive lung and SSBM treatment from February 1999 to December 2017. A lung-molecular graded prognostic assessment (lung-molGPA) score was assigned for each patient using age, performance status score, and, where carried out, molecular status. Overall survival and progression-free survival (PFS) were calculated using Kaplan-Meier methods. Cox proportional hazard models determined OS and PFS prognostic factors., Results: Forty-nine patients newly diagnosed with NSCLC and SSBM had a median age of 63 years (range 34-76). The median follow-up of all patients was 3.9 years. Thirty-three patients (67%) had ≥T2 disease, 23 (47%) had ≥N2. At 2 years, 45% of first failures were intracranial only (95% confidence interval 30-59). At 3 and 5 years, OS was 45% (95% confidence interval 32-63) and 30% (95% confidence interval 18-51), respectively. In ≥N1 disease, 5-year OS was 34% (95% confidence interval 18-63). The 3- and 5-year PFS was 8% (95% confidence interval 3-22) and 0%, respectively. Higher lung-molGPA was associated with longer OS (hazard ratio 0.26, 95% confidence interval 0.11-0.61, P = 0.002). Higher lung-molGPA (hazard ratio 0.33, 95% confidence interval 0.15-0.71, P = 0.005) and lower N-stage (hazard ratio 1.56, 95% confidence interval 1.13-2.15, P = 0.007) were associated with longer PFS., Conclusions: Definitive treatment of patients with NSCLC and SSBM staged with FDG-PET/CT can result in 5-year survivors, including those with ≥N1 disease., (Copyright © 2020 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Patients with stage III non-small-cell lung cancer (NSCLC) treated with chemoradiotherapy (CRT) in low- and middle-income countries (LMIC) continue to have a poor prognosis. It is known that FDG PET/CT improves staging, treatment selection and target volume delineation (TVD), and although its use has grown rapidly, it is still not widely available in LMIC. CRT is often used as sequential treatment, but is known to be more effective when given concurrently. The aim of the PERTAIN study was to assess the impact of introducing FDG PET/CT-guided concurrent CRT, supported by training and quality control (QC), on the overall survival (OS) and progression-free survival (PFS) of patients with stage III NSCLC., Methods: The study included patients with stage III NSCLC from nine medical centres in seven countries. A retrospective cohort was managed according to local practices between January 2010 and July 2014, which involved only optional diagnostic FDG PET/CT for staging (not for TVD), followed by sequential or concurrent CRT. A prospective cohort between August 2015 and October 2018 was treated according to the study protocol including FDG PET/CT in treatment position for staging and multimodal TVD followed by concurrent CRT by specialists trained in protocol-specific TVD and with TVD QC. Kaplan-Meier analysis was used to assess OS and PFS in the retrospective and prospective cohorts., Results: Guidelines for FDG PET/CT image acquisition and TVD were developed and published. All specialists involved in the PERTAIN study received training between June 2014 and May 2016. The PET/CT scanners used received EARL accreditation. In November 2018 a planned interim analysis was performed including 230 patients in the retrospective cohort with a median follow-up of 14 months and 128 patients in the prospective cohort, of whom 69 had a follow-up of at least 1 year. Using the Kaplan-Meier method, OS was significantly longer in the prospective cohort than in the retrospective cohort (23 vs. 14 months, p = 0.012). In addition, median PFS was significantly longer in the prospective cohort than in the retrospective cohort (17 vs. 11 months, p = 0.012)., Conclusion: In the PERTAIN study, the preliminary results indicate that introducing FDG PET/CT-guided concurrent CRT for patients with stage III NSCLC in LMIC resulted in a significant improvement in OS and PFS. The final study results based on complete data are expected in 2020.

PET scanning plays key roles in planning the management of patients with lung cancer who are candidates for curative-intent treatment with radiotherapy and has contributed to improvements in survival. 18 F-fluorodeoxyglucose-PET is the most important modality for staging, patient selection, and radiotherapy target volume definition in patients with unresectable non-small cell lung cancer. Developments include the availability of alternative tracers, such as 18 F-fluorothymidine, for imaging proliferation and a range of hypoxia imaging agents. The role of response-adapted therapy, based on interim PET scans performed during the treatment course, is being explored as a way of improving local disease control., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Non-small-cell lung cancer (NSCLC) is a heterogeneous disease comprising not only different histological subtypes but also different molecular subtypes., Aim: To describe the frequency of oncogenic drivers in patients with metastatic NSCLC, the proportion of patients tested and survival difference according to mutation status in a single-institution study., Methods: Metastatic NSCLC patients enrolled in a prospective Thoracic Malignancies Cohort Study between July 2012 and August 2016 were selected. Patients underwent molecular testing for epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK) gene rearrangements, Kirsten rat sarcoma (KRAS), B-Raf proto-oncogene (BRAF) mutations and ROS1 gene rearrangements. Survival was calculated using the Kaplan-Meier method for groups of interest, and comparisons were made using the log-rank test., Results: A total of 392 patients were included, 43% of whom were female with median age of 64 years (28-92). Of 296 patients tested, 172 patients (58%) were positive for an oncogenic driver: 81 patients (27%) were EGFR positive, 25 patients (9%) were ALK positive, 57 patients (19%) had KRAS mutation and 9 patients (3%) were ROS1 or BRAF positive. Patients with an actionable mutation (EGFR/ALK) had a survival advantage when compared with patients who were mutation negative (hazard ratio (HR) 0.49; 95% confidence interval (CI) 0.33-0.71; P < 0.01). Survival difference between mutation negative and mutation status unknown was not statistically significant when adjusted for confounding factors in a multivariate analysis (HR 1.29; 95% CI 0.97-1.78, P = 0.08)., Conclusion: In this prospective cohort, the presence of an actionable mutation was the strongest predictor of overall survival. These results confirm the importance of molecular testing and suggest likely survival benefit of identification and treatment of actionable oncogenes., (© 2017 Royal Australasian College of Physicians.)

