The impact of pre-treatment smoking status on survival after chemoradiotherapy for locally advanced non-small-cell lung cancer.

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.

Early circulating tumor DNA dynamics at the commencement of curative-intent radiotherapy or chemoradiotherapy for NSCLC.

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.

Risk-Directed Ambulatory Thromboprophylaxis in Lung and Gastrointestinal Cancers: The TARGET-TP Randomized Clinical Trial.

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.

Patterns of care for people with small cell lung cancer in Victoria, 2011-19: a retrospective, population-based registry data study.

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.

Assessment of lung doses in patients undergoing total body irradiation for haematological malignancies with and without lung shielding.

INTRODUCTION: Total body irradiation (TBI) practices vary considerably amongst centres, and the risk of treatment related toxicities remains unclear. We report lung doses for 142 TBI patients who underwent either standing TBI with lung shield blocks or lying TBI without blocks. METHODS: Lung doses were calculated for 142 TBI patients treated between June 2016 and June 2021. Patients were planned using Eclipse (Varian Medical Systems) using AAA_15.6.06 for photon dose calculations and EMC_15.6.06 for electron chest wall boost fields. Mean and maximum lung doses were calculated. RESULTS: Thirty-seven patients (26.2%) were treated standing using lung shielding blocks with 104 (73.8%) treated lying down. Lowest relative mean lung doses were achieved using lung shielding blocks in standing TBI, reducing the mean lung doses to 75.2% of prescription (9.9 Gy), ±4.1% (range 68.6-84.1%) for a prescribed dose of 13.2 Gy in 11 fractions, including contributions from electron chest wall boost fields, compared to 12 Gy in 6 fraction lying TBI receiving 101.6% mean lung dose (12.2 Gy) ±2.4% (range 95.2-109.5%) (P ≪ 0.05). Patients treated lying down with 2 Gy single fraction received the highest relative mean lung dose on average, with 108.4% (2.2 Gy) ±2.6% of prescription (range 103.2-114.4%). CONCLUSION: Lung doses have been reported for 142 TBI patients using the lying and standing techniques described herein. Lung shielding blocks significantly reduced mean lung doses despite the addition of electron boost fields to the chest wall.

Automated radiosynthesis of [89Zr]Zr-DFOSq-Durvalumab for imaging of PD-L1 expressing tumours in vivo.

OBJECTIVES: 89Zr-labelled proteins are gaining importance in clinical research in a variety of diseases. To date, no clinical study has been reported that utilizes an automated approach for radiosynthesis of 89Zr-labelled radiopharmaceuticals. We aim to develop an automated method for the clinical production of 89Zr-labelled proteins and apply this method to Durvalumab, a monoclonal antibody targeting PD-L1 immune-checkpoint protein. PD-L1 expression is poorly understood and can be up-regulated over the course of chemo- and radiotherapy treatment. The ImmunoPET multicentre study aims to examine the dynamics of PD-L1 expression via 89Zr-Durvalumab PET imaging before, during, and after chemoradiotherapy. The developed automated technique will enable reproducible clinical production of [89Zr]Zr-DFOSq-Durvalumab for this study at three different sites. METHODS: Conjugation of Durvalumab to H3DFOSqOEt was optimized for optimal chelator-to-antibody ratio. Automated radiolabelling of H3DFOSq-Durvalumab with zirconium-89 was optimized on the disposable cassette based iPHASE technologies MultiSyn radiosynthesizer using a modified cassette. Activity losses were tracked using a dose calibrator and minimized by optimizing fluid transfers, reaction buffer, antibody formulation additives and pH. The biological profile of the radiolabelled antibody was confirmed in vivo in PD-L1+ (HCC827) and PD-L1- (A549) murine xenografts. Clinical process validation and quality control were performed at three separate study sites to satisfy clinical release criteria. RESULTS: H3DFOSq-Durvalumab with an average CAR of 3.02 was obtained. Radiolabelling kinetics in succinate (20 mM, pH 6) were significantly faster when compared to HEPES (0.5 M, pH 7.2) with >90 % conversion observed after 15 min. Residual radioactivity in the 89Zr isotope vial was reduced from 24 % to 0.44 % ± 0.18 % (n = 7) and losses in the reactor vial were reduced from 36 % ± 6 % (n = 4) to 0.82 % ± 0.75 % (n = 4) by including a surfactant in the reaction and formulation buffers. Overall process yield was 75 % ± 6 % (n = 5) and process time was 40 min. Typically, 165 MBq of [89Zr]Zr-DFOSq-Durvalumab with an apparent specific activity of 315 MBq/mg ± 34 MBq/mg (EOS) was obtained in a volume of 3.0 mL. At end-of-synthesis (EOS), radiochemical purity and protein integrity were always >99 % and >96 %, respectively, and dropped to 98 % and 65 % after incubation in human serum for 7 days at 37 °C. Immunoreactive fraction in HEK293/PD-L1 cells was 83.3 ± 9.0 (EOS). Preclinical in vivo data at 144 h p.i. showed excellent SUVmax in PD-L1+ tumour (8.32 ± 0.59) with a tumour-background ratio of 17.17 ± 3.96. [89Zr]Zr-DFOSq-Durvalumab passed all clinical release criteria at each study site and was deemed suitable for administration in a multicentre imaging trial. CONCLUSION: Fully automated production of [89Zr]Zr-DFOSq-Durvalumab for clinical use was achieved with minimal exposure to the operator. The cassette-based approach allows for consecutive productions on the same day and offers an alternative to currently used manual protocols. The method should be broadly applicable to other proteins and has the potential for clinical impact considering the growing number of clinical trials investigating 89Zr-labelled antibodies.

