Small extracellular vesicles (sEVs) offer a promising, non-invasive method for cancer detection. Despite global research efforts, successful translation of sEV-based diagnostics remains limited. In this study, we identify a 4-protein sEV biomarker panel (thrombospondin-1, nidogen-1, pentraxin-3, and versican) based on proteomic profiles obtained from an isogenic cancercell line model. The panel's performance is validated across 22 cancer cell lines and 764 retrospective plasma/serum samples spanning multiple cancer types, yielding robust performance (area under the curve [AUC]: 0.91-1.00). To facilitate clinical application, we develop a multiplex sEV device that integrates nanoshearing-based microfluidics and surface-enhanced Raman scattering (SERS) for simultaneous detection of the 4-protein panel. Using this device on a prospective cohort of 68 patients, we accurately differentiate between benign lung changes and early-stage lung cancer. These findings underscore the potential of sEVs as diagnostic markers for cancer screening. Furthermore, the multiplex microfluidic device's scalability, simplicity, and cost-effectiveness indicate feasibility for large-scale population screening.

BACKGROUND AND PURPOSE:The recently-updated TROG 99.03/ALLGLow5 multicentre randomised controlled trial showed that long-term progression-free survival (PFS) in early-stage (I-II) follicular lymphoma (ESFL) after involved-field radiotherapy (IFRT) was dramatically improved by adjuvant rituximab-cyclophosphamide/vincristine/prednisolone (R-CVP) but not CVP. Secondary analyses are presented here. MATERIALS AND METHODS:We analysed toxicity of RT and RT plus systemic therapy, outcomes for discontinuous stage II disease, second malignancy risks, prognostic impact of indeterminate bone marrow (BM) aggregates and the effect of rituximab on histological transformation. BM trephines from 55 patients from the pre-rituximab era were centrally reviewed. RESULTS:As previously-reported, 150 patients were randomised to IFRT (n = 75) or IFRT plus systemic therapy (n = 75). After 11.3 years median follow-up, IFRT + R-CVP was associated with improved PFS compared to IFRT or IFRT + CVP (HR 0.36, p = 0.01). Short-term RT-related grade I-II toxicity occurred in >90%, but toxicity after >6 months was rare. Worst acute systemic therapy toxicity was G1 (16 patients, G2 31 and G3 20) with 3 grade 3 neuropathies. R-CVP and CVP were equally toxic. Only 2 of 5 patients with non-contiguous stage II relapsed. Of 64 relapsed patients, 39 commenced salvage therapies and 17 had second progressions. Second malignancies showed no relationship to irradiated-volumes or systemic therapy use. Indeterminate BM aggregates did not worsen PFS. CONCLUSION:The improvement in PFS, reduced salvage therapy requirements, and prevention of histological transformation with R-CVP outweigh its significant but transient toxicity, supporting its justifiable use. Patients with indeterminate BM lymphoid aggregates or non-contiguous stage II FL may merit consideration for curative-intent treatment.

Following salvage chemotherapy (SC) and autologous stem-cell transplantation (ASCT), 30-60% of patients with relapsed/refractory Hodgkin lymphoma (r/rHL) experience disease relapse. Appropriate patient selection for consolidation radiotherapy (cRT) may improve outcomes. Positron-emission tomography (PET) is a powerful prognostic tool, with potential utility in PET-directed therapy. Predictive roles of post-SC metabolic and structural response assessments, and prognostic impact of peri-transplant cRT, were retrospectively evaluated in r/rHL patients from two tertiary hospitals, median follow-up >5 years. Five-year progression-free survival (PFS) was 65% (95%CI 55-74%). Metabolic response post-SC significantly predicted PFS. For patients with complete metabolic response (CMR) post-SC, structural residuum ≥2 cm suggested inferior PFS. Potential PFS advantages from cRT were observed in all subgroups with limited-stage r/rHL, regardless of response post-SC. Peri-transplant cRT may abrogate the negative predictive value of non-CMR or residual masses ≥2 cm in CMR post-SC. In advanced-stage r/rHL, post-SC non-CMR predicted for poor outcomes, warranting prioritization of alternative salvage strategies.