Introduction: Non-small-cell lung cancer outcomes are poor but heterogeneous, even within stage groups. To improve prognostic precision we aimed to develop and validate a simple prognostic model using patient and disease variables., Methods: Prospective registry and study data were analysed using Cox proportional hazards regression to derive a prognostic model (hospital 1, n=695), which was subsequently tested (Harrell's c-statistic for discrimination and Cox-Snell residuals for calibration) in two independent validation cohorts (hospital 2, n=479 and hospital 3, n=284)., Results: The derived Lung Cancer Prognostic Index (LCPI) included stage, histology, mutation status, performance status, weight loss, smoking history, respiratory comorbidity, sex, and age. Two-year overall survival rates according to LCPI in the derivation and two validation cohorts, respectively, were 84, 77, and 68% (LCPI 1: score⩽9); 61, 61, and 42% (LCPI 2: score 10-13); 33, 32, and 14% (LCPI 3: score 14-16); 7, 16, and 5% (LCPI 4: score ⩾15). Discrimination (c-statistic) was 0.74 for the derivation cohort, 0.72 and 0.71 for the two validation cohorts., Conclusions: The LCPI contributes additional prognostic information, which may be used to counsel patients, guide trial eligibility or design, or standardise mortality risk for epidemiological analyses.

Background: Primary non-small cell lung cancer cavitation and central photopenia, detected by radiology and FDG-PET scanning respectively, are thought to be the result of tumor necrosis. Such regions may contain hypoxic but viable carcinoma cells which may be relatively radioresistant compared with fully oxygenated regions. We hypothesized that photopenic tumors treated with radiotherapy with or without chemotherapy would be associated with worse survival compared with tumors not showing central photopenia., Patients and Methods: The data were from a prospective trial (TROG 99-05) investigating the prognostic significance of primary tumor volume in patients receiving radical radiotherapy for locoregional non-small cell lung cancer (NSCLC). A subset of patients who had a pre-treatment FDG-PET scan formed the study population. The scans were evaluated by two observers for central photopenia in the primary tumor using a visual scoring system. The relationship of photopenia with survival was determined after adjusting for other prognostic factors., Results: There were 172 eligible patients. The two observers agreed on the presence of photopenia in 90% of cases (Kappa=0.822, p<0.001). Seventy-three patients were scored as having photopenia. Photopenia was not associated with worse survival, either on univariate analysis, or after adjusting for sex, performance status and nodal status (HR=1.20, 95% CI 0.78-1.87, p=0.4) Photopenia was however significantly associated with larger tumor volume and weight loss., Conclusions: This study failed to demonstrate a significantly worse survival associated with central photopenia in patients treated with radiotherapy for NSCLC., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Introduction: We addressed the uncertainty of comorbidity as a prognosticator by evaluating comorbidity and the Simplified Comorbidity Score (SCS) as predictors of overall survival in non-small cell lung cancer (NSCLC)., Methods: A prospective study included patients in whom NSCLC was diagnosed at an Australian cancer hospital between 2012 and 2014. Patients were assessed for SCS at recruitment and followed up every 3 months until death., Results: The cohort included 633 patients; their median age was 67 years (range 28-93), 63% were male, and 86% were ever-smokers. The median SCS at enrolment was 8 (range 0-19); 20% had an SCS higher than 9, and 11% had an SCS of 0. An SCS higher than 9 was associated with male sex, age older than 75 years, an Eastern Cooperative Oncology Group performance status of 2 or higher, and fewer cancer treatments. The 1-year overall survival rate was 62% (95% confidence interval: 58-66). In multivariate analysis, the strongest associations with mortality were metastatic disease (hazard ratio [HR] = 2.8, p < 0.01), Eastern Cooperative Oncology Group performance status of 2 or higher (HR = 2.0, p < 0.01), male sex (HR = 1.6, p < 0.01), more than 10% weight loss at diagnosis (HR = 1.5, p < 0.01), and age older than 75 years (HR = 1.5, p = 0.01). An SCS higher than 9 was not associated with overall survival (HR = 1.0, p = 0.8), and the effect of continuous SCS (HR = 1.1, p < 0.01) was explained by smoking status., Conclusions: In this cohort of patients with NSCLC the SCS was not a clinically significant predictor of overall survival over and above basic patient and disease factors., (Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Purpose: Proliferating bone marrow is exquisitely sensitive to ionizing radiation. Knowledge of its distribution could improve radiation therapy planning to minimize unnecessary marrow exposure and avoid consequential prolonged myelosuppression. [18F]-Fluoro-3-deoxy-3-L-fluorothymidine (FLT)-positron emission tomography (PET) is a novel imaging modality that provides detailed quantitative images of proliferating tissues, including bone marrow. We used FLT-PET imaging in cancer patients to produce an atlas of marrow distribution with potential clinical utility., Methods and Materials: The FLT-PET and fused CT scans of eligible patients with non-small cell lung cancer (no distant metastases, no prior cytotoxic exposure, no hematologic disorders) were reviewed. The proportions of skeletal FLT activity in 10 predefined bony regions were determined and compared according to age, sex, and recent smoking status., Results: Fifty-one patients were studied: 67% male; median age 68 (range, 31-87) years; 8% never smokers; 70% no smoking in the preceding 3 months. Significant differences in marrow distribution occurred between sex and age groups. No effect was detected from smoking in the preceding 3 months. Using the mean percentages of FLT uptake per body region, we created an atlas of the distribution of functional bone marrow in 4 subgroups defined by sex and age., Conclusions: This atlas has potential utility for estimating the distribution of active marrow in adult cancer patients to guide radiation therapy planning. However, because of interindividual variation it should be used with caution when radiation therapy risks ablating large proportions of active marrow; in such cases, individual FLT-PET scans may be required., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Aim: To compare outcomes of single-fraction and multi-fraction stereotactic ablative body radiotherapy (SABR) for pulmonary metastases., Materials and Methods: A retrospective review from two academic institutions of patients with one to three pulmonary metastases staged with (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) scans. For single-fraction SABR, 26 Gy was prescribed for peripheral targets and 18 Gy for central targets. In the multi-fraction cohort, 48 Gy/4 or 50 Gy/5 was prescribed for peripheral targets and 50 Gy/5 was prescribed for central targets. Three-dimensional conformal radiotherapy (3D-CRT), intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc therapy (VMAT) plans were delivered using heterogeneity corrections. Conformity indices at an intermediate dose (R50%) and at a high dose (R100%) were used to assess a relationship with the planning target volume (PTV). Overall survival, local and distant progression and toxicity rates were analysed from the date of treatment completion., Results: Between February 2010 and June 2013, 65 patients with 85 pulmonary metastases were reviewed. The median follow-up was 2.1 years. Metastases most commonly originated from colorectal cancer (31%), followed by non-small cell lung cancer (25%). 3D-CRT was used in 52 targets, IMRT in 21 and VMAT in 12. 3D-CRT showed a lower median R50% (P=0.01), but a higher median R100% than IMRT/VMAT (P=0.04). The R50% index was inversely correlated to the PTV with all techniques (P=0.01). Overall survival at 1 and 2 years in all patients was 93% (95% confidence interval 87-100%) and 71% (95% confidence interval 58-86%), respectively. The 2 year freedom from local and distant progression was 93% (95% confidence interval 86-100%) and 38% (95% confidence interval 27-55%), respectively. There were no significant differences between overall survival (P=0 .14), time to distant progression (P=0.06) or toxicity rates (P=0.75) between single- and multi-fraction cohorts., Conclusion: We report comparable local control, overall survival and toxicity rates between single-fraction and multi-fraction SABR treatments in patients with FDG-PET-staged pulmonary oligometastases. We propose a guideline for R50% conformity incorporating 3D-CRT/IMRT/VMAT techniques with heterogeneity corrected planning algorithms., (Copyright © 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

