A Prospective, Real-World, Multinational Study of Naloxegol for Patients with Cancer Pain Diagnosed with Opioid-Induced Constipation—The NACASY Study

Cancer pain; Naloxegol; Ppioid-induced constipationDolor por cáncer; Naloxegol; Estreñimiento inducido por opioidesDolor per càncer; Naloxegol; Restrenyiment induït per opioidesThe Naloxegol Cancer Study (NACASY) was a multinational European study aimed to evaluate the 4-week safety and efficacy of naloxegol in a real-world setting in patients with cancer pain diagnosed with opioid-induced constipation. The primary safety endpoint was the incidence of adverse events leading to study discontinuation. We recruited 170 patients who received at least one dose of naloxegol (i.e., safety population). Out of 170 patients, 20 (11.8%, 95%CI 6.9–16.6) discontinued the study due to adverse events, and, of them, 12 (7.1%, 95%CI 3.2–10.9%) were study discontinuations due to naloxegol-related adverse events. From 76 patients subjects who had completed both 4 weeks of treatment and 28 days of the diary, 55 patients (72.4%, 95% CI 62.3–82.4%) were regarded as responders (i.e., showed ≥3 bowel-movements per week and an increase of ≥1 bowel-movement over baseline) to naloxegol treatment. The Patient Assessment of Constipation—Quality of Life Questionnaire total score and all its subscales improved from baseline to 4 weeks of follow up. Our findings support and provide new evidence about the beneficial effect of naloxegol in terms of improvement of constipation and quality-of-life in patients with cancer-related pain and opioid-induced constipation and show a safety profile consistent with previous pivotal and real-world studies.This project was funded by Kyowa Kirin International. Role of the funding source: The funder of the study and its employees and assignees were involved in study design, data collection, data analysis, data interpretation, and writing of all related reports and publications

The Society for Immunotherapy of Cancer perspective on regulation of interleukin-6 signaling in COVID-19-related systemic inflammatory response

The pandemic caused by the novel coronavirus SARS-CoV-2 has placed an unprecedented burden on healthcare systems around the world. In patients who experience severe disease, acute respiratory distress is often accompanied by a pathological immune reaction, sometimes referred to as ‘cytokine storm’. One hallmark feature of the profound inflammatory state seen in patients with COVID-19 who succumb to pneumonia and hypoxia is marked elevation of serum cytokines, especially interferon gamma, tumor necrosis factor alpha, interleukin 17 (IL-17), interleukin 8 (IL-8) and interleukin 6 (IL-6). Initial experience from the outbreaks in Italy, China and the USA has anecdotally demonstrated improved outcomes for critically ill patients with COVID-19 with the administration of cytokine-modulatory therapies, especially anti-IL-6 agents. Although ongoing trials are investigating anti-IL-6 therapies, access to these therapies is a concern, especially as the numbers of cases worldwide continue to climb. An immunology-informed approach may help identify alternative agents to modulate the pathological inflammation seen in patients with COVID-19. Drawing on extensive experience administering these and other immune-modulating therapies, the Society for Immunotherapy of Cancer offers this perspective on potential alternatives to anti-IL-6 that may also warrant consideration for management of the systemic inflammatory response and pulmonary compromise that can be seen in patients with severe COVID-19

Lesson by SARS-CoV-2 disease (COVID-19): whole-body CT angiography detection of "relevant" and "other/incidental" systemic vascular findings

Objectives: Increasing evidence suggests that SARS-CoV-2 infection may lead to severe and multi-site vascular involvement. Our study aimed at assessing the frequency of vascular and extravascular events' distribution in a retrospective cohort of 42 COVID-19 patients. Methods: Patients were evaluated by whole-body CT angiography between March 16 and April 30, 2020. Twenty-three out of the 42 patients evaluated were admitted to the intensive care unit (ICU). Vascular and extravascular findings were categorized into "relevant" or "other/incidental," first referring to the need for immediate patient care and management. Student T-test, Mann-Whitney U test, or Fisher exact test was used to compare study groups, where appropriate. Results: Relevant vascular events were recorded in 71.4% of cases (n = 30). Pulmonary embolism was the most frequent in both ICU and non-ICU cases (56.5% vs. 10.5%, p = 0.002). Ischemic infarctions at several sites such as the gut, spleen, liver, brain, and kidney were detected (n = 20), with multi-site involvement in some cases. Systemic venous thrombosis occurred in 30.9% of cases compared to 7.1% of systemic arterial events, the first being significantly higher in ICU patients (p = 0.002). Among incidental findings, small-sized splanchnic arterial aneurysms were reported in 21.4% of the study population, with no significant differences in ICU and non-ICU patients. Conclusions: Vascular involvement is not negligible in COVID-19 and should be carefully investigated as it may significantly affect disease behavior and prognosis. Key points: • Relevant vascular events were recorded in 71.4% of the study population, with pulmonary embolism being the most frequent event in ICU and non-ICU cases. • Apart from the lung, other organs such as the gut, spleen, liver, brain, and kidneys were involved with episodes of ischemic infarction. Systemic venous and arterial thrombosis occurred in 30.9% and 7.1% of cases, respectively, with venous events being significantly higher in ICU patients (p = 0.002). • Among incidental findings, small-sized splanchnic arterial aneurysms were reported in 21.4% of the whole population

Exploratory findings from a prematurely closed international, multicentre, academic trial: RAVELLO, a phase III study of regorafenib versus placebo as maintenance therapy after first-line treatment in RAS wild-type metastatic colorectal cancer

