CHARIOT: a phase I study of berzosertib with chemoradiotherapy in oesophageal and other solid cancers using time to event continual reassessment method.

BACKGROUND: Berzosertib (M6620) is a highly potent (IC50 = 19 nM) and selective, first-in-class ataxia telangiectasia-mutated and Rad3-related protein kinase (ATR) inhibitor. This trial assessed the safety, preliminary efficacy, and tolerance of berzosertib in oesophageal cancer (A1 cohort) with RT and advanced solid tumours (A2 cohort) with cisplatin and capecitabine. METHODS: Single-arm, open-label dose-escalation (Time-to-Event Continual Reassessment Method) trial with 16 patients in A1 and 18 in A2. A1 tested six dose levels of berzosertib with RT (35 Gy over 15 fractions in 3 weeks). RESULTS: No dose-limiting toxicities (DLTs) in A1. Eight grade 3 treatment-related AEs occurred in five patients, with rash being the most common. The highest dose (240 mg/m2) was determined as the recommended phase II dose (RP2D) for A1. Seven DLTs in two patients in A2. The RP2D of berzosertib was 140 mg/m2 once weekly. The most common grade ≥3 treatment-related AEs were neutropenia and thrombocytopenia. No treatment-related deaths were reported. CONCLUSIONS: Berzosertib combined with RT is feasible and well tolerated in oesophageal cancer patients at high palliative doses. Berzosertib with cisplatin and capecitabine was well tolerated in advanced cancer. Further investigation is warranted in a phase 2 setting. CLINICAL TRIALS IDENTIFIER: EU Clinical Trials Register (EudraCT) - 2015-003965-27 ClinicalTrials.gov - NCT03641547.

Synergistic effect of Betulinic acid, Apigenin and Skimmianine (BASk) in high cholesterol diet rabbit: Involvement of CD36-TLR2 signaling pathway.

BACKGROUND: Progression of chronic inflammatory disease, atherosclerosis is a multifactorial process. Cluster of differentiation 36 (CD36) mediated downstream activation of Toll like receptor 2 (TLR2) and NLRP3 (Nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3) inflammasome signaling pathway actively participates during chronic inflammation. Nowadays, synergistic combinations of bioactive compounds attained priority in the field of drug discovery and development as therapeutic agents. An investigation regarding the anti-inflammatory potential of a novel drug formulation, BASk which is a combination of three bioactive compounds Betulinic acid (B):Apigenin (A):Skimmianine (Sk) remains the focus area of this research study. We also elucidate the molecular mechanism behind the therapeutic potential of BASk through CD36 mediated activation TLR2-NLRP3 signaling pathway. METHODS: OxLDL induced hPBMCs used to screen out a suitable combination of BASk via MTT, COX, LOX, NOS and MPO assays. Hypercholesterolemia is induced in rabbits by supplementing with 1% cholesterol + 0.5% cholic acid and treated with BASk (2:2:1) (5 mg/Kg) and atorvastatin (10 mg/Kg) for 60 days. CD36, TLR2, NLRP3, NFκB, cytokines, endothelial damage were quantified by reverse transcription, real time PCR, ELISA, flow cytometry and histopathology. RESULTS: hPBMCs pretreated with BASk at 2:2:1 ratio significantly decreased the activities of COX, 15-LOX, NOS and MPO on OxLDL induction than quercetin. Down regulation of CD36, TLR2, MyD88, TRAF6 by BASk further buttressed NLRP3 inflammasome activation mediated by the transcription factor NFκB. This is in correlation with the effect of BASk by balancing pro (IL-1ß, IL-18) and anti-inflammatory (TGF-ß) mediators in the aortic endothelial cells. CONCLUSION: BASk exerted its anti-inflammatory potential by reducing pro-inflammatory mediators during cholesterol supplementation via down regulating CD36 mediated TLR2 - NLRP3 inflammasome cascade. This deciphers a synergistic combination named BASk (2:2:1) as a novel drug formulation against chronic inflammatory disease, atherosclerosis.

Feasibility of abdominal fat quantification on MRI and impact on effectiveness of abdominal compression for radiotherapy motion management.