(18)F-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) plays a key role in the evaluation of undiagnosed lung nodules, when primary lung cancer is strongly suspected, or when it has already been diagnosed by other techniques. Although technical factors may compromise characterization of small or highly mobile lesions, lesions without apparent FDG uptake can generally be safely observed, whereas FDG-avid lung nodules almost always need further evaluation. FDG-PET/CT is now the primary staging imaging modality for patients with lung cancer who are being considered for curative therapy with either surgery or definitive radiation therapy., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Molecular imaging with positron emission tomography (PET) has dramatically changed the management of patients with lung cancer who are treated with radiotherapy. Uptake of the most widely used PET radiopharmaceutical (18)F-fluorodeoxyglucose identifies lung nodules or intrathoracic lymph nodes as likely to be malignant and frequently identifies previously unsuspected sites of malignant disease outside the thorax. Patients with non-small cell lung cancer, especially those with apparently more advanced locoregional disease to start with, are often upstaged, and this has a profound effect on their subsequent management. Better patient selection, primarily by excluding patients with PET-detected advanced disease, and better targeting of radiotherapy to avoid geographic miss have contributed significantly to improvements in outcome in recent series of patients treated with definitive chemoradiation. Advances in motion management with 4-dimensional PET/computed tomography and research into sequential imaging during treatment to permit response-adapted therapy hold promise for further improvements in treatment outcomes. Research involving novel PET tracers that can characterize biological properties of tumors, such as proliferation or hypoxia, may help develop more personalized approaches to patient management in the future., (Copyright © 2015 Elsevier Inc. All rights reserved.)

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.

Purpose: The purpose of this study was to report the opinions and self-reported practices of clinicians, as well as the availability of decision support tools, regarding appropriate thromboprophylaxis for patients with lung cancer to identify variation in practice and/or divergence from evidence-based clinical practice guidelines (CPG)., Methods: A computer-generated survey (SurveyMonkey software) was distributed to surgical, radiation and medical oncologists with lung cancer specialisation, via membership of the Australian Lung Cancer Trials Group (ALTG) from May to September 2013., Results: Seventy-two clinicians, from public, private, specialist and general hospitals, completed the survey (46% response rate). Hospital-endorsed CPG were widely available (91%); however, these routinely lacked robust recommendations for the ambulatory care setting (98%) and risk stratification tools (65%). Clinicians consistently identified ambulatory care treatment modalities (chemotherapy, alone or in combination with radiotherapy) as having similar (high) thrombotic risk as surgery. Timing and duration of pharmacological thromboprophylaxis prescribing among surgical oncologists varied and were divergent from guideline recommendations. Fifty-eight percent of surveyed clinicians cited a lack of high-quality data to guide preventative strategies in lung cancer patients., Conclusion: Clinicians consistently identified patients with lung cancer as having a high thromboembolic risk in both ambulatory and surgical settings, but with differences in recommendations and variation in practice. CPG lacked robust recommendations for the ambulatory care setting, the main arena for the multimodality lung cancer treatment paradigm.

