Patients with detectable ctDNA after radical intent treatment of metastatic spread from colorectal cancer (mCRC) have a very high risk of recurrence, which might be prevented with intensified adjuvant chemotherapy (aCTh). In low-stage CRC, a ctDNA-guided approach for aCTh resulted in less use of chemotherapy without compromising outcome. In OPTIMISE, we investigate ctDNA-guided aCTh after radical intent treatment of mCRC. The preplanned interim analysis aimed at testing feasibility at an early time, with the possibility of optimizing study and laboratory setup and sample size calculations, if needed, before continuing in a large-scale phase II, multicenter, randomized controlled trial. OPTIMISE is an open-label 1:1 randomized trial comparing ctDNA-guided aCTh against standard of care (SOC), with a run-in phase investigating feasibility measures. Analyses of plasma samples for ctDNA were done by ddPCR, detecting CRC-specific mutations and methylation of the NPY gene. Key inclusion criteria were radical intent treatment for mCRC and clinically eligible for triple-agent chemotherapy. All included patients underwent a PET/CT scan before randomization. Patients randomized to the standard arm were treated according to SOC. In the ctDNA-guided arm, ctDNA positivity led to an escalation strategy with triple-agent chemotherapy, and ctDNA negativity led to a de-escalation strategy by shared-decision making. Feasibility measures for the run-in phase were; inclusion of 30 patients over 12 months in two Danish hospitals, compliance with randomization >80%, rate of unexpected PET-CT-positive cases 80%. Thirty-two patients were included. The rate of PET-CT-positive cases was 22% (n=7/32). Five of the PET-CT-positive cases underwent radical intent treatment and hereafter randomization. One patient awaits randomization due to ongoing treatment of residual disease. 97% of the patients were randomized (n=30/31). Fourteen patients were randomly assigned to SOC and sixteen to ctDNA-guided adjuvant treatment and follow-up. All analyses of the baseline plasma samples in the ctDNA-guided arm passed the quality control process. The median time to result was 3 working days. 19% (n=3/16) had a ctDNA-positive baseline plasma sample. All ctDNA-positive patients were eligible for triple-agent chemotherapy. The median time from inclusion until the start of aCTh was 22 days. The delay from inclusion to the start of aCTh was primarily due to the study-specific PET/CT scan. To the best of our knowledge, this is the first randomized clinical trial evaluating ctDNA-guided adjuvant treatment after radical intent treatment for mCRC. Hence, there were significant reservations when planning the study, so it was of utmost importance to test feasibility early. When taking into account the low number of patients and the consequent uncertainty in the estimates, the feasibility measures were complied with. Furthermore, the median time to result and the quality of analyses were adequate. A minor modification of the study flow has been made to reduce the delay from inclusion to the start of aCTh; solely ctDNA-positive patients in the experimental arm will undergo a PET/CT scan. In conclusion, the study has proven feasible and continues with an optimized study flow in the planned large-scale phase II, multicenter, randomized controlled trial.

Patients with detectable circulating tumor DNA (ctDNA) after surgery for colorectal cancer are considered to have microscopic residual disease and consequently a high risk of recurrence. The same applies to patients after local ablative treatment (LAT) for metastatic colorectal cancer (mCRC). We observed a temporal clearance of ctDNA during adjuvant chemotherapy, but ctDNA recurrence after therapy termination. This indicate that patients with ctDNA positive status may need more intensified adjuvant chemotherapy than standard of care (SOC).

Background Decisions regarding tumor staging, operability, resectability, and treatment strategy in patients with esophageal cancer are made at multidisciplinary team (MDT) conferences. We aimed to assess interobserver agreement from four national MDT conferences and whether this would have a clinical impact.Methods A total of 20 patients with esophageal cancer were included across all four upper gastrointestinal (GI) cancer centers. Fully anonymized patient data were distributed among the MDT conferences which decided on TNM category, resectability, operability, curability, and treatment strategy blinded to each other’s decisions. The interobserver agreement was expressed as both the raw observer agreement and with Krippendorff’s α values. Finally, a case-by-case evaluation was performed to determine if disagreement would have had a clinical impact.Results A total of 80 MDT evaluations were available for analysis. A moderate to near-perfect observer agreement of 79.2%, 55.8%, and 82.5% for TNM category was observed, respectively. Substantial agreement for resectability and moderate agreement for curability were found. However, an only fair agreement was observed for the operability category. The treatment strategies had a slight agreement which corresponded to disagreement having a clinical impact in 12 patients.Conclusions Esophageal cancer MDT conferences had an acceptable interobserver agreement on resectability and TM categories; however, the operability assessment had a high level of disagreement. Consequently, the agreement on treatment strategy was reduced with a potential clinical impact. In future MDT conferences, emphasis should be on prioritizing the relevant information being readily available (operability, T & M categories) to minimize the risk of disagreement in the assessments and treatment strategies, and thus, delayed or suboptimal treatment.