BACKGROUND:Single-fraction stereotactic ablative radiotherapy (SABR) is a curative treatment option for patients with early lung cancer. We undertook a feasibility study to assess whether simulation, planning and treatment could be undertaken within a single day and whether this expedited pathway was acceptable to patients. METHODS:A multidisciplinary team of radiation oncologists, radiation therapists and medical physicists developed a workflow to permit all aspects of planning and treatment to be conducted within a single working day. All aspects of the pathway were timed. Prescription dose was 30 Gray. Patients completed an Experience Survey within two weeks of treatment. The study would be deemed successful if it met both dual primary endpoints of feasibility (7/10 patients treated within 8 working hours) and patient satisfaction (7/10 expressing overall satisfaction). RESULTS:Ten patients were treated. These included 6 women and 4 men. Median age was 76.5 and 9 patients had been deemed to be medically inoperable. Median time from commencement of CT simulation to end of treatment was 6 h 50 min (IQR 6 h 42 m - 7 h 4 m); 9/10 patients were treated within the target 8-hour window. All 10 patients expressed overall satisfaction with the service. All 10 felt it was more convenient than our usual treatment pathway would have been. CONCLUSION:Same-day single-fraction SABR is feasible and acceptable to patients. This pathway should be considered for those who live a significant distance from treatment centres or who have other difficulties in attending for multiple visits.

INTRODUCTION:Total body irradiation (TBI) practice varies globally. The optimal technique for TBI has not yet been determined, although guidelines and recommendations are available. Five years after the initial Australia and New Zealand (ANZ) practice survey in 2019, we report updated 2024 TBI practice patterns from 19 ANZ centres who are members of the ANZ Transplant and Cellular Therapies (ANZTCT) TBI Special Interest Group (TBISIG). METHOD:The 2024 survey was distributed in November 2024. Survey questions covered patient cohorts and caseloads, TBI regimens and dose-fractionations, TBI techniques, planning considerations, quality assurance, and treatment delivery. For all centres, one staff member from each discipline (Radiation Oncology, Medical Physics, and Radiation Therapy) was invited to respond. RESULTS:Responses were received from all 19 centres. Seven centres use modulated techniques in 2024, whereas only one centre delivered modulated TBI in 2019. Twelve centres use large open fields in 2024, six of which are considering changing to volumetric modulated arc therapy (VMAT) TBI. Compared to large open fields, modulated techniques (1) require dedicated patient immobilisation equipment and treatment planning software, (2) reduce dose to organs at risk (such as lungs and kidneys) below the prescription dose, (3) have higher dose rates, and (4) require more time for planning and treatment delivery. CONCLUSION:The 2024 survey showed diverse TBI practice patterns in ANZ. Compared to 2019, more centres are using or actively considering the implementation of modulated techniques, such as VMAT TBI, which adds to the complexity of treatment planning and delivery.

PURPOSE:Radiation therapy (RT) is curative for the majority of patients with primary indolent orbital adnexal lymphoma (IOAL). Some reports suggest inferior outcomes for bilateral IOAL, leading to uncertainty regarding optimal management for this presentation. This multicenter, retrospective study evaluated long-term outcomes of bilateral IOAL patients treated with RT alone. METHODS AND MATERIALS:One hundred and eighty-four patients with synchronous (defined as ≤90 days between orbit diagnoses), or metachronous bilateral IOAL, and no prior lymphoma history, received RT to both orbits. Overall (OS), failure-free survival (FFS), freedom from local failure (FFLF), freedom from distant failure (FFDF), and toxicity were evaluated. The study met local institutional review board requirements. RESULTS:A total of 184 patients were treated for IOAL from 16 centers. The median age at first orbit diagnosis was 51 years (15-91 years) with 170 (92%) of patients having marginal zone lymphoma. Disease location included the conjunctiva in 265 (72%) of orbits. The RT dose (per orbit) was 4 Gy for 40 (11%), 20 to 26 Gy for 217 (59%), 27 to 30.6 Gy for 87 (24%), and >30.6 Gy for 24 (6.5%). Radiation therapy volume was whole orbit for 162 (44%), conjunctiva only for 177 (48%), and other partial orbit for 29 (8%). The median follow-up was 5.7 years. Ten-year OS and FFS were 99% (95% CI, 95-100) and 72% (95% CI, 62-79), respectively. Ten-year FFLF and FFDF were 87% (95% CI, 80-92) and 81% (95% CI, 72-88), respectively. Ten-year FFS was 85% (95% CI, 75-91) and 50% (95% CI, 32-65) for patients with conjunctival-only disease versus any nonconjunctival disease, respectively. Late toxicities included dry eye in 42% of patients (grade 1 in 86%) and cataract in 27%. CONCLUSIONS:In this large, multicenter experience, patients with bilateral IOAL treated with RT alone had outcomes comparable with historical series of unilateral disease. These results support the treatment of bilateral IOAL as a localized process with curative intent RT.