Unlabelled: We aimed to prospectively observe cellular metabolism and proliferation in patients with non-small-cell lung cancer (NSCLC) during radical chemoradiation therapy using serial PET/CT with (18)F-FDG and 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT)., Methods: Twenty patients with stage I-III NSCLC and candidates for radical chemoradiation therapy (60 Gy in 30 fractions over 6 wk) were recruited. (18)F-FDG and (18)F-FLT PET/CT were performed at baseline and during therapy (weeks 2 and 4). Tumor response was assessed semiquantitatively and using visual response criteria., Results: The median and range for primary tumor volume (cm(3)) at baseline on (18)F-FDG were 28 and 2-241, respectively, and on (18)F-FLT 31 and 2-184, respectively. At week 2, (18)F-FDG was 26 (range, 2-164), and (18)F-FLT was 11 (range, 0-111). At week 4, (18)F-FDG was 19 (1-147), and (18)F-FLT was 7 (0-48). The median and range of maximum standardized uptake value (SUVmax) at baseline on (18)F-FDG were 14 and 4-31, respectively, and on (18)F-FLT 6 and 2-12, respectively. Week 2 (18)F-FDG median SUVmax was 10 (2-31), and (18)F-FLT median SUVmax was 3 (1-15); week 4 (18)F-FDG median SUVmax was 10 (2-15), and (18)F-FLT median SUVmax was 2 (2-9). There was fair agreement between visual tumor response on (18)F-FDG and (18)F-FLT during therapy (Cohen's unweighted κ statistic, 0.27 at week 2 and 0.355 at week 4). Cerebral metastases were detected on 1 baseline (18)F-FLT scan, resulting in palliative management. Progressive disease was detected on week 2 scans in 3 patients, resulting in changes to radiation therapy (2 patients) and treatment intent (1 patient)., Conclusion: This study demonstrates that (18)F-FLT PET/CT is a more sensitive tracer of early treatment response than (18)F-FDG PET/CT. The ability of these tracers to detect distinct biologic processes may lead to their use as biomarkers for personalized radiation therapy and prognosis in the future., (© 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Unlabelled: Historically, it has been difficult to monitor the acute impact of anticancer therapies on hematopoietic organs on a whole-body scale. Deeper understanding of the effect of treatments on bone marrow would be of great potential value in the rational design of intensive treatment regimens. 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) is a functional radiotracer used to study cellular proliferation. It is trapped in cells in proportion to thymidine-kinase 1 enzyme expression, which is upregulated during DNA synthesis. This study investigates the potential of (18)F-FLT to monitor acute effects of chemotherapy on cellular proliferation and its recovery in bone marrow, spleen, and liver during treatment with 2 different chemotherapy regimens., Methods: Sixty patients with non-small cell lung cancer underwent concurrent radical chemoradiotherapy to 60 Gy in 6 wk with either cisplatin/etoposide (C/E, n = 28) weeks 1 and 5 or weekly carboplatin/paclitaxel (C/P, n = 32) regimens. (18)F-FLT and (18)F-FDG PET with CT were performed at baseline, week 2 (day 9 for (18)F-FLT and day 10 for (18)F-FDG PET), and week 4 (day 23 for (18)F-FLT and day 24 for (18)F-FDG PET). Visual and semiquantitative standardized uptake value (SUV) measurements were performed in bone marrow outside the radiotherapy field, liver, spleen, and small bowel. These were correlated to blood counts and smears in a subset of patients., Results: The C/E group exhibited a drop in bone marrow (18)F-FLT uptake at week 2 (median SUVmax [maximum SUV] decrease to 31%, 8.7-6.0, P < 0.001), with recovery at week 4, reflecting the absence of chemotherapy between these times. By contrast, the weekly C/P group showed gradually declining bone marrow uptake (P > 0.05). Spleen uptake in both cohorts decreased at week 2, with intense rebound activity at week 4 (SUVmax week 4 at 58% above baseline: 2.4-3.8, for C/E, respectively, 30% for C/P: 2.7-3.5, P < 0.001). Liver uptake changed little. (18)F-FLT changes preceded neutrophil count reductions. (18)F-FDG uptake in marrow liver and spleen changed much less than (18)F-FLT., Conclusion: (18)F-FLT imaging may be used to quantify impairment and recovery of bone marrow by specific chemotherapy regimens and may also enable imaging of organ-specific processes such as spleen activation. (18)F-FLT is superior to (18)F-FDG for this purpose. This technology may support novel treatment planning and monitoring approaches in oncology patients., (© 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Introduction: Thromboembolism is common in lung cancer. Current thromboprophylaxis guidelines lack specific recommendations for appropriate strategies in this high thrombotic risk patient cohort. We profiled lung cancer patients receiving anti-cancer therapy. Thromboembolism incidence and thromboembolism-related mortality rates are reported and we explored patient, disease, and treatment-related risk factors associated with higher thrombotic rates., Methods: Retrospective review of lung cancer patients referred to a Comprehensive Cancer Centre between 01/07/2011 and 30/06/2012 for anti-cancer therapy. Data were collected from medical, pharmacy, pathology and diagnostic imaging electronic records., Results: After a median follow up of 10 months (range: 0.03-32 months), 24/222 patients (10.8%) had developed radiologically confirmed thromboembolism; 131 events per 1000 person-years (95%CI 87-195). Thromboembolism occurred equally in patients with non-small cell and small cell lung cancer (10.8% and 10.5% respectively), and more frequently among patients with adenocarcinoma compared to squamous cell carcinoma (14.7% and 5.3% respectively). Chemotherapy-treated patients experienced thromboembolism more often than patients who did not receive chemotherapy (HR 5.7 95%CI 2.2-14.8). Radiotherapy was also associated with more frequent thromboembolism (HR 5.2 95%CI 2.0-13.2). New lung cancer diagnosis, presence of metastatic disease, second primary malignancy and Charlson Index ≥ 5 were also associated with higher rates of thromboembolism. Importantly, pharmacological thromboprophylaxis (P-TP) was not routinely or systematically prescribed for ambulant lung cancer patients during any treatment phase, at this institution. The majority (83%) of thromboembolic events occurred in the ambulatory care setting., Conclusion: Morbidity and mortality from thromboembolism occurs frequently in lung cancer. Thromboprophylaxis guidelines should be developed for the ambulatory care setting., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background and Purpose: The integration of positron emission tomography (PET) information for target volume delineation in radiation treatment planning is routine in many centers. In contrast to automatic contouring, research on visual-manual delineation is scarce. The present study investigates the dependency of manual delineation on experience and qualification., Patients and Methods: A total of 44 international interdisciplinary observers each defined a [(18)F]fluorodeoxyglucose (FDG)-PET based gross tumor volume (GTV) using the same PET/CT scan from a patient with lung cancer. The observers were "experts" (E; n = 3), "experienced interdisciplinary pairs" (EP; 9 teams of radiation oncologist (RO) + nuclear medicine physician (NP)), "single field specialists" (SFS; n = 13), and "students" (S; n = 10). Five automatic delineation methods (AM) were also included. Volume sizes and concordance indices within the groups (pCI) and relative to the experts (eCI) were calculated., Results: E (pCI = 0.67) and EP (pCI = 0.53) showed a significantly higher agreement within the groups as compared to SFS (pCI = 0.43, p = 0.03, and p = 0.006). In relation to the experts, EP (eCI = 0.55) showed better concordance compared to SFS (eCI = 0.49) or S (eCI = 0.47). The intermethod variability of the AM (pCI = 0.44) was similar to that of SFS and S, showing poorer agreement with the experts (eCI = 0.35)., Conclusion: The results suggest that interdisciplinary cooperation could be beneficial for consistent contouring. Joint delineation by a radiation oncologist and a nuclear medicine physician showed remarkable agreement and better concordance with the experts compared to other specialists. The relevant intermethod variability of the automatic algorithms underlines the need for further standardization and optimization in this field.