The impact of fat on abdominal compression effectiveness in abdominal cancers was determined using magnetic resonance imaging (MRI). Visceral and subcutaneous fat were delineated on T2W 3D MRI, and motion change with compression was measured on 2D cine MRI. Results from 16 participants showed no correlation between fat percentage, body mass index (BMI), and motion change. Median BMI was 28.7 (SD, 4.9). Mean motion reduction was 7.8 mm (IQR, 5.0; p = 0.001) with compression. While no direct link was found between fat, BMI, and compression effectiveness, abdominal compression remains crucial for motion management in radiotherapy planning, providing dosimetric benefits.

SCOPE 2 - Still Answering the Unanswered Questions in Oesophageal Radiotherapy? SCOPE 2: a Randomised Phase II/III Trial to Study Radiotherapy Dose Escalation in Patients with Oesophageal Cancer Treated with Definitive Chemoradiation with an Embedded Phase II Trial for Patients with a Poor Early Response using Positron Emission Tomography/Computed Tomography.

The SCOPE 2 trial of definitive chemoradiotherapy in oesophageal cancer investigates the benefits of radiotherapy dose escalation and systemic therapy optimisation. The trial opened in 2016. The landscape of oesophageal cancer treatment over the lifetime of this trial has changed significantly and the protocol has evolved to reflect this. However, with the recent results of the Dutch phase III ART DECO study showing no improvement in local control or overall survival with radiotherapy dose escalation in a similar patient group, we sought to determine if the SCOPE 2 trial is still answering the key unanswered questions for oesophageal radiotherapy. Here we discuss the rationale behind the SCOPE 2 trial, outline the trial schema and review current data on dose escalation and outline recommendations for future areas of research.

A treatment planning comparison of photon stereotactic ablative radiotherapy and proton beam therapy for the re-irradiation of pelvic cancer recurrence.

BACKGROUND: Patients who experience a pelvic cancer recurrence in or near a region that received initial radiotherapy, typically have few options for treatment. Organs at risk (OAR) have often reached their dose constraint limits leaving minimal dose remaining for standard re-irradiation (reRT). However, photon based stereotactic ablative radiotherapy (SABR) has been utilised for reRT with promising initial results although meeting OAR constraints can be challenging. Proton beam therapy (PBT) could offer an advantage. MATERIALS AND METHODS: SABR plans used for treatment for ten pelvic reRT patients were dosimetrically compared to PBT plans retrospectively planned using the same CT and contour data. PBT plans were created to match the CTV dose coverage of SABR treatment plans with V100% ≥95%. An 'as low as reasonably achievable' approach was taken to OAR tolerances with consideration of OAR dose from the initial radiation (using equivalent dose in 2 Gy fractions). RESULTS: Dosimetric comparison of relevant OAR statistics showed a decrease in OAR dose using PBT over SABR in all patients, with equivalent target coverage. The largest statistically significant reduction was seen for the colon D0.5 cm3 with a median reduction from 13.1 Gy to 5.9 Gy. There were statistically significant dose reductions in the median dose to small bowel, sacral plexus and cauda equina. CONCLUSION: PBT has the potential for significant dose reductions for OARs in the pelvic reRT setting compared to SABR. However, it remains unclear if the magnitude of these OAR dose reductions will translate into clinical benefit.

The Promise of Proton Beam Therapy for Oesophageal Cancer: A Systematic Review of Dosimetric and Clinical Outcomes.

AIMS: Due to its physical advantages over photon radiotherapy, proton beam therapy (PBT) has the potential to improve outcomes from oesophageal cancer. However, for many tumour sites, high-quality evidence supporting PBT use is limited. We carried out a systematic review of published literature of PBT in oesophageal cancer to ascertain potential benefits of this technology and to gauge the current state-of-the-art. We considered if further evaluation of this technology in oesophageal cancer is desirable. MATERIALS AND METHODS: A systematic literature search of Medline, Embase, Cochrane Library and Web of Science using structured search terms was carried out. Inclusion criteria included non-metastatic cancer, full articles and English language studies only. Articles deliberating technical aspects of PBT planning or delivery were excluded to maintain a clinical focus. Studies were divided into two sections: dosimetric and clinical studies; qualitatively synthesised. RESULTS: In total, 467 records were screened, with 32 included for final qualitative synthesis. This included two prospective studies with the rest based on retrospective data. There was heterogeneity in treatment protocols, including treatment intent (neoadjuvant or definitive), dose, fractionation and chemotherapy used. Compared with photon radiotherapy, PBT seemed to reduce dose to organs at risk, especially lung and heart, although not for all reported parameters. Toxicity outcomes, including postoperative complications, were reduced compared with photon radiotherapy. Survival outcomes were reported to be at least comparable with photon radiotherapy. CONCLUSION: There is a paucity of high-quality evidence supporting PBT use in oesophageal cancer. Wide variation in intent and treatment protocols means that the role and 'gold-standard' treatment protocol are yet to be defined. Current literature suggests significant benefit in terms of toxicity reduction, especially in the postoperative period, with comparable survival outcomes. PBT in oesophageal cancer holds significant promise for improving patient outcomes but requires robust systematic evaluation in prospective studies.