Background Definitive concurrent chemoradiotherapy (CRT) is the primary curative-intent treatment option for unresectable locally advanced nonsmall-cell lung cancer (NSCLC). Completion of CRT is generally required for eligibility for consolidation durvalumab, which significantly improves survival. We sought to establish CRT completion rates at a comprehensive cancer center. Patients and Methods 265 patients were treated with concurrent CRT over the decade 2012-2022, during which durvalumab became available. 63% were male, median age was 67, and 91% had performance status 0-1. All patients were recruited into the AURORA prospective cohort study which captured baseline demographics and comorbidities, and prospectively updated treatment and outcome data at subsequent hospital visits. Data were analyzed retrospectively to evaluate CRT completion rates, reasons for noncompletion, and survival outcomes. Survival was also analyzed based on durvalumab availability and administration. Results CRT was completed as planned by 246/265 (93%) patients. Reasons for noncompletion included treatment related toxicity (n = 6/19), unrelated illnesses (n = 7/19), local disease progression (n = 2/19), and distant progression (n = 4/19). Median overall survival (OS) was 2.2 years (95% CI, 1.7-2.8) for the entire cohort and 1.0 years (95% CI, 0.2-1.5) for those who ceased CRT early. No specific baseline characteristics predicted noncompletion of CRT. Consolidation durvalumab was associated with improved OS (HR 0.39; 95% CI, 0.21-0.72, P = .002). Conclusion With appropriate supportive care, most patients initially considered suitable for CRT could complete it and access consolidation durvalumab. Consolidation durvalumab was associated with improved survival in this “real-world” stage III NSCLC cohort.

PURPOSE:To utilize 68Gallium (Ga) Ventilation-Perfusion (V/Q) 4-dimensional (4D) PET/CT to establish the impact of curative radiotherapy (RT) doses on lung ventilation and perfusion, and to evaluate associations with clinical outcomes. METHODS AND MATERIALS:This prospective non-randomized observational clinical trial included 67 patients undergoing definitive RT +/-chemotherapy for NSCLC. Patients underwent 68Ga 4D V/Q PET/CT at baseline, mid-treatment, and at 3- and 12-months post-treatment. Pulmonary Function Tests (PFTs) and toxicities were assessed at baseline and 3 monthly after treatment. Linear mixed models were used to assess for associations between radiotherapy dose-volume, applied to ventilated and perfused lung at 5 %, 30 % and 70 % thresholds as defined by 68Ga 4D V/Q PET/CT, and toxicity. RESULTS:Sixty-seven patients were evaluable, of whom 44 (66 %) were male, mean age was 68, and 61 (91 %) were ECOG 0-1. Sixty-three patients completed treatment and grade ≥2 pneumonitis occurred in 20 (32 %). Lung ventilation and perfusion, and FEV1 and DLCO, fell slightly from baseline to 3-months post treatment. V54 Gy of perfused lung at the 30 % threshold was higher in those with grade ≥2 pneumonitis (median 12.9 % (IQR 8.7-14.8 %) vs 6.3 % (IQR 3.7-8.5 %), p = 0.003). No association between grade ≥2 pneumonitis and the absolute change in ventilated (p = 0.12) or perfused (p = 0.14) lung was observed. CONCLUSIONS:We observed a decrease in lung ventilation and perfusion on 68Ga 4D V/Q PET/CT from baseline to 3 months after RT. The association between the volume of well-perfused lung receiving near-therapeutic RT doses and the development of grade ≥2 pneumonitis warrants future investigation.

ABSTRACT Background The TROG 99.03 trial demonstrated improved progression‐free survival for patients with early‐stage follicular lymphoma (FL) treated with systemic therapy using rituximab‐cyclophosphamide, vincristine, prednisolone (R‐CVP) after involved‐field radiotherapy (RT) versus RT. As systemic therapy was associated with more acute toxicity, the possibility of long‐term toxicity, and no survival benefit yet, the cost‐effectiveness of RT+R‐CVP is important. Aim We performed a cost‐effectiveness analysis of RT (reference), RT+CVP, and RT+R‐CVP from the TROG 99.03 trial. Methods We constructed a Markov model (15‐year horizon) to compare treatments: RT (reference), RT+CVP and RT+R‐CVP from the 150 patients in the TROG 99.03 trial. Median follow‐up was 11.3 years (range: 4.4–17.8). Lifetime direct health care costs, quality‐adjusted life‐years (QALYs) and incremental cost‐effectiveness ratios (ICERs) were calculated. Australian dollars AUD$50,000 was defined as the proposed willingness‐to‐pay threshold (WTP). Results RT+R‐CVP was associated with an improvement of 0.711 QALYs compared to RT, 0.532 QALYs compared to RT+CVP, and was the dominant strategy. The costs of adverse events or retreatment for relapses or transformation had a minimal influence on the ICERs. Sensitivity analyses resulted in ICER values below the WTP with RT+R‐CVP remaining the dominant strategy. Conclusion RT+R‐CVP is clearly cost‐effective and was the dominant strategy in early‐stage FL compared to RT or RT+CVP as it delivers superior outcomes at a lower cost from the Australian tax‐payer's perspective. Trial Registration The authors have confirmed clinical trial registration is not needed for this submission

