Which patients are prone to undergo disproportionate recurrent CT imaging and should we worry?

Purpose: To identify the spectrum of patients who undergo disproportionate recurrent computed tomography (CT) imaging, and to explore the cumulative effects of radiation exposure and intravenously injected contrast agents in these patients. Methods: This retrospective study investigated all patients who had undergone 40 or more CT scans at a tertiary care center between 2007–2017. Results: Fifty-six patients who had undergone a median of 47 (range: 40–92) CT scans were included. The main reason for CT scanning in all patients was oncological, and 55 patients (98.2 %) had metastatic disease. Twenty-six patients (45.6) had received chemotherapy, 35 (62.5 %) radiation therapy, 38 (67.9 %) targeted therapy, 12 (21.4 %) liver tumor microwave ablation, 44 (78.6 %) major surgery, and 34 (60.7 %) had participated in a therapeutic trial. Mean cumulative effective dose was 187.4 mSv (range: 120.7–278.4 mSv). Median estimated radiation-induced lifetime attributable risk (LAR) of cancer incidence was 1.0 % (range: 0.20–2.36 %). Mean estimated radiation-induced LAR of cancer mortality was 0.68 % (range: 0.18–1.37 %). Mean cumulative volume of intravenously injected iomeprol was 2339 mL (range: 540−3605 mL). Three patients (5.4 %) had developed severely decreased kidney function (estimated glomerular filtration rate between 15 and 29 mL/min per 1.73 m² for at least 3 months). Conclusion: Patients with metastatic disease who experience a relatively long survival may be prone to undergo disproportionate recurrent CT imaging. The non-negligible CT radiation-induced cancer risk and mortality should be taken into account in these patients, while the effect of cumulatively administered CT contrast agents on kidney function requires further investigation

Reconsider radiation exposure from imaging during immune checkpoint inhibitor trials to reduce risk of secondary cancers in long-term survivors?

Immune checkpoint inhibitors (ICI) have improved outcomes for patients with advanced cancers, and results in increasing numbers of long-term survivors. For registration studies, progression-free survival and disease-free survival often serve as primary endpoints. This requires repeated computed tomography (CT) scans for tumour imaging which might lead to major radiation exposure. To determine this, all immune checkpoint inhibitors trials that led to FDA approval were retrieved up to July 29, 2019. From the available protocols, imaging modalities and schedules used in each trial were identified. The anticipated cumulative number of scans made after 1, 3, 5, and 10 years study participation were calculated. The percentage of lifetime attributable cancer risk was calculated using the Biological Effects of Ionizing Radiation VII report. Fifty-one trials were identified, from which 39 protocols were retrieved. Four were adjuvant trials. All protocols required repeated chest-abdomen imaging and specified CT scans as preferred imaging modality. Median calculated cumulative numbers of chest-abdomen CT scans after 1, 3, 5, and 10 years study participation were 7, 16, 24 and 46, respectively. For ages 20-70 years at study entry, the average lifetime attributable cancer risk after 1 year of study participation ranged from 1.11 to 0.40% for men and from 1.87 to 0.46% for women. At 10 years study participation, this risk increased to a range of 5.91 to 1.96% for men and 9.64 to 2.32% for women. Given high imaging radiation exposure for long-term survivors in current ICI trials an adaptive imaging interval and imaging termination rules should be considered for long-term survivors

Lessons learnt from scoring adjuvant colon cancer trials and meta-analyses using the ESMO-Magnitude of Clinical Benefit Scale V.1.1