Impact of Peer Review in Reducing Uncertainty in the Definition of the Lung Target Volume Among Trainee Oncologists.

AIMS: To evaluate the impact of peer review and contouring workshops on reducing uncertainty in target volume delineation for lung cancer radiotherapy. MATERIALS AND METHODS: Data from two lung cancer target volume delineation courses were analysed. In total, 22 trainees in clinical oncology working across different UK centres attended these courses with priori experience in lung cancer radiotherapy. The courses were made up of short presentations and contouring practice sessions. The participants were divided into two groups and asked to first individually delineate (IND) and then individually peer review (IPR) the contours of another participant. The contours were discussed with an expert panel consisting of two consultant clinical oncologists and a consultant radiologist. Contours were analysed quantitatively by measuring the volume and local distance standard deviation (localSD) from the reference expert consensus contour and qualitatively through visual analysis. Feedback from the participants was obtained using a questionnaire. RESULTS: All participants applied minor editing to the contours during IPR, leading to a non-statistically significant reduction in the mean delineated volume (IND = 140.92 cm3, IPR = 125.26 cm3, P = 0.211). The overall interobserver variation was similar, with a localSD of 0.33 cm and 0.38 cm for the IND and IPR, respectively (P = 0.848). Six participants (29%) carried out correct major changes by either including tumour or excluding healthy tissue. One participant (5%) carried out an incorrect edit by excluding parts of the tumour, while another observer failed to identify a major contour error. The participants' level of confidence in target volume delineation increased following the course and identified the discussions with the radiologist and colleagues as the most important highlights of the course. CONCLUSION: IPR could improve target volume delineation quality among trainee oncologists by identifying most major contour errors. However, errors were also introduced after IPR, suggesting the need to further discuss major changes with a multidisciplinary team.

Outcome of Weekly Carboplatin-Paclitaxel-based Definitive Chemoradiation in Oesophageal Cancer in Patients Not Considered to be Suitable for Platinum-Fluoropyrimidine-based Treatment: A Multicentre, Retrospective Review.

AIMS: Although cisplatin-fluoropyrimidine-based definitive chemoradiotherapy (dCRT) is a standard of care for oesophageal cancer, toxicity is significant and limits its use in elderly and frail patients. Weekly carboplatin-paclitaxel-based dCRT provides a viable alternative, although prospective data are lacking in the dCRT setting. Here we report the results of a national, multicentre retrospective review of outcome in patients treated with weekly carboplatin-paclitaxel-based dCRT. MATERIALS AND METHODS: In this multicentre retrospective study of nine radiotherapy centres across the UK we evaluated the outcome of patients who had non-metastatic, histologically confirmed carcinoma of the oesophagus (adenocarcinoma, squamous cell or undifferentiated; World Health Organization performance status 0-2; stage I-III disease) and had been selected to receive weekly carboplatin-paclitaxel-based dCRT as they were considered not suitable for cisplatin-fluoropyrimidine-based dCRT. dCRT consisted of carboplatin AUC 2 and paclitaxel 50 mg/m2 (days 1, 8, 15, 22, 29) and the recommended radiation dose was 50 Gy in 25 daily fractions. We assessed overall survival, progression-free survival (PFS; overall, local and distant), proportion of patients who were failure free at the response assessment (12 weeks after dCRT), treatment compliance and toxicity. RESULTS: In total, 214 patients from nine UK centres were treated between 15 February 2013 and 19 March 2019: 39.7% of patients were ≥75 years; 18.7% ≥ 80 years. Indications for weekly carboplatin-paclitaxel-based dCRT were comorbidities (47.2%), clinician choice (36.4%) and poor tolerance/progression on cisplatin-fluoropyrimidine induction chemotherapy (15.8%). The median overall survival was 24.28 months (95% confidence interval 20.07-30.09) and the median PFS was 16.33 months (95% confidence interval 14.29-20.96). Following treatment, 69.1% (96/139) had a combined complete response on endoscopy with non-progression (complete response/partial response/stable disease) on imaging. The 1- and 2-year overall survival rates for this patient group were 81.9% (95% confidence interval 75.6-86.8%) and 50.6% (95% confidence interval 40.5-60.0%), respectively. Thirty-three per cent (n = 70) of patients experienced at least one grade 3 + acute toxicity (grade 3/4 haematological: 10%; grade 3/4 non-haematological: 32%) and there were no treatment-related deaths. 86.9% of patients completed at least four cycles of concomitant weekly carboplatin-paclitaxel-based chemotherapy and planned radiotherapy was completed in 97.7% (209/214). CONCLUSION: Weekly carboplatin-paclitaxel-based CRT seems to be well tolerated in elderly patients and in those with comorbidities, where cisplatin-fluoropyrimidine-based dCRT is contraindicated. Survival outcomes are comparable with cisplatin-fluoropyrimidine-based dCRT.