Introduction: The purpose of this study is to assess the impact of a vacuum immobilisation system on reproducibility of patient set-up, interfraction stability and tumour motion amplitude., Methods: From February 2010 to February 2012 as part of a prospective clinical trial 12 patients with solitary pulmonary metastases had consecutive four-dimensional computed tomography (4DCT) scans performed with and without vacuum immobilisation. The displacement of the tumour centroid position was recorded in each of the 10 phases of the 4DCT reconstruction. A further six patients with seven metastases underwent single fraction stereotactic ablative body radiotherapy (SABR) during this period (a total of 19 targets) and were included in an analysis of positional reproducibility and intrafraction immobilisation. Couch shifts recorded in the medio-lateral (X), cranio-caudal (Y) and ventero-dorsal (Z) planes., Results: For the 19 treatments delivered, the median (0-90% range) shift required immediately pretreatment was 1 mm (0-3) in the X-plane, 2 mm (0-6) in the Y-plane and 4 mm (0-8) in the Z-plane, respectively. The mean (+/- standard deviation) of mid-treatment shifts were 0.3 mm (+/- 0.7), 1.1 mm (+/- 2) and 0.8 mm (+/- 1.5) in the X, Y and Z planes, respectively. Mid-treatment shifts were <2 mm in all directions (P = < 0.001). The length of treatment time correlated to the required shifts in the Z plane (r(2)  = 0.377, P = 0.005), but not in the X or Y planes (P = 0.198 and P = 0.653, respectively). In the subset of 12 patients who had two 4DCTs, the median (range) amplitude of tumour displacements in the X, Y and Z planes when immobilised were 0.9 mm (0.3-2.9), 2.6 mm (0.2-10.6) and 1.6 mm (0.5-5.5), respectively. Immobilisation reduced the volume of tumour displacement during respiration by a median of 52.6% (P = 0.021)., Conclusions: Vacuum immobilisation reduces total tumour excursion, facilitates reproducible positioning and provides robust intrafractional immobilisation during SABR treatments for pulmonary metastases., (© 2013 The Royal Australian and New Zealand College of Radiologists.)

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).

Introduction: The Peter MacCallum Cancer Centre has established a stereotactic lung radiosurgery program for the treatment of isolated lung metastases. The aim of this study was to critically assess the technical feasibility of performing stereotactic lung radiosurgery in an Australian institution., Methods: A single 26-Gy fraction of radiotherapy was delivered to patients with positron emission tomography (PET) staged solitary lung metastases. Motion management was addressed using four-dimensional computed tomographic simulation, and cone beam CT (CBCT) online soft-tissue matching. Treatments were with multiple coplanar and non-coplanar asymmetric beams. Patients were immobilised in a dedicated stereotactic body cradle. Quality assurance (QA) of treatment plans with both ion chamber and film measurements was performed accounting for patient-specific respiratory motion., Results: Between February 2010 and February 2011, nine patients received stereotactic lung radiosurgery. One grade 1 toxicity and one grade 2 toxicity were recorded after treatment. The mean planning target volume was 22.6 cc. A median of eight beams were delivered per treatment plan (range 7-10) with a median of two non-coplanar beams (range 0-6). At treatment plan QA, the difference between planned and delivered dose was ≤1.76% in all static and dynamic ion chamber recordings. A mid-treatment CBCT was performed at a median time of 21 min, with the mean displacement discrepancy from initial set-up being 0.4 mm (range 0-2 mm)., Conclusions: Stereotactic radiosurgery to the lung was both feasible and tolerable at our institution. Intrafractional immobilisation within 2 mm was reproducible. Excellent concordance between planned and delivered treatments was achieved in the phantom QA., (© 2012 The Authors. Journal of Medical Imaging and Radiation Oncology © 2012 The Royal Australian and New Zealand College of Radiologists.)

Accurate delineation of the primary tumor and of involved lymph nodes is a key requisite for successful curative radiotherapy in non-small cell lung cancer (NSCLC). In recent years, it has become clear that the incorporation of FDG PET-CT scan information into the related processes of patient selection and radiotherapy planning has lead to significant improvements for patients with NSCLC. The use of FDG PET-CT information in radiotherapy planning allows better target volume definition, reduces inter-observer variability and encourages selective irradiation of involved mediastinal lymph nodes. PET-CT also opens the door for innovative radiotherapy delivery and the development of new concepts. However, care must be taken to avoid a variety of technical pitfalls and specific education is necessary, for clinicians and physicists alike., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: The authors studied growth and progression of untreated nonsmall cell lung cancer (NSCLC) by comparing diagnostic and radiotherapy (RT) planning fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) scans before proposed radical chemo-RT., Methods: Patients enrolled on a prospective clinical trial were eligible for this analysis if they underwent 2 pretreatment whole body FDG-PET/CT scans, >7 days apart. Scan 1 was performed for diagnosis/disease staging and scan 2 for RT planning. Interscan comparisons included disease stage, metabolic characteristics, tumor doubling times, and change in treatment intent., Results: Eighty-two patients underwent planning PET/CT scans between October 2004 and February 2007. Of these, 28 patients (61% stage III, 18% stage II) had undergone prior staging PET/CT scans. The median interscan period was 24 days (range, 8-176 days). Interscan disease progression (TNM stage) was detected in 11 (39%) patients. The probability of upstaging within 24 days was calculated to be 32% (95% confidence interval [CI], 18%-49%). Treatment intent changed from curative to palliative in 8 (29%) cases, in 7 because of PET. For 17 patients who underwent serial PET/CT scans under standardized conditions, there was a mean relative interscan increase of 19% in tumor maximum standardized uptake value (SUV) (P=.022), 16% in average SUV (P=.004), and 116% in percentage injected dose (P=.002). Estimated doubling time of FDG avid tumor was 66 days (95% CI, 51-95 days)., Conclusions: Rapid tumor progression was detected in patients with untreated, predominantly stage III, NSCLC on serial FDG-PET/CT imaging, highlighting the need for prompt diagnosis, staging, and initiation of therapy in patients who are candidates for potentially curative therapy., (Copyright © 2010 American Cancer Society.)

