An International Comparison of Presentation, Outcomes and CORONET Predictive Score Performance in Patients with Cancer Presenting with COVID-19 across Different Pandemic Waves.

Patients with cancer have been shown to have increased risk of COVID-19 severity. We previously built and validated the COVID-19 Risk in Oncology Evaluation Tool (CORONET) to predict the likely severity of COVID-19 in patients with active cancer who present to hospital. We assessed the differences in presentation and outcomes of patients with cancer and COVID-19, depending on the wave of the pandemic. We examined differences in features at presentation and outcomes in patients worldwide, depending on the waves of the pandemic: wave 1 D614G (n = 1430), wave 2 Alpha (n = 475), and wave 4 Omicron variant (n = 63, UK and Spain only). The performance of CORONET was evaluated on 258, 48, and 54 patients for each wave, respectively. We found that mortality rates were reduced in subsequent waves. The majority of patients were vaccinated in wave 4, and 94% were treated with steroids if they required oxygen. The stages of cancer and the median ages of patients significantly differed, but features associated with worse COVID-19 outcomes remained predictive and did not differ between waves. The CORONET tool performed well in all waves, with scores in an area under the curve (AUC) of >0.72. We concluded that patients with cancer who present to hospital with COVID-19 have similar features of severity, which remain discriminatory despite differences in variants and vaccination status. Survival improved following the first wave of the pandemic, which may be associated with vaccination and the increased steroid use in those patients requiring oxygen. The CORONET model demonstrated good performance, independent of the SARS-CoV-2 variants.

Establishment of CORONET, COVID-19 Risk in Oncology Evaluation Tool, to Identify Patients With Cancer at Low Versus High Risk of Severe Complications of COVID-19 Disease On Presentation to Hospital.

PURPOSE: Patients with cancer are at increased risk of severe COVID-19 disease, but have heterogeneous presentations and outcomes. Decision-making tools for hospital admission, severity prediction, and increased monitoring for early intervention are critical. We sought to identify features of COVID-19 disease in patients with cancer predicting severe disease and build a decision support online tool, COVID-19 Risk in Oncology Evaluation Tool (CORONET). METHODS: Patients with active cancer (stage I-IV) and laboratory-confirmed COVID-19 disease presenting to hospitals worldwide were included. Discharge (within 24 hours), admission (≥ 24 hours inpatient), oxygen (O2) requirement, and death were combined in a 0-3 point severity scale. Association of features with outcomes were investigated using Lasso regression and Random Forest combined with Shapley Additive Explanations. The CORONET model was then examined in the entire cohort to build an online CORONET decision support tool. Admission and severe disease thresholds were established through pragmatically defined cost functions. Finally, the CORONET model was validated on an external cohort. RESULTS: The model development data set comprised 920 patients, with median age 70 (range 5-99) years, 56% males, 44% females, and 81% solid versus 19% hematologic cancers. In derivation, Random Forest demonstrated superior performance over Lasso with lower mean squared error (0.801 v 0.807) and was selected for development. During validation (n = 282 patients), the performance of CORONET varied depending on the country cohort. CORONET cutoffs for admission and mortality of 1.0 and 2.3 were established. The CORONET decision support tool recommended admission for 95% of patients eventually requiring oxygen and 97% of those who died (94% and 98% in validation, respectively). The specificity for mortality prediction was 92% and 83% in derivation and validation, respectively. Shapley Additive Explanations revealed that National Early Warning Score 2, C-reactive protein, and albumin were the most important features contributing to COVID-19 severity prediction in patients with cancer at time of hospital presentation. CONCLUSION: CORONET, a decision support tool validated in health care systems worldwide, can aid admission decisions and predict COVID-19 severity in patients with cancer.

Carboplatin dose capping affects pCR rate in HER2-positive breast cancer patients treated with neoadjuvant Docetaxel, Carboplatin, Trastuzumab, Pertuzumab (TCHP).

PURPOSE: Estimated glomerular filtration rate (eGFR) is commonly used to calculate carboplatin doses and capping the eGFR may be used to reduce the risk of excessive dosing and toxicity. We sought to retrospectively examine the impact of our carboplatin guidelines on pathological complete response rates (pCR) and toxicity in women with HER2+ breast cancer receiving neoadjuvant docetaxel, carboplatin, trastuzumab and pertuzumab (TCHP). METHODS: The delivered area under the curve (dAUC) was calculated [(actual carboplatin dose at cycle 1 ÷ dose calculated with uncapped/unbanded eGFR) × 6] and dichotomized at the median value. The impact of this and other clinical factors on pCR rate, dose intensity (DI) and toxicity was assessed. RESULTS: 124 eligible patients were identified of whom 63.7% (79/124) achieved pCR. The median dAUC at cycle 1 was 5.75 mg × ml/min. Those with lower dAUC were more frequently younger and overweight/obese. Patients with lower dAUC had significantly inferior pCR rates of 54.8% (34/62) vs 72.6% (45/62), respectively (p = 0.040). Similar results were seen in the ER+ subgroup; 45.2% (19/42) vs 68.3% (28/41), p = 0.037%, whereas no significant difference was seen among ER- patients; 75.0% (15/20) vs 81.0% (17/21), p = 0.72. DI and toxicity were comparable between the two dAUC groups. CONCLUSIONS: The overall pCR rate was high in patients with HER2+ breast cancer receiving the TCHP regimen; however, carboplatin dose capping resulted in inferior pCR rates, particularly in the ER+ subgroup. To ensure optimal dosing, isotopic measurement of renal function is warranted in patients who would otherwise have their eGFR and dose capped.