Comparative Dosimetric Analysis and Normal Tissue Complication Probability Modelling of Four-Dimensional Computed Tomography Planning Scans Within the UK NeoSCOPE Trial.

AIMS: NeoSCOPE is a trial of two different neoadjuvant chemoradiotherapy regimens for resectable oesophageal cancer and was the first multicentre trial in the UK to incorporate four-dimensional computed tomography (4D-CT) into radiotherapy planning. Despite 4D-CT being increasingly accepted as a standard of care for lower third and junctional oesophageal tumours, there is limited evidence of its benefit over standard three-dimensional computed tomography (3D-CT). MATERIALS: Using NeoSCOPE 4D-CT cases, we undertook a dosimetric comparison study of 3D-CT versus 4D-CT plans comparing target volume coverage and dose to organs at risk. We used established normal tissue complication probability models to evaluate the potential toxicity reduction of using 4D-CT plans in oesophageal cancer. RESULTS: 4D-CT resulted in a smaller median absolute PTV volume and lower dose levels for all reported constraints with comparable target volume coverage. NTCP modelling suggests a significant relative risk reduction of cardiac and pulmonary toxicity endpoints with 4D-CT. CONCLUSION: Our work shows that incorporating 4D-CT into treatment planning may significantly reduce the toxicity burden from this treatment.

Hypofractionated Radiotherapy in Oesophageal Cancer for Patients Unfit for Systemic Therapy: A Retrospective Single-Centre Analysis.

AIMS: Chemoradiotherapy (CRT) is established as a superior treatment option to definitive radiotherapy in the non-surgical management of oesophageal cancer. For patients precluded from CRT through choice or comorbidity there is little evidence to guide delivery of single-modality radiotherapy. In this study we outline outcomes for patients unfit for CRT who received a hypofractionated radiotherapy (HRT) regimen. MATERIALS AND METHODS: A retrospective UK single-centre analysis of 61 consecutive patients with lower- or middle-third adenocarcinoma (OAC; 61%) or squamous cell carcinoma of the oesophagus managed using HRT with radical intent between April 2009 and 2014. Treatment consisted of 50 Gy in 16 fractions (n = 49, 80.3%) or 50-52.5 Gy in 20 fractions (n = 12, 19.7%). Outcomes were referenced against a contemporaneous comparator cohort of 80 (54% OAC) consecutive patients managed with conventionally fractionated CRT within the same centre. RESULTS: Three-year and median overall survival were, respectively, 56.9% and 29 months with HRT compared with 55.5% and 26 months for CRT; adjusted hazard ratio 0.79 (95% confidence interval 0.48-1.28). Grade 3 and 4 toxicity rates were low at 16.4% (n = 10) for those receiving HRT and 40.2% (n = 32) for the CRT group. In patients with OAC, CRT delivered superior overall survival (hazard ratio 0.46; 95% confidence interval 0.25-0.85) and progression-free survival (hazard ratio 0.45; 95% confidence interval 0.23-0.88) when compared with HRT. CONCLUSIONS: The HRT regimen described here was safe and tolerable in patients unable to receive CRT, and delivered promising survival outcomes. The use of HRT for the treatment of oesophageal cancer, both alone and as a sequential or concurrent treatment with chemotherapy, requires further study. New precision radiotherapy technologies may provide additional scope for improving outcomes in oesophageal cancer using HRT-based approaches and should be evaluated.