Purpose: Positron emission tomography/computed tomography (PET/CT) is increasingly used for delineating gross tumor volume (GTV) in non-small-cell lung cancer (NSCLC). The methodology for contouring tumor margins remains controversial. We developed a rigorous visual protocol for contouring GTV that uses all available clinical information and studied its reproducibility in patients from a prospective PET/CT planning trial., Methods and Materials: Planning PET/CT scans from 6 consecutive patients were selected. Six "observers" (two radiation oncologists, two nuclear medicine physicians, and two radiologists) contoured GTVs for each patient using a predefined protocol and subsequently recontoured 2 patients. For the estimated GTVs and axial distances, least-squares means for each observer and for each case were calculated and compared, using the F test and pairwise t-tests. In five cases, tumor margins were also autocontoured using standardized uptake value (SUV) cutoffs of 2.5 and 3.5 and 40% SUV(max)., Results: The magnitude of variation between observers was small relative to the mean (coefficient of variation [CV] = 3%), and the total variation (intraclass correlation coefficient [ICC] = 3%). For estimation of superior/inferior (SI), left/right (LR), and anterior/posterior (AP) borders of the GTV, differences between observers were also small (AP, CV = 2%, ICC = 0.4%; LR, CV = 6%, ICC = 2%; SI, CV 4%, ICC = 2%). GTVs autocontoured generated using SUV 2.5, 3.5, and 40% SUV(max) differed widely in each case. An SUV contour of 2.5 was most closely correlated with the mean GTV defined by the human observers., Conclusions: Observer variation contributed little to total variation in the GTV and axial distances. A visual contouring protocol gave reproducible results for contouring GTV in NSCLC., (Copyright 2010 Elsevier Inc. All rights reserved.)

Introduction: Hypofractionated stereotactic body radiotherapy (SBRT) is an emerging noninvasive technique for the treatment of oligometastatic cancer. The use of small numbers of large doses, should in theory, achieve high rates of local control. The aim of this literature review is to critically assess the use of SBRT for the treatment of pulmonary metastases as judged by its effect on local control, survival, and toxicity., Methods: A systematic literature search was performed. Both single fraction stereotactic radiosurgery (SRS) and hypofractionated radiotherapy (SBRT) were considered individually. Thirteen institutions reported results regarding SBRT and seven institutions regarding SRS (a total of 29 publications). Outcomes, techniques, radiobiology, and the scientific rigor of the reported studies were analyzed., Results: A wide range of techniques, doses, and dose fractionation schedules were found. Three hundred thirty-four patients with 564 targets were reported in the SBRT series. The 2-year weighted local control was 77.9%. The corresponding 2-year weighted overall survival was 53.7%, with a 4% rate of grade 3 or higher radiation toxicities. One hundred fifty-four patients with 174 targets were treated in the SRS series. The 2-year weighted local control was 78.6%. The corresponding weighted 2-year overall survival was 50.3%, with 2.6% rate of grade 3 or higher toxicities., Conclusion: There was insufficient evidence to recommend a consensus view for optimal tumor parameters, dose fractionation, and technical delivery of treatment. This indicates the need for further prospective studies. However, high local control rates that could potentially lead to a survival benefit justifies the consideration of stereotactic radiotherapy for patients with limited pulmonary oligometastases.

This study evaluated the variability among six radiation therapy planners in planning radiation treatment for four patients with lung cancer using two treatment protocols. The interplanner variability for target conformity and homogeneity was smaller than the variability among the patients and planning approaches. The same was found for the dose volume indices achieved for most critical structures, indicating that interplanner variability is not likely to be an important source of variation in radiotherapy studies if concise treatment protocols are followed.

Imaging with F-18 fluorodeoxyglucose positron emission tomography (PET) significantly improves lung cancer staging, especially when PET and CT information are combined. We describe a method for obtaining CT and PET images at separate acquisitions, which allows coregistration and incorporation of PET information into the radiotherapy (RT) planning process for non-small-cell lung cancer. The influence of PET information on RT planning was analysed for 10 consecutive patients. Computed tomography and PET images were acquired with the patient in an immobilization device, in the treatment position. Using specially written software, PET and CT data were coregistered using fiducial markers and imported into our RT planning system (Cadplan version 6). Treatment plans were prepared with and without access to PET/CT coregistered images and then compared. PET influenced the treatment plan in all cases. In three cases, geographic misses (gross tumour outside planning target volume) would have occurred had PET not been used. In a further three cases, better planning target volume marginal coverage was achieved with PET. In four patients, three with atelectasis, there were significant reductions in V20 (percentage of the total lung volume receiving 20 Gy or more). Use of coregistered PET/CT images significantly altered treatment plans in a majority of cases. This method could be used in routine practice at centres without access to a combined PET/CT scanner .

Introduction: Evidence that has been published in the last decade indicates that in patients with limited-stage small-cell lung cancer (SCLC), hyperfractionated accelerated thoracic radiotherapy (RT) given twice daily and prophylactic cranial irradiation (PCI) have each separately improved survival. Concerns about the toxicities associated with these treatments and uncertainty about their impact on survival outside the trial setting may have restricted the extent to which they have been incorporated into standard treatment protocols. We have reviewed the experience at Peter MacCallum Cancer Centre to determine the tolerability of these treatments in routine practice and to determine their effects on survival., Methods: A retrospective review of patients with limited-stage SCLC receiving a radical course of thoracic RT between June 1998 and May 2002, including either conventional fractionation at 50 Gy for 5 weeks, or hyperfractionated accelerated RT at 45 Gy for 3 weeks. Patients achieving a complete response were offered PCI at 36 Gy in 18 fractions. The main outcomes recorded were RT toxicity (graded using CTCAE v. 3.0 and RTOG/EORTC late scoring criteria), response, relapse-free survival, and overall survival., Results: Ninety patients were identified as having undergone radical-intent thoracic RT, with a median potential follow-up of 4.2 years. Fifty-seven patients (63%) were treated with hyperfractionated accelerated RT, and 33 (37%) were treated with conventional fractionation. Forty-six patients (51%) received PCI. Patients receiving hyperfractionated accelerated RT compared with conventional fractionation had higher rates of grade 3 and 4 esophagitis (14% versus 6%; p = 0.312), a higher rate of treatment interruptions (12% versus 3%; p = 0.250), and a higher hospital admission rate (39% versus 15%; p = 0.031). The majority of patients were able to complete the planned treatment, and there were no treatment-related deaths. Median survival for all patients from commencement of RT was 14.2 months (95% confidence interval [CI]: 11.9-18.1 months), and survival at 2 years was 24.8% (95% CI: 16.9-35.0%). On multifactor analysis, the only factor associated with longer survival was PCI (hazard ratio = 0.40; p < 0.001)., Conclusions: Hyperfractionated accelerated RT was more toxic than conventional fractionation, but it was possible to deliver treatment as planned in the majority of patients. PCI was associated with improved survival. Both treatments can be incorporated into routine practice.