Background In patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC), the role of maintenance therapy after first-line treatment with chemotherapy plus antiepidermal growth factor receptor (EGFR) monoclonal antibodies (MoAb) is still an object of debate. Methods We assessed the efficacy and safety of regorafenib as a switch maintenance strategy after upfront 5-fluorouracil-based chemotherapy plus an anti- EGFR MoAb in patients with RAS WT mCRC. RAVELLO was a phase III, international, double-blind, placebocontrolled, academic trial. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival and toxicity. Regorafenib or placebo were administered daily for 3 weeks of 4-week cycle until disease progression or unacceptable toxicity, up to 24 months. Results The study was stopped prematurely due to slow accrual and lack of funding after the randomisation of 21 patients: 11 in the regorafenib arm and 10 in the placebo arm. The small sample size precludes any statistical analysis. Toxicity was acceptable and consistent with the known regorafenib safety profile. Median PFS was similar in the two arms. However, a subgroup of patients treated with regorafenib experienced a remarkably long PFS. Three patients were progression free at 9 months in the regorafenib arm versus one patient in the placebo arm, whereas at 12 months two regorafenib-treated patients were still progression free versus none in the placebo arm. Conclusion RAVELLO trial demonstrated that growing financial and bureaucratic hurdles affect the feasibility of independent academic research. Although stopped prematurely and within the limited sample size, RAVELLO suggests that regorafenib has not a major activity in maintenance setting after upfront chemotherapy and anti-EGFR MoAb. However, a subgroup of patients experienced a remarkable long PFS, indicating that a better refinement of the patient population would help to identify subjects that might benefit from a regorafenib personalised approach in the switch maintenance settin

Development and validation of a patient-reported outcome tool to assess cancer-related financial toxicity in Italy

Introduction. Financial toxicity (FT) is a well-recognized problem in oncology. US-based studies have shown that: (a) cancer patients have a 2.7 times risk of bankruptcy; (b) patients who declare bankruptcy have a 79% greater hazard of death; (c) financial burden significantly impairs quality of life (QoL), and (d) reduces compliance and adherence to treatment prescriptions. The aim of the project is to develop and validate a patient-reported-outcome (PRO) measure to assess FT of cancer patients in Italy, where, despite the universal health coverage given by the national health service, FT is an emerging issue. Methods and analysis. Our hypothesis is that a specific FT measure, which considers the relevant socio-cultural context and health care system, would allow to understand the main determinants of cancer-related financial toxicity in Italy and to contrast them. According to the International Society for Pharmaco-economics and Outcomes Research (ISPOR) guidelines on PROs, the project will include the following steps: (1) concept elicitation (from focus groups with patients and caregivers; literature; oncologists; nurses) and analysis, creating a coding library; (2) item generation (using a format that includes a question and a response on a 4-point Likert scale) and analysis through patients’ cognitive interviews of item importance within different coding categories to produce the draft instrument; (3) factor analysis and internal validation (with Cronbach’s alpha and test-retest for reliability) to produce the final instrument; (4) external validation with QoL anchors and depression scales. The use of the FT measure in prospective trials is also planned. Ethics and dissemination. The protocol is approved by the ethical committees of all the participating centres. The project will tentatively produce a validated tool by the spring 2021.The project might also represent a model and the basis for future cooperation with other European countries, with different health care systems and socio-economic conditions

Cetuximab continuation after first progression in metastatic colorectal cancer (CAPRI-GOIM): A randomized phase II trial of FOLFOX plus cetuximab versus FOLFOX

Background: Cetuximab plus chemotherapy is a first-line treatment option in metastatic KRAS and NRAS wild-type colorectal cancer (CRC) patients. No data are currently available on continuing anti-epidermal growth factor receptor (EGFR) therapy beyond progression. Patients and methods: We did this open-label, 1:1 randomized phase II trial at 25 hospitals in Italy to evaluate the efficacy of cetuximab plus 5-fluorouracil, folinic acid and oxaliplatin (FOLFOX) as second-line treatment of KRAS exon 2 wild-type metastatic CRC patients treated in first line with 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) plus cetuximab. Patients received FOLFOX plus cetuximab (arm A) or FOLFOX (arm B). Primary end point was progressionfree survival (PFS). Tumour tissues were assessed by next-generation sequencing (NGS). This report is the final analysis. Results: Between 1 February 2010 and 28 September 2014, 153 patients were randomized (74 in arm A and 79 in arm B). Median PFS was 6.4 [95% confidence interval (CI) 4.7-8.0] versus 4.5 months (95% CI 3.3-5.7); [hazard ratio (HR), 0.81; 95% CI 0.58-1.12; P = 0.19], respectively. NGS was performed in 117/153 (76.5%) cases; 66/117 patients (34 in arm A and 32 in arm B) had KRAS, NRAS, BRAF and PIK3CA wild-type tumours. For these patients, PFS was longer in the FOLFOX plus cetuximab arm [median 6.9 (95% CI 5.5-8.2) versus 5.3 months (95% CI 3.7-6.9); HR, 0.56 (95% CI 0.33-0.94); P = 0.025]. There was a trend in better overall survival: median 23.7 [(95% CI 19.4-28.0) versus 19.8 months (95% CI 14.9-24.7); HR, 0.57 (95% CI 0.32-1.02); P = 0.056]. Conclusions: Continuing cetuximab treatment in combination with chemotherapy is of potential therapeutic efficacy in molecularly selected patients and should be validated in randomized phase III trials