Click here to listen to the Podcast BACKGROUND: Form 1 of the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS) serves to grade therapies with curative intent. Hitherto only few trials with curative intent have been field tested using form 1. We aimed to evaluate the applicability of the scale and to assess the reasonableness of the generated scores in early colon cancer, in order to identify shortcomings that may be rectified in future amendments. METHODS: Adjuvant studies were identified in PubMed, Food and Drug Administration and European Medicines Agency registration sites, as well as ESMO and National Comprehensive Cancer Network guidelines. Studies meeting inclusion criteria were graded using form 1 of the ESMO-MCBS V.1.1 and field tested by ESMO Colorectal Cancer Faculty. Shortcomings of the scale were identified and evaluated. RESULTS: Eighteen of 57 trials and 7 out of 14 meta-analyses identified met criteria for ESMO-MCBS V.1.1 grading. In stage III colon cancer, randomised clinical trials and meta-analyses of modulated 5-fluorouracil (5-FU) based chemotherapy versus surgery scored ESMO-MCBS grade A and randomised controlled trials (RCTs) and meta-analyses comprising oxaliplatin added to this 5-FU backbone showed a more modest additional overall survival benefit (grade A and B). For stage II colon cancer, the findings are less consistent. The fluoropyrimidine trials in stage II were graded 'no evaluable benefit' but the most recent meta-analysis demonstrated a 5.4% survival advantage after 8 years follow-up (grade A). RCTs and a meta-analysis adding oxaliplatin demonstrated no added benefit. Exploratory toxicity evaluation and annotation was problematic given inconsistent toxicity reporting and limited results of late toxicity. Field testers (n=37) reviewed the scores, 25 confirmed their reasonableness, 12 found them mostly reasonable. Moreover, they identified the inability of crediting improved convenience in non-inferiority trials as a shortcoming. CONCLUSION: Form 1 of the ESMO-MCBS V.1.1 provided very reasonable grading for adjuvant colon cancer studies

Molecular imaging to support cancer immunotherapy

The advent of immune checkpoint inhibitors has reinvigorated the field of immuno-oncology. These monoclonal antibody-based therapies allow the immune system to recognize and eliminate malignant cells. This has resulted in improved survival of patients across several tumor types. However, not all patients respond to immunotherapy therefore predictive biomarkers are important. There are only a few Food and Drug Administration-approved biomarkers to select patients for immunotherapy. These biomarkers do not consider the heterogeneity of tumor characteristics across lesions within a patient. New molecular imaging tracers allow for whole-body visualization with positron emission tomography (PET) of tumor and immune cell characteristics, and drug distribution, which might guide treatment decision making. Here, we summarize recent developments in molecular imaging of immune checkpoint molecules, such as PD-L1, PD-1, CTLA-4, and LAG-3. We discuss several molecular imaging approaches of immune cell subsets and briefly summarize the role of FDG-PET for evaluating cancer immunotherapy. The main focus is on developments in clinical molecular imaging studies, next to preclinical studies of interest given their potential translation to the clinic

Opportunities on the horizon for the management of early colon cancer

There is a clear unmet need to improve early colon cancer management. This review encompasses the current systemic treatment landscape and summarises novel and pivotal trials. The Immunoscore and circulating tumour DNA (ctDNA) are studied to evaluate which patients should receive no, 3, or 6 months of adjuvant treatment. Several trials also test escalating treatment strategies for non-cleared ctDNA following standard adjuvant chemotherapy. Advances made in treating patients with metastatic colon cancer are now being translated to the early colon cancer setting. Two ongoing RCTs study immune checkpoint inhibitors (ICI) in patients with microsatellite instable high (MSI-H) early colon cancer as adjuvant treatment. Neo-adjuvant treatment is being studied in several ongoing RCTs as well. The complete response rate in patients with MSI-H tumours following ICI in neoadjuvant trials has potential organ-sparing implications

Urine as Sample Type for Molecular Diagnosis of Natural Yellow Fever Virus Infections.

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Potential, Limitations and Risks of Cannabis-Derived Products in Cancer Treatment

The application of cannabis products in oncology receives interest, especially from patients. Despite the plethora of research data available, the added value in curative or palliative cancer care and the possible risks involved are insufficiently proven and therefore a matter of debate. We aim to give a recommendation on the position of cannabis products in clinical oncology by assessing recent literature. Various types of cannabis products, characteristics, quality and pharmacology are discussed. Standardisation is essential for reliable and reproducible quality. The oromucosal/sublingual route of administration is preferred over inhalation and drinking tea. Cannabinoids may inhibit efflux transporters and drug-metabolising enzymes, possibly inducing pharmacokinetic interactions with anticancer drugs being substrates for these proteins. This may enhance the cytostatic effect and/or drug-related adverse effects. Reversely, it may enable dose reduction. Similar interactions are likely with drugs used for symptom management treating pain, nausea, vomiting and anorexia. Cannabis products are usually well tolerated and may improve the quality of life of patients with cancer (although not unambiguously proven). The combination with immunotherapy seems undesirable because of the immunosuppressive action of cannabinoids. Further clinical research is warranted to scientifically support (refraining from) using cannabis products in patients with cancer