Comparison of Changes in Pulmonary Function After Stereotactic Body Radiation Therapy Versus Conventional 3-Dimensional Conformal Radiation Therapy for Stage I and IIA Non-Small Cell Lung Cancer: An Analysis of the TROG 09.02 (CHISEL) Phase 3 Trial.

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.

Are dynamic or fixed FDG-PET measures of disease of greater prognostic value in patients with relapsed/refractory diffuse large B-cell lymphoma undergoing autologous haematopoietic stem cell transplantation?

Positron emission tomography (PET) response assessment using the Deauville score has prognostic utility in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) undergoing autologous stem-cell transplantation (ASCT). Improved predictive methods are required to identify patients with poor outcomes who may be better considered for other salvage options. We investigated the prognostic value of mean tumour volume (MTV) and maximum standardised uptake value (SUVmax) at pre-salvage and pre-ASCT time-points, and the quantitative changes between scans (∆MTV and ∆SUVmax). One hundred and twenty-five patients with R/R DLBCL underwent salvage immunochemotherapy and ASCT: 80 patients had pre-salvage PET and 90 had pre-ASCT PET available. With a median follow-up of 5.6 years, 5-year progression-free survival (PFS) and overall survival (OS) were 52% and 65%, respectively. For patients with PET-positive residual disease after salvage therapy, pre-ASCT MTV was a significant negative prognosticator for PFS (HR 1.19 per 100 ml, p < 0.001) and OS (HR 1.78 per 100 ml, p < 0.001). Similarly, pre-ASCT SUVmax was negatively associated with PFS (HR 1.08, p < 0.001) and OS (HR 1.08, p < 0.001). Notably, pre-salvage MTV and SUVmax and ∆MTV and ∆SUVmax were not associated with PFS or OS. In conclusion, pre-ASCT MTV and SUVmax appear to be of greater predictive value than the degree of response. Potential application may exist for PET-directed management of R/R DLBCL patients.

Peritransplant Radiation Therapy in Patients With Refractory or Relapsed Hodgkin Lymphoma Undergoing Autologous Stem Cell Transplant: Long-Term Results of a Retrospective Study of the Fondazione Italiana Linfomi.