Abstract: Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) are highly radiosensitive with immune-driven abscopal responses reported. Programmed cell death 1/programmed cell death ligand 1 (PD-L1) inhibitors are relatively ineffective in DLBCL/FL; however, evidence suggests synergy with radiotherapy (RT), but no clear biomarkers. This phase 1 study examined the safety of escalating RT dose and treated volumes with durvalumab (PD-L1 inhibitor) in 34 adults with relapsed/refractory DLBCL and relapsed/refractory FL, and the role of immune-cell subsets on outcomes. Patients received external-beam RT (2.5-30 Gray [Gy], 5 or 10 fractions up to 3 target sites) plus durvalumab from RT day 2, until progression. Novel positron emission tomography (PET) biodistribution studies of 89Zr-durvalumab and CD8 T-cell minibody-89Zr-Df-crefmirlimab were incorporated. The RT recommended phase 2 dose was 10 Gy/5 fractions and 30 Gy/10 fractions to 3 sites for FL and DLBCL, respectively. The most common grade 3 to 4 toxicities included anemia (9%), neutropenia (11%), and liver dysfunction (5%). Overall response was 60% in FL (3/5; complete response, 40% [2/5]), and 14% in DLBCL (4/27; complete response, 7% [2/27]). Distinct peripheral blood and tumor T-cell features, including CD8 PET–determined intratumoral CD8 T-cells, correlated with response (P < .05). RT-durvalumab with 30 Gy/10 fractions of RT to 3 disease sites is safe, and offers promising responses in FL. Intratumoral and peripheral blood CD8 T-cell dysregulation correlate with treatment response. This trial was registered at www.clinicaltrials.gov as #NCT03610061.

BACKGROUND:During a phase 0 clinical trial of an investigational programmed cell death ligand-1 (PD-L1) PET tracer in patients with non-small cell lung cancer (NSCLC), three patients received booster doses of COVID-19 vaccines before PD-L1 imaging.METHODS:Five patients underwent whole-body PET/CT imaging with a novel PD-L1 tracer, constructed by attaching 89Zr to the anti PD-L1 antibody durvalumab. Intramuscular (deltoid) booster doses of mRNA BNT162b2 COVID-19 mRNA vaccine were coincidentally given to three patients in the month before PD-L1 tracer injection.RESULTS:Two recently-vaccinated patients, in remission of NSCLC and receiving non-immunosuppressive cancer therapies (immunotherapy and tyrosine kinase inhibitor respectively), showed increasing PD-L1 tracer uptake in ipsilateral axillary lymph nodes. No asymmetric nodal uptake was seen in a third recently-vaccinated patient who was receiving immunosuppressive chemotherapy, or in two patients not recently-vaccinated.CONCLUSION:Immune response to mRNA BNT162b2 vaccination may involve regulation by PD-L1 positive immune cells in local draining lymph nodes in immunocompetent patients.TRIAL REGISTRATION:This trial was registered with the Australian New Zealand Clinical Trials Registry. Registration number ACTRN12621000171819. Date of Trial Registration 8/2/2021. Date of enrolment of 1st patient 11/4/2021. URL of trial registry record: https://www.australianclinicaltrials.gov.au/anzctr/trial/ACTRN12621000171819 .

Although radiotherapy continues to evolve as a mainstay of the oncological armamentarium, research and innovation in radiotherapy in low-income and middle-income countries (LMICs) faces challenges. This third Series paper examines the current state of LMIC radiotherapy research and provides new data from a 2022 survey undertaken by the International Atomic Energy Agency and new data on funding. In the context of LMIC-related challenges and impediments, we explore several developments and advances—such as deep phenotyping, real-time targeting, and artificial intelligence—to flag specific opportunities with applicability and relevance for resource-constrained settings. Given the pressing nature of cancer in LMICs, we also highlight some best practices and address the broader need to develop the research workforce of the future. This Series paper thereby serves as a resource for radiation professionals.