89Zr-3,2-HOPO-mesothelin antibody PET imaging reflects tumor uptake of mesothelin targeted 227Th-conjugate therapy in mice

Rationale: Mesothelin targeted thorium-227 conjugate (227Th-MSLN) is a novel targeted alpha therapy developed to treat mesothelin overexpressing cancers. We radiolabeled the same antibody-chelator conjugate with zirconium-89 (89Zr-MSLN) to evaluate if positron emission tomography (PET) imaging with 89Zr-MSLN matches with 227Th-MSLN tumor uptake, biodistribution, and antitumor activity. Experimental design: Serial PET imaging with protein doses of 4, 20, or 40 μg 89Zr-MSLN and 89Zr-control was performed up to 168 h post tracer injection (pi) in high (HT29-MSLN) and low (BxPc3) mesothelin expressing human tumor-bearing nude mice. 89Zr-MSLN and 227Th-MSLN ex vivo tumor uptake and biodistribution were compared at 6 time-points in HT29-MSLN and in medium mesothelin expressing (OVCAR-3) tumor-bearing mice. 89Zr-MSLN PET imaging was performed before 227Th-MSLN treatment in HT29-MSLN and BxPc3 tumor-bearing mice. Results: 89Zr-MSLN PET imaging showed mean standardized uptake value (SUVmean) in HT29-MSLN tumors of 2.2 ± 0.5. Ex vivo tumor uptake was 10.6% ± 2.4% injected dose per gram (%ID/g) at 168 h. 89Zr-MSLN tumor uptake was higher than uptake of 89Zr-control (P = 0.0043). 89Zr-MSLN and 227Th-MSLN showed comparable tumor uptake and biodistribution in OVCAR-3 and HT29-MSLN tumor-bearing mice. SUVmean was 1.8-fold higher in HT29-MSLN than in BxPc3 tumors, matching with stronger 227Th-MSLN antitumor activity. Conclusion: 89Zr-MSLN PET imaging reflected mesothelin expression and matched with 227Th-MSLN tumor uptake, biodistribution, and antitumor activity. Our data support the clinical exploration of 89Zr-MSLN PET imaging together with 227Th-MSLN therapy, both using the same antibody-chelator conjugate

Abstract CT207: A phase 1 open-label, dose escalation and expansion trial to investigate the safety, pharmacokinetics and pharmacodynamics of CB307, a Trispecific Humabody® T-cell enhancer, in patients with PSMA+ advanced and/or metastatic solid tumors (POTENTIA)