PURPOSE: In this multicenter collaboration, we report real-world data in the largest published series of long-term outcomes for patients with relapsed/refractory (r/r) Hodgkin lymphoma (HL) treated with peritransplant radiation therapy (pt-RT) and high-dose chemotherapy with autologous stem cell transplant (ASCT). METHODS AND MATERIALS: We conducted a retrospective analysis including data from 12 institutions. Eligibility required histologic diagnosis of HL, receipt of ASCT plus pt-RT between 2004 and 2014 for r/r HL, and age ≥18 years at the time of ASCT. All patients received salvage chemotherapy for maximum debulking before ASCT. Metabolic responses were scored according to the Lugano Classification. The primary endpoint was overall survival (OS). Univariate and multivariate Cox proportional hazards were calculated to estimate the effect of covariates on patients' outcome. RESULTS: One hundred thirty-one patients were eligible: 68 were male (52%), and median age at ASCT was 32 years (range, 18-70). At the time of diagnosis with r/r HL, 92 patients (70%) had limited (stage I-II) disease, and 10 patients (8%) had bulky disease. Pt-RT was given pre-ASCT in 32 patients (24%) and post-ASCT in 99 (76%); median prescribed dose was 30.6 Gy (range, 20-44 Gy). With median follow-up of 60 months, 3- and 5-year OS were 84% and 77%, while 3- and 5-year progression-free survival were 75% and 72%, respectively. On univariate and multivariate analysis, advanced stage at relapse (hazard ratio [HR], 2.18; P = .04), irradiation of >3 sites (HR, 3.69; P = .01), and incomplete metabolic response after salvage chemotherapy (HR, 2.24; P = .01) had a negative effect on OS. The sequencing of pt-RT (pre- vs post-ASCT) did not affect outcomes. CONCLUSIONS: Overall, the addition of pt-RT to ASCT for patients with r/r HL is associated with very good outcomes. Limited relapsed disease with ≤3 sites involved and achievement of complete metabolic response after salvage chemotherapy were predictive of more favorable prognosis.

An epithelial-to-mesenchymal transition induced extracellular vesicle prognostic signature in non-small cell lung cancer.

Despite significant therapeutic advances, lung cancer remains the leading cause of cancer-related death worldwide1. 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.

Large variation in radiation therapy fractionation for multiple myeloma in Australia.

AIM: To evaluate the patterns of use of different radiation therapy (RT) fractionation for multiple myeloma (MM) bone disease. METHODS: This is a population-based cohort of patients with MM who had RT between 2012 and 2017 as captured in the statewide Victorian Radiotherapy Minimum Data Set in Australia. Data linkage was performed to identify subsets of RT delivered within 3 months of death. RT fractionation was classified into four groups: single-fraction (SFRT), 2-5, 6-10, and > 10 fractions. Changes in RT fractionation use over time were evaluated with the Cochran-Armitage test for trend. Factors associated with RT fractionation were evaluated using multivariate logistic regressions. RESULTS: Nine hundred and sixty-seven courses of RT were delivered in 623 patients. The proportion of SFRT, 2-5, 6-10 and > 10 fractions RT was 18%, 47%, 28%, and 7%, respectively. There was an increase in the use of 2-5 fractions, from 48% in 2012 to 60% in 2017 (p-trend < .001), with corresponding decrease in the use of 6-10 fractions, from 26% in 2012 to 20% in 2017 (p-trend = .003). Nine percent (40/430) of RT courses at private institutions were SFRT, compared to 25% (135/537) in public institutions (p < .001). In multivariate analyses, treatment in private institution was the strongest predictor of multifraction RT use. SFRT use was more common closer to the end of life-18%, 14%, and 33% of RT within 2-3, 1-2, < 1 month of death, respectively. CONCLUSION: There is increasing use of shorter course RT (2-5 fractions) for MM over time. SFRT use remains low, with large variation in practice.

ImmunoPET: IMaging of cancer imMUNOtherapy targets with positron Emission Tomography: a phase 0/1 study characterising PD-L1 with 89Zr-durvalumab (MEDI4736) PET/CT in stage III NSCLC patients receiving chemoradiation study protocol.

BACKGROUND: ImmunoPET is a multicentre, single arm, phase 0-1 study that aims to establish if 89Zr-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 89Zr-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 89Zr-durva dose found in organs of interest (2) Absorbed organ doses (µSv/MBq of administered 89Zr-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 89Zr-durva and FDG-PET/CT before, during and after chemoradiation. In order to establish the feasibility of 89Zr-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.