The role of concurrent chemoradiotherapy (CRT) in patients with non-small-cell lung cancer (NSCLC) unsuitable for radical therapy but who require locoregional treatment has not been defined. The aims of this phase I trial were thus to develop a novel regimen of weekly chemotherapy concurrent with high-dose palliative RT (40 Gy/20 fractions) and assess its tolerability, objective and symptomatic response rates. Eligible patients had stage I-IIIB NSCLC unsuitable for radical RT or limited stage IV disease, ECOG PS

The optimal chemoradiation regimen for stage III non-small cell lung cancer (NSCLC) has not been determined. In this phase I/II study, the use of twice-weekly paclitaxel concomitant with weekly cisplatin and thoracic radiotherapy (RT) was evaluated. Patients with stage III NSCLC (without pleural effusion or cervical lymphadenopathy) were treated with thoracic RT (60 Gy in 30 fractions over 6 weeks) with concurrent weekly cisplatin 20 mg/m(2) and escalating doses of twice-weekly paclitaxel (starting dose of paclitaxel of 20 mg/m(2) increased in increments of 5 mg/m(2)) in successive cohorts of three to six patients until two or more patients experienced dose limiting toxicities (DLTs) at a particular dose level. All patients were planned to be given a further two cycles of consolidation chemotherapy consisting of paclitaxel 175 mg/m(2) and carboplatin AUC 5 after completion of RT. Twenty-five patients were enrolled in this study from two institutions. At a dose of paclitaxel 35 mg/m(2), two of four treated patients had DLTs (1 grade 3 oesophagitis and pulmonary toxicity; 1 grade 3 oesophagitis and infection). The recommended dose was therefore determined to be 30 mg/m(2) and a total of 15 patients were enrolled in an expanded cohort at this level. The overall response rate for all patients was 64% (95% CI: 43-82%). The estimated median survival was 23.6 months with an estimated 1-year and 2-year survival of 72 and 49%, respectively. Paclitaxel can be safely given twice-weekly at a dose of 30 mg/m(2) in combination with weekly cisplatin (20 mg/m(2)) and thoracic RT (60 Gy), and this regimen has significant activity in stage III NSCLC.

The purpose of this study was to document the accuracy of (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET) with sodium iodide detectors in characterizing indeterminate lung nodules or masses and in identifying additional extra-lesional findings. 50 consecutive patients without a confident diagnosis of malignancy on CT underwent (18)FDG PET with and without attenuation correction. The diagnosis of malignancy was made using visual diagnostic criteria, and tumour-to-blood pool ratios were calculated. The final diagnosis was established by surgery, biopsy or long-term follow-up. Any additional findings made at PET were recorded and similarly verified. Using blinded visual diagnostic criteria for the differentiation of malignant from benign nodules, sodium iodide PET achieved a sensitivity of 91% (30 of 33 cases), a specificity of 88% (15 of 17 cases), a positive predictive value for malignancy of 94% (30 of 32 cases) and a negative predictive value of 83% (15 of 18 cases). False positives occurred with active tuberculosis and sarcoidosis. False negatives were a 3 cm bronchoalveolar carcinoma, a 1.3 cm sarcoma metastasis and a 1 cm carcinoma. Use of tumour-to-blood pool ratios did not improve performance. PET suggested the presence of nodal or distant metastases in 13 of 33 patients with a malignant pulmonary lesion. These PET findings were confirmed in 11 patients. These results indicate that sodium iodide PET is an accurate tool for the characterization of indeterminate pulmonary masses or nodules and simultaneously provides non-invasive staging information that can alter patient management in up to one-third of such patients. Performance of sodium iodide PET is comparable with reported results for PET scanners using other detector materials.

Unlabelled: After potentially curative therapy of non-small cell lung cancer (NSCLC), masses or symptoms suggestive of relapse are common but may be difficult to characterize. Early detection is important because salvage therapies are available for localized recurrence. This study evaluated whether (18)F-FDG PET is useful and predictive of outcome in this setting., Methods: For 63 consecutive patients with suspected relapse >6 mo after definitive treatment of NSCLC, the apparent extent of disease on conventional restaging was compared with that on FDG PET. Patients with already confirmed systemic metastases were excluded unless locally aggressive treatment of these was being considered. Serial imaging and pathologic results were obtained during a median follow-up of 19 mo to validate diagnostic findings. Prognostic significance was tested using the Cox proportional hazards regression model., Results: PET had positive findings in 41 of 42 patients with confirmed relapse (sensitivity, 98%). No disease was evident during a minimum follow-up of 12 mo in 14 of 15 patients with clinically suspected relapse but negative PET findings (negative predictive value, 93%). PET induced a major management change in 40 patients (63%), including 6 whose treatment was changed from curative to palliative, 3 whose treatment was changed from palliative to curative, and 9 for whom negative PET findings prevented active management. Both the presence (P = 0.012) and the extent (P < 0.0001) of relapse on PET were highly significant prognostic factors. There was also significant prognostic stratification based on the treatment delivered after the PET study (P = 0.011), but after adjustment for this treatment, PET status remained highly predictive of survival., Conclusion: PET better assesses the status of disease and stratifies prognosis than does conventional staging, affects patient management, and should be incorporated into paradigms for suspected recurrence of NSCLC.

Unlabelled: Survival of lung cancer patients remains poor despite increasingly aggressive treatment. Conventional staging has well-described limitations. (18)F-FDG PET has been shown to stage lung cancer more accurately than does CT scanning, but the impact on patient treatment and outcome is poorly defined. This study evaluated this impact in routine clinical practice within a tertiary oncology facility., Methods: For 153 consecutive patients with newly diagnosed non-small cell lung cancer, the treatment plan based on conventional staging methods was compared with the treatment plan based on incorporation of PET findings. Survival was analyzed using the Cox proportional hazards regression model., Results: For broad groupings of stage, 10% of cases were downstaged and 33% upstaged by PET. When assessable, the PET stage was confirmed in 89% of patients. PET had a high impact on 54 patients (35%), including 34 whose therapy was changed from curative to palliative, 6 whose therapy was changed from palliative to curative, and 14 whose treatment modality was changed but not the treatment intent. For 39 patients (25%), a previously selected therapy was altered because of the PET findings. The Cox model indicated that the pre-PET stage was significantly associated with survival (P = 0.013) but that the post-PET stage provided much stronger prognostic stratification (P < 0.0001) and remained significant after adjustment for treatment delivered., Conclusion: Staging that incorporated PET provided a more accurate prognostic stratification than did staging based on conventional investigations. Further, the additional information provided by PET significantly and appropriately changed management in the majority of patients.