Aim: Autologous anti-CD19 CAR T-cell therapy is an established standard-of-care (SOC) for relapsed/refractory (R/R) LBCL, but successful delivery requires disease control through the manufacturing period. The effects of bridging radiotherapy (RT) on outcome are unclear and impacted by disease factors such as bulk and distribution. We sought to compare outcomes of patients receiving RT-alone versus systemic-based bridging therapies (BT) delivered after apheresis and prior to axi-cel infusion. Method: Data were collected retrospectively for all patients with R/R LBCL treated with SOC axi-cel between 2020-2024 with ≥3 months of follow-up post CAR T-cell infusion. Patients were included in the RT-alone group if they received radiotherapy and no systemic therapy (apart from corticosteroids) as their BT. All other patients were included in the systemic-based bridging (ST) group. The primary endpoints were complete response (CR) rate and progression-free survival (PFS) measured from date of axi-cel infusion. We performed univariable and multivariable Cox proportional hazards (CoxPH) modelling of candidate predictive factors at two time points: (1) apheresis, and (2) pre-LD chemotherapy. Results: 98 patients received axi-cel with a median follow-up of 12.9 months. 35 patients received RT-alone and 63 patients received ST (including 22 patients in the ST group who received systemic and RT to a dominant mass as BT). Baseline characteristics were similar between RT-alone and ST groups at both the pre-apheresis and pre-LD timepoint. Median age pre-LD was 63 (range 22-81), RT median age 62 (range 42-80); ST median age 64 (range 22-81)), pre-LD ECOG ≥1 n=38, 39% (RT n=12, 34%; ST n=26, 41%), 54% had elevated LDH pre-apheresis (RT n=21, 62%; ST n=31, 49%), 42% had elevated LDH pre-LD (RT n=15, 43%; ST n=26, 41%), median total metabolic tumour volume (TMTV, ml) pre-apheresis was 48 (range 0 - 2809, RT median 46 (range 1 -1562); ST median 48.5 (range 0 - 2809)), median TMTV pre-LD was 21.5 (range 0 - 2777, RT median 22 (range 0 - 948); ST median 21 (range 0 - 2777)), 64% had stage 3-4 disease pre-apheresis (RT n=16, 46%; ST n=45, 75%) and 56% of patients had stage 3-4 disease pre-LD (RT n=19, 54%; ST n=36, 57%). Within the RT group, the median dosage was 30 (range 8-40) Gy delivered in a median of 10 fractions (range 1-20), with volumetric modulated arc therapy (VMAT) utilised in the 14/17 patients with assessable data. The CR rate post axi-cel infusion was 76%: 85% in the RT and 71% in the ST group (p=0.21). PFS at 12 months was 58% (95% CI: 0.49 - 0.69) for all patients: 75% (95%CI: 0.61 - 0.92) in the RT and 49% (95% CI: 0.38 - 0.64) in the ST group (p=0.02, log-rank test). Within the ST group, those who received concurrent RT (n=22) had near identical 12-month PFS when compared to the remaining patients in the ST group (n=41) - 12-month PFS 53% (95% CI: 0.35 - 0.79) versus 53% (95% CI: 0.37 - 0.75). On univariable CoxPH modelling, elevated LDH (Hazard Ratio (HR) 2.29, 95% CI 1.22 - 4.29) and TMTV continuous per 100ml (HR 1.10, 95% CI 1.05 - 1.15) were negatively associated with PFS at the pre-LD time point. This association was not seen at apheresis (elevated LDH HR 1.15 (95% CI 0.61 - 2.14) and TMTV HR 1.03 (95% C1 0.97 - 1.08)) suggesting that the impact of these risk factors is modifiable with BT. On multivariable CoxPH modelling of PFS adjusted for pre-LD ECOG, LDH, TMTV, and stage, RT alone in comparison to ST was associated with improved PFS (HR 0.41, 95% CI 0.19 - 0.88). Rates of grade 3 or above CAR T-cell associated toxicity were similar between groups, namely cytokine release syndrome n=2, 2% (RT n=1, 3%; ST n=1, 2%), immune effector cell associated neurotoxicity syndrome n=15, 15% (RT n=6, 17%; ST n=9, 14%), month 3 neutropenia n=13, 17% (RT n=7, 21%; ST n=6, 13%) and thrombocytopenia n=7, 9% (RT n=1, 3%; ST n=6, 15%). Conclusion: Bridging with radiotherapy-alone to axi-cel was associated with improved CR rates and PFS for LBCL in third-line and beyond, over systemic therapy-based BT. Multivariable analysis, adjusted for predictors of poor PFS, suggests the effect is not simply explained by better disease control at infusion. In this retrospective analysis it was not possible to separate the impact of disease distribution that is amenable to radiotherapy from the impact of radiotherapy itself. However, given the favourable outcomes seen, radiotherapy should be considered as part of the bridging strategy wherever feasible.