Driving developments in UK oesophageal radiotherapy through the SCOPE trials.

BACKGROUND: The SCOPE trials (SCOPE 1, NeoSCOPE and SCOPE 2) have been the backbone of oesophageal RT trials in the UK. Many changes in oesophageal RT techniques have taken place in this time. The SCOPE trials have, in addition to adopting these new techniques, been influential in aiding centres with their implementation. We discuss the progress made through the SCOPE trials and include details of a questionnaire sent to participating centres. to establish the role that trial participation played in RT changes in their centre. METHODS: Questionnaires were sent to 47 centres, 27 were returned. RESULTS: 100% of centres stated their departmental protocol for TVD was based on the relevant SCOPE trial protocol. 4DCT use has increased from 42 to 71%. Type B planning algorithms, mandated in the NeoSCOPE trial, were used in 79.9% pre NeoSCOPE and now in 83.3%. 12.5% of centres were using a stomach filling protocol pre NeoSCOPE, now risen to 50%. CBCT was mandated for IGRT in the NeoSCOPE trial. 66.7% used this routinely pre NeoSCOPE/SCOPE 2 which has risen to 87.5% in the survey. CONCLUSION: The results of the questionnaires show how participation in national oesophageal RT trials has led to the adoption of newer RT techniques in UK centres, leading to better patient care.

Expression of the chemokine antagonist vMIP II using a non-viral vector can prolong corneal allograft survival.

BACKGROUND: The expression of chemokines is central to the recruitment of inflammatory cells for graft rejection, and modulation of chemokine action is of potential in preventing graft rejection. We have examined chemokine expression in a murine model of corneal allograft rejection, and also determined the effect of expressing a broad acting chemokine antagonist, viral macrophage inflammatory protein II (vMIP II), on graft survival. METHOD: The expression of chemokines in a murine model of corneal transplantation was determined by real time RT-PCR and, in the case of regulated on activation normal T-cell expressed and secreted, by ELISA. The plasmid encoding the virally derived chemokine antagonist, vMIP II, was introduced into the corneal endothelial cells using a non-viral vector consisting of liposomes and transferrin. The expression and activity of vMIP II was determined by ELISA and functional assays, and the effect on graft survival noted. RESULTS: After allotransplantation, there was up-regulation of all 11 chemokines examined. After gene delivery, there was expression of active vMIP II for more than 14 days and considerable prolongation of graft survival. This was associated with a decrease in leukocyte infiltration of the stroma of the cells. CONCLUSION: As expected there was considerable up-regulation of chemokines during allograft rejection. The expression of vMIP II showed considerable prolongation of graft survival. This is the first time we have observed prolongation of graft survival after a non-viral (as opposed to viral) means of gene delivery and indicates the potential of interfering with chemokine action to prevent corneal graft failure.

Knockdown of mouse VCAM-1 by vector-based siRNA.

Graft rejection is critically dependent on the recruitment of leukocytes via adhesion molecules on the endothelium, and inhibition of these interactions can prolong graft survival. We have therefore developed an approach using siRNA to inhibit the expression of VCAM-1 in endothelial cells. We transfected siRNA constructs into murine corneal and vascular endothelium and looked at expression of VCAM-1 and other surface molecules by flow cytometry. Adhesion assays (both static and under flow) were used to determine the effect of VCAM-1 inhibition. The activation of cellular stress responses was assessed by RT-PCR. Constructs encoding siRNA can block expression of VCAM-1 in both corneal and vascular endothelial cells (in the latter case after cytokine stimulation). Inhibition of VCAM-1 expression reduced the ability of T cells to adhere to endothelium. However, there were non-specific effects of siRNA expression, including upregulation of (Programmed Death Ligand 1) PDL1 and decreased cell growth. Analysis of stress pathways showed that the endothelial cells transfected with siRNA had upregulated molecules associated with cell stress. While these data are supportive of a potential therapeutic role for siRNA constructs in blocking the expression of adhesion molecules, they also highlight potential non-specific effects of siRNA that must be carefully considered in any application of this technology.

Superiority of Deformable Image Co-registration in the Integration of Diagnostic Positron Emission Tomography-Computed Tomography to the Radiotherapy Treatment Planning Pathway for Oesophageal Carcinoma.