Thallium-201 (Tl-201) single photon emission computed tomography (SPECT) is funded for evaluation of malignancy in Australia and may have utility for staging of non-small cell lung cancer (NSCLC) if CT results are equivocal. Fluorine-18 fluorodeoxyglucose (F-18 FDG) positron emission tomography (PET) is superior to CT for staging NSCLC but is more expensive and less widely available than Tl-201 SPECT. Therefore, these techniques were prospectively compared in 27 radical radiation therapy candidates. Patients were allocated a conventional, PET and Tl-201 stage. Tumour to background ratios (TBR) were recorded for the primary on both techniques. Metastatic disease was confirmed by surgical pathology, serial imaging or clinical follow up. Tumour to background ratios were consistently higher for FDG PET than Tl-201 SPECT (P < 0.0001). Positron emission tomography detected all known primary tumours but Tl-201 failed to image four primary tumours (15%). In 10 of 18 cases of discordance between PET and Tl-201 SPECT regarding stage, corroboration was available from pathology or disease progression. Positron emission tomography was shown to have a 100% positive predictive value, including all three patients with PET-detected distant metastases (P=0.002). Results indicate that PET is superior to Tl-201 SPECT scanning in the staging of NSCLC for radical radiation therapy, and that the low sensitivity for detection of local and metastatic disease is likely to limit the clinical impact and cost-effectiveness of this technique despite its lower cost.

Objective: To document the usefulness of positron emission tomography (PET) in diagnosing lung masses where tissue diagnosis is not possible or is unhelpful., Design: Cohort study (partly retrospective)., Setting: Departments of positron emission tomography and diagnostic imaging of a tertiary referral dedicated cancer hospital in Melbourne., Patients: 40 of 60 consecutive patients referred for evaluation of an indeterminate lung nodule or mass, comprising 15 in whom biopsy was not possible and 25 in whom biopsy had either failed or did not confirm malignancy or a specific benign diagnosis., Main Outcome Measures: Accuracy of blinded reading of PET scans in determining whether the lung lesion is benign or malignant (final diagnosis established either through surgical biopsy or from long term clinical and imaging follow-up)., Results: PET yielded 23 true positives, 13 true negatives, 3 false positives (2 tuberculosis, 1 sarcoidosis) and 1 false negative (an adenocarcinoma), giving a sensitivity of 96%, a specificity of 81%, a negative predictive value of 93%, and a positive predictive value of 88% (for malignancy)., Conclusions: For lung nodules where tissue diagnosis was not possible or was unhelpful, the negative predictive power of PET was sufficiently high to avoid open biopsy, and to follow such patients with serial surveillance. On the other hand, most lesions that were positive on PET were either malignant or required specific active management determined from histological characterisation. PET therefore contributed to improved patient management and has reduced the need for open thoracotomy.

Purpose: Most radical radiotherapy (RT) candidates with non-small-cell lung cancer (NSCLC) have Stage III disease and ultimately die with distant metastases. We tested the hypothesis that positron emission tomography (PET) using 18-F fluorodeoxyglucose (FDG) would detect more unsuspected metastases in apparent Stage III disease than in Stages I-II., Methods and Materials: Staging FDG-PET was performed for 167 NSCLC patients, with Stage I-III by conventional workup, who were candidates for curative therapy with surgery (n = 8), radical chemo/RT or RT (n = 156), or preoperative chemo/RT (n = 3). Each patient was allocated a conventional "pre-PET stage" and a "post-PET stage" that relied on PET when discordance with conventional staging occurred., Results: Stage distribution pre-PET was n = 39 (Stage I), n = 28 (Stage II), and n = 100 (Stage III). In 32 patients (19%), PET detected distant metastasis, most commonly abdominal with 17 cases (adrenal, n = 7; liver, n = 4; other, n = 6). Other sites included lung (n = 10) and bone (n = 6). PET-detected metastasis increased with increasing pre-PET stage from I (7.5%) through II (18%) to III (24%, p = 0.016), and, in particular, was significantly higher in Stage III (p = 0.039). Biopsy confirmation was not routine, but progression occurred at PET-detected metastatic sites or other metastatic sites in all but 3 of the 32 patients by last review., Conclusion: PET staging is recommended for radical RT candidates with NSCLC. The highest yield of unexpected distant metastases is observed in Stage III.

Purpose: To prospectively study the impact of (18)F fluorodeoxyglucose (FDG) positron emission tomography (PET) on clinical management of patients with non-small-cell lung cancer (NSCLC)., Patients and Methods: One hundred five consecutive patients with NSCLC undergoing (18)F FDG PET were analyzed. Before PET, referring physicians recorded scan indication, conventional clinical stage, and proposed treatment plan. PET scan results were reported in conjunction with available clinical and imaging data, including results of computed tomography (CT). Subsequent management and appropriateness of PET-induced changes were assessed by follow-up for at least 6 months or until the patient's death., Results: Indications for PET were primary staging (n = 59), restaging (n = 34), and suspected malignancy subsequently proven to be NSCLC (n = 12). In 27 (26%) of 105 of cases, PET results led to a change from curative to palliative therapy by upstaging disease extent. Validity of the PET result was established in all but one case. PET appropriately downstaged 10 of 16 patients initially planned for palliative therapy, allowing either potentially curative treatment (four patients) or no treatment (six patients). PET influenced the radiation delivery in 22 (65%) of 34 patients who subsequently received radical radiotherapy. Twelve patients considered probably inoperable on conventional imaging studies were downstaged by PET and underwent potentially curative surgery. PET missed only one primary tumor (5-mm scar carcinoma). CT and PET understaged three of 20 surgical patients (two with N1 lesions < 5 mm and one with unrecognized atrial involvement), and PET missed one small intrapulmonary metastasis apparent on CT. No pathological N2 disease was missed on PET., Conclusion: FDG PET scanning changed or influenced management decisions in 70 patients (67%) with NSCLC. Patients were frequently spared unnecessary treatment, and management was more appropriately targeted.