Humabodies* are fully human VH antibody components that can be connected by short peptide linkers to make multi-specific therapeutics. CB307 is a tri-specific Humabody targeting prostate specific membrane antigen (PSMA/FOLH1), CD137 (4-1BB/TNFSF9) and human serum albumin (HSA). Unlike CD3 targeting bispecific compounds, stimulation of CD137 on T cells can promote T cell cytotoxicity, proliferation, survival and memory T cell formation without compromising safety, including cytokine release syndrome (CRS). In addition, HSA binding assists CB307 penetration into the tumor since albumin is enriched in the tumor microenvironment. Several cancers including prostate cancer and lung cancer are known to have PSMA expression. The objectives of the POTENTIA study are to determine the maximum tolerated dose (MTD) and pharmacokinetics of CB307 and to assess preliminary anti-tumor activity in patients with PSMA+ solid tumor.Methods: The phase 1 study consists of dose escalation (part 1) and cohort expansion (part 2) components, and the study is currently enrolling patients in part 1 without dose limiting toxicities (DLTs). The dose escalation uses an accelerated titration design (ATD) and a modified continual reassessment method (mCRM) to guide the MTD and the recommended phase 2 dose (RP2D). The key inclusion criteria are as follows: histologically confirmed advanced or metastatic PSMA expressing solid tumors determined by immunohistochemistry; not amenable to standard-of-care; RECIST measurable disease or increased serum PSA at baseline (for bone metastasis-only prostate cancer). The key exclusion criteria are patients with brain metastases; patients who have discontinued previous immunotherapy due to intolerable immune-related adverse events; patients with acute infections or autoimmune diseases. Cohort expansion uses the same eligibility criteria, however, at least 3 patients with castration-resistant prostate cancer harboring either BRCA1, BRCA2, ATM and/or CDK12 mutation(s) will be enrolled. CB307 is administered intravenously every week. PSMA-PET scan and tumor biopsy are taken to understand the mechanism of action of CB307 as well as a change of PSMA expression during CB307 treatment. NCT04839991 * “Humabody” is a registered trademark ® of Crescendo Biologics Ltd.Citation Format: Johann S. de Bono, Hendrik-Tobias Arkenau, Eelke H. Gort, Lot L. Devriese, Elisa Fontana, Daan G. Knapen, Crescens Tiu, Anja Williams, Derk Jan A. de Groot, Ulug M. Gunaydin, Phillip Bartlett, Andrew J. Pierce, Philip Bland-Ward, Kenji Hashimoto, E.G. Elisabeth de Vries. A phase 1 open-label, dose escalation and expansion trial to investigate the safety, pharmacokinetics and pharmacodynamics of CB307, a Trispecific Humabody® T-cell enhancer, in patients with PSMA+ advanced and/or metastatic solid tumors (POTENTIA) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12Suppl):Abstract nr CT207

Abstract 5611:LAG-3 PET imaging in patients with cancer before immune checkpoint inhibitor therapy

Background: Immune checkpoint inhibitors (ICIs) can induce durable responses in multiple different tumor types. Lymphocyte activation gene-3 (LAG-3) is one of the immune checkpoints for which therapeutic antibodies are being developed. PET imaging with radiolabeled ICIs can visualize whether the drug reaches the tumor, and might serve as a target expression readout. Therefore, we aimed to evaluate the safety of the radiolabeled LAG-3 antibody 89Zr-DFO-REGN3767, to determine the optimal tracer dose and imaging time point, and to get insight into 89Zr-DFO-REGN3767 whole body distribution.Methods: Patients with advanced solid tumors received 37 MBq 89Zr-DFO-REGN3767 together with unlabeled antibody to achieve a 2, 5, 10, 20, or 40 mg total protein dose (NCT04706715). Patients underwent PET/CT scans on days 0, 2, 4, and 7 after injection, followed by a tumor biopsy. After that, they received treatment with cemiplimab alone or combined with platinum-containing chemotherapy. PET scans were analyzed by placing volumes of interest (VOIs) in tumor lesions and normal tissues. Tracer uptake was measured in the VOIs and expressed as the maximum standardized uptake value (SUVmax) for tumor lesions and as the mean standardized uptake value (SUVmean) for normal tissues.Results: The 16 included patients experienced no 89Zr-DFO-REGN3767-related side effects. Tumor-to-blood ratios for all dose levels increased from days 0 to 7. Therefore, imaging 7 days after tracer injection was deemed optimal to achieve the highest contrast. The 40 mg tracer dose resulted in the most favorable blood kinetics. At this dose, tracer uptake in tumor lesions (n = 17) varied between patients (geometric mean SUVmax 6.2; SD 1.7). In normal tissues, uptake was seen in the spleen (x̄ 11.2; SD 1.6), and bone marrow (x̄ 2.2; SD 0.7), which increased from days 0 to 7. Tracer uptake was visually present in regions with inflammation.Conclusion: 89Zr-DFO-REGN3767 PET imaging is feasible and studied patients did not experience tracer related side effects. Optimal imaging results were achieved with the 40 mg protein dose and imaging on day 7 89Zr-DFO-REGN3767 shows specific accumulation in LAG-3 rich tissues and tumor lesions