AIMS: To investigate the use of image co-registration in incorporating diagnostic positron emission tomography-computed tomography (PET-CT) directly into the radiotherapy treatment planning pathway, and to describe the pattern of local recurrence relative to the PET-avid volume. MATERIALS AND METHODS: Fourteen patients were retrospectively identified, six of whom had local recurrence. The accuracy of deformable image registration (DIR) and rigid registration of the diagnostic PET-CT and recurrence CT, to the planning CT, were quantitatively assessed by comparing co-registration of oesophagus, trachea and aorta contours. DIR was used to examine the correlation between PET-avid volumes, dosimetry and site of recurrence. RESULTS: Positional metrics including the dice similarity coefficient (DSC) and conformity index (CI), showed DIR to be superior to rigid registration in the co-registration of diagnostic and recurrence imaging to the planning CT. For diagnostic PET-CT, DIR was superior to rigid registration in the transfer of oesophagus (DSC=0.75 versus 0.65, P<0.009 and CI=0.59 versus 0.48, P<0.003), trachea (DSC=0.88 versus 0.65, P<0.004 and CI=0.78 versus 0.51, P<0.0001) and aorta structures (DSC=0.93 versus 0.86, P<0.006 and CI=0.86 versus 0.76, P<0.006). For recurrence imaging, DIR was superior to rigid registration in the transfer of trachea (DSC=0.91 versus 0.66, P<0.03 and CI=0.83 versus 0.51, P<0.02) and oesophagus structures (DSC=0.74 versus 0.51, P<0.004 and CI=0.61 versus 0.37, P<0.006) with a non-significant trend for the aorta (DSC=0.91 versus 0.75, P<0.08 and CI=0.83 versus 0.63, P<0.06) structure. A mean inclusivity index of 0.93 (range 0.79-1) showed that the relapse volume was within the planning target volume (PTVPET-CT); all relapses occurred within the high dose region. CONCLUSION: DIR is superior to rigid registration in the co-registration of PET-CT and recurrence CT to the planning CT, and can be considered in the direct integration of PET-CT to the treatment planning process. Local recurrences occur within the PTVPET-CT, suggesting that this is a suitable target for dose-escalation strategies.

Risk of recurrent venous thromboembolism and major hemorrhage in cancer-associated incidental pulmonary embolism among treated and untreated patients: a pooled analysis of 926 patients.

UNLABELLED: ESSENTIALS: We performed a pooled analysis of 926 patients with cancer-associated incidental pulmonary embolism (IPE). Vitamin K antagonists (VKA) are associated with a higher risk of major hemorrhage. Recurrence risk is comparable after subsegmental and more proximally localized IPE. Our results support low molecular weight heparins over VKA and similar management of subsegmental IPE. BACKGROUND: Incidental pulmonary embolism (IPE) is defined as pulmonary embolism (PE) diagnosed on computed tomography scanning not performed for suspected PE. IPE has been estimated to occur in 3.1% of all cancer patients and is a growing challenge for clinicians and patients. Nevertheless, knowledge about the treatment and prognosis of cancer-associated IPE is scarce. We aimed to provide the best available evidence on IPE management. METHODS: Incidence rates of symptomatic recurrent venous thromboembolism (VTE), major hemorrhage, and mortality during 6-month follow-up were pooled using individual patient data from studies identified by a systematic literature search. Subgroup analyses based on cancer stage, thrombus localization, and management were performed. RESULTS: In 926 cancer patients with IPE from 11 cohorts, weighted pooled 6-month risks of recurrent VTE, major hemorrhage and mortality were 5.8% (95% confidence interval [CI] 3.7-8.3%), 4.7% (95% CI 3.0-6.8%), and 37% (95% CI 28-47%). VTE recurrence risk was comparable under low molecular weight heparins (LMWH) and vitamin K antagonists (VKAs) (6.2% vs. 6.4%; hazard ratio [HR] 0.9; 95% CI 0.3-3.1), while 12% in untreated patients (HR 2.6; 95% CI 0.91-7.3). Risk of major hemorrhage was higher under VKAs than under LMWH (13% vs. 3.9%; HR 3.9; 95% CI 1.6-10). VTE recurrence risk was comparable in patients with an subsegmental IPE and those with a more proximally localized IPE (HR 1.1; 95% CI 0.50-2.4). CONCLUSION: These results support the current recommendation to anticoagulate cancer-associated IPE with LMWH and argue against different management of subsegmental IPE.