Plasma Tie2 is a tumor vascular response biomarker for VEGF inhibitors in metastatic colorectal cancer.

Oncological use of anti-angiogenic VEGF inhibitors has been limited by the lack of informative biomarkers. Previously we reported circulating Tie2 as a vascular response biomarker for bevacizumab-treated ovarian cancer patients. Using advanced MRI and circulating biomarkers we have extended these findings in metastatic colorectal cancer (n = 70). Bevacizumab (10 mg/kg) was administered to elicit a biomarker response, followed by FOLFOX6-bevacizumab until disease progression. Bevacizumab induced a correlation between Tie2 and the tumor vascular imaging biomarker, Ktrans (R:-0.21 to 0.47) implying that Tie2 originated from the tumor vasculature. Tie2 trajectories were independently associated with pre-treatment tumor vascular characteristics, tumor response, progression free survival (HR for progression = 3.01, p = 0.00014; median PFS 248 vs. 348 days p = 0.0008) and the modeling of progressive disease (p < 0.0001), suggesting that Tie2 should be monitored clinically to optimize VEGF inhibitor use. A vascular response is defined as a 30% reduction in Tie2; vascular progression as a 40% increase in Tie2 above the nadir. Tie2 is the first, validated, tumor vascular response biomarker for VEGFi.

A phase 1 trial of intravenous 4-(N-(S-glutathionylacetyl)amino) phenylarsenoxide (GSAO) in patients with advanced solid tumours.

BACKGROUND: 4-(N-(S-glutathionylacetyl)amino) phenylarsenoxide (GSAO) is a water-soluble mitochondrial toxin that binds to adenine nucleotide translocase in the inner mitochondrial membrane, thereby targeting cell proliferation. This phase 1 study investigated safety, dose-limiting toxicities (DLTs), maximum tolerated dose (MTD) and pharmacokinetics (PK) of GSAO as a daily 1-h infusion for 5 days a week for 2 weeks in every three. Pharmacodynamics of GSAO was evaluated by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and circulating markers of angiogenesis. METHODS: Patients with advanced solid tumours received GSAO in a dose-escalation trial according to a standard '3 + 3' design that was guided by toxicity and, for the final dose escalation, by arsenic PK data. RESULTS: A total of 34 patients were treated with GSAO across 9 dose levels (1.3-44.0 mg/m(2)). Treatment was well tolerated with few adverse events. An additional three patients were enrolled at the 12.4 mg/m(2) dose level following a DLT of derangement of liver function tests (grade 4). At the 44.0 mg/m(2) dose level, two out of three patients had DLTs (reversible encephalopathy; paroxysmal atrial fibrillation). CONCLUSIONS: The MTD of GSAO was 22.0 mg/m(2)/day. There was no biomarker evidence from DCE-MRI or circulating markers of angiogenesis of an anti-vascular effect of GSAO.

Is the toxicity of anti-angiogenic drugs predictive of outcome? A review of hypertension and proteinuria as biomarkers of response to anti-angiogenic therapy.

INTRODUCTION: The prototypic anti-angiogenic agents, VEGF inhibitors, are increasingly used in clinical practice to treat a variety of tumours. Although generally well tolerated, their toxicities can be significant or occasionally life threatening. The ability to identify those patients whose disease will respond to VEGF inhibitors would minimise exposure to ineffective drugs for some patients. To date, there are no validated predictive or prognostic biomarkers for anti-angiogenic drugs. Toxicities such as hypertension and proteinuria are related to the effect of VEGF inhibition on the vasculature. This has led to the investigation of these toxicities as potential biomarkers of clinical outcome in patients treated with these agents. AREAS COVERED: Putative mechanisms for the development of hypertension and proteinuria, and their potential role as clinically useful biomarkers in relation to anti-angiogenic drugs are discussed in this article. PUBMED, EMBASE and abstracts presented at the American Society of Clinical Oncology until July 2011 were searched to identify relevant English language articles. Studies of anti-angiogenic therapies testing the relationship of either hypertension or proteinuria with outcome were included. EXPERT OPINION: The evidence in support of the hypothesis that hypertension and proteinuria are biomarkers of response to anti-angiogenic drugs is inconclusive. Current evidence suggests that hypertension is a pharmacodynamic effect of anti-angiogenic agents. Future studies should aim to measure and report toxicities in a standardised manner to facilitate comparisons between studies.