Changes in Apparent Diffusion Coefficient (ADC) in Serial Weekly MRI during Radiotherapy in Patients with Head and Neck Cancer: Results from the PREDICT-HN Study.

Background: The PREDICT-HN study aimed to systematically assess the kinetics of imaging MR biomarkers during head and neck radiotherapy. Methods: Patients with intact squamous cell carcinoma of the head and neck were enrolled. Pre-, during, and post-treatment MRI were obtained. Serial GTV and ADC measurements were recorded. The correlation between each feature and the GTV was calculated using Spearman's correlation coefficient. The linear mixed model was used to evaluate the change in GTV over time. Results: A total of 41 patients completed the study. The majority (76%) had oropharyngeal cancer. A total of 36 patients had intact primary tumours that can be assessed on MRI, and 31 patients had nodal disease with 46 nodes assessed. Median primary GTV (GTVp) size was 14.1cc. The rate of GTVp shrinkage was highest between pre-treatment and week 4. Patients with T3-T4 tumours had a 3.8-fold decrease in GTVp compared to T1-T2 tumours. The ADC values correlated with residual GTVp. The median nodal volume (GTVn) was 12.4cc. No clinical features were found to correlate with GTVn reduction. The overall change in ADC for GTVn from pre-treatment was significant for 35th−95th percentiles in weeks 1−4 (p < 0.001). Conclusion: A discrepancy in the trajectory of ADC between primary and nodal sites suggested that they exhibit different treatment responses and should be analysed separately in future studies.

Impact of Medical Operability and Total Metastatic Ablation on Outcomes After SABR for Oligometastases.

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 [BED10]≥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.

Imaging immunity in patients with cancer using positron emission tomography.

Immune checkpoint inhibitors and related molecules can achieve tumour regression, and even prolonged survival, for a subset of cancer patients with an otherwise dire prognosis. However, it remains unclear why some patients respond to immunotherapy and others do not. PET imaging has the potential to characterise the spatial and temporal heterogeneity of both immunotherapy target molecules and the tumor immune microenvironment, suggesting a tantalising vision of personally-adapted immunomodulatory treatment regimens. Personalised combinations of immunotherapy with local therapies and other systemic therapies, would be informed by immune imaging and subsequently modified in accordance with therapeutically induced immune environmental changes. An ideal PET imaging biomarker would facilitate the choice of initial therapy and would permit sequential imaging in time-frames that could provide actionable information to guide subsequent therapy. Such imaging should provide either prognostic or predictive measures of responsiveness relevant to key immunotherapy types but, most importantly, guide key decisions on initiation, continuation, change or cessation of treatment to reduce the cost and morbidity of treatment while enhancing survival outcomes. We survey the current literature, focusing on clinically relevant immune checkpoint immunotherapies, for which novel PET tracers are being developed, and discuss what steps are needed to make this vision a reality.

Blood-Derived Extracellular Vesicle-Associated miR-3182 Detects Non-Small Cell Lung Cancer Patients.

With five-year survival rates as low as 3%, lung cancer is the most common cause of cancer-related mortality worldwide. The severity of the disease at presentation is accredited to the lack of early detection capacities, resulting in the reliance on low-throughput diagnostic measures, such as tissue biopsy and imaging. Interest in the development and use of liquid biopsies has risen, due to non-invasive sample collection, and the depth of information it can provide on a disease. Small extracellular vesicles (sEVs) as viable liquid biopsies are of particular interest due to their potential as cancer biomarkers. To validate the use of sEVs as cancer biomarkers, we characterised cancer sEVs using miRNA sequencing analysis. We found that miRNA-3182 was highly enriched in sEVs derived from the blood of patients with invasive breast carcinoma and NSCLC. The enrichment of sEV miR-3182 was confirmed in oncogenic, transformed lung cells in comparison to isogenic, untransformed lung cells. Most importantly, miR-3182 can successfully distinguish early-stage NSCLC patients from those with benign lung conditions. Therefore, miR-3182 provides potential to be used for the detection of NSCLC in blood samples, which could result in earlier therapy and thus improved outcomes and survival for patients.

18 F-FDG PET and PET/CT as a diagnostic method for Ewing sarcoma: A systematic review and meta-analysis.

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.