BACKGROUND:In radiotherapy (RT) of lung cancer, dose to functional lung (FL) volumes segmented with two different methods (perfusion SPECT (Q-SPECT) and 4D-CT (4D) ventilation (V)) have been shown to correlate with the incidence of radiation pneumonitis (RP). This study aims to compare the FL volumes identified by both methods. MATERIAL AND METHODS:Thirty lung cancer patients had a 4D and Q-SPECT prior to treatment. Seventeen of these patients also had a ventilation SPECT (V-SPECT). FL sub-volumes were segmented automatically, using cut-off values. The volumes were compared in terms of overlap fraction (OF) relative to the minimal volume, and intersection fraction (IF) of the FL volume relative to the total lung volume (VLung). RESULTS:Cut-off values suggested in literature for Q-SPECT and 4D-V resulted in volumes differing in size by a median 18% [6%;31%], and a median OF and IF of 0.48 [0.23;0.70] and 0.09 [0.02;0.25], respectively. Segmenting volumes of comparable size of about 1/3 of VLung (FL-m(1/3), m = method) resulted in a median OF and IF of 0.43 [0.23;0.58] and 0.12 [0.06;0.19], respectively. Twenty-five patients (83%) had a reasonable overlap between FL-Q(1/3) and FL-4D-V(1/3) volumes, with OF values above 0.33. IF increased significantly (p = .036) compared to using fixed cut-off values. Similarly, volumes of comparable size of about 1/3 VLung were produced for V-SPECT, and FL-Q(1/3), FL-V(1/3), and FL-4D-V(1/3) were compared. The overlaps and intersections of FL-V(1/3) with FL-Q(1/3) volumes were significantly (p<.001) larger than the corresponding overlaps and intersections of FL-Q(1/3) with FL-4D(1/3) and FL-V(1/3) with FL-4D(1/3). CONCLUSION:The Q-SPECT and 4D-V methods do not segment entirely the same FL volumes. A reasonable overlap of the volumes along with the findings of other studies that both correlate to RP incidence, suggests that a combination of both volumes, e.g. using the IF, may be useful in RT treatment planning.

Background Although older studies argue that fluorine-18-fluorodeoxyglucose (FDG) positron emissions tomography (PET)/CT cannot demonstrate inflammation in cranial arteries the spatial resolution of modern PET systems have greatly improved allowing for more precise diagnostics of small structures. FDG PET/CT is widely used to diagnose large-vessel (LV) giant cell arteritis (GCA). Recognising FDG uptake in cranial arteries potentially adds to FDG PET/CTs diagnostic accuracy for GCA. Objectives To evaluate the diagnostic accuracy of conventional FDG PET/CT of the cranial arteries in GCA. Methods In a cohort of consecutively included glucocorticoid-naïve patients suspected of new-onset GCA, patients full-filling 1990 ACR criteria for GCA were identified. Conventional FDG PET/CT and clinical assessment was performed before treatment. Controls were age- and sex-matched patients with malignant melanoma (MM) who had a metastatic-disease-free follow-up FDG PET/CT≥6 months after MM resection. All PET images were evenly cropped to include only head and neck. Images were randomly assessed by 2 nuclear medicine physicians (10 years experience) blinded to clinical symptoms and findings. Training included review of 5 GCA-PET examinations (not part of cohort). Temporal (TA), maxillary (MA) and vertebral (VA) arteries were visually scored bilaterally. Arterial FDG uptake above surrounding tissue was considered indicative of inflammation and graded low or high. If disagreement between readers occurred, final score was settled by an expert nuclear medicine physician. Student t test was used for quantitative data. Inter-reader agreement was evaluated by Cohens weighted kappa (disagreement on diagnosis weighted 0, disagreement on FDG uptake intensity weighted 0.2). Results A total of 44 patients and 44 controls were identified. In both case and control group, the mean age was 69 years (p=0.45) and 25/44 were women. Large-vessel involvement was seen in 39/42 patients, and 35/42 were temporal artery biopsy positive. GCA patients’ median global assessment of disease activity was 8 (IQR: 5–10) and median CRP was 70 (95% CI: 58; 85) mg/L. Considering only FDG uptake in TA and/or MA, diagnostic sensitivity and specificity was 66% (95% CI: 50%–80%) and 100% (95% CI: 92%–100%). Including VA, sensitivity increased to 86% (95% CI: 73%–95%) and specificity remained high, 98% (95% CI: 88% to 100%). Cohens weighted kappa was 0.82 (agreement 93%, p=0.000) in a per segment analysis and kappa was 0.84 (agreement 92%, p=0.000) in diagnosis. Conclusions Inter-reader agreement on FDG uptake in cranial arteries is almost perfect, and cranial arteritis in glucocorticoid-naïve GCA patients can be readily and accurately diagnosed by conventional FDG PET/CT. The high diagnostic specificity suggests that TAB can be avoided in patients with FDG uptake in cranial arteries. Moreover, FDG PET/CT performed in patients with suspected vasculitis should always include head and neck. Disclosure of Interest None declared

Conclusion:The proposed iterative 4D CBCT reconstruction algorithm is more than an order of magnitude faster than other iterative algorithms described in the literature.It produces sharp, streak free images from standard 60s acquisitions used for 3D CBCT.For purposes such as patient setup and verification of tumour motion, the fast reconstruction algorithm presented enables online usage of 4D CBCT as a part of the clinical treatment routine.