There is no established standard chemotherapy for patients with locally advanced or metastatic biliary tract cancer. We initially conducted a randomized, phase 2 study involving 86 patients to ...compare cisplatin plus gemcitabine with gemcitabine alone. After we found an improvement in progression-free survival, the trial was extended to the phase 3 trial reported here.
We randomly assigned 410 patients with locally advanced or metastatic cholangiocarcinoma, gallbladder cancer, or ampullary cancer to receive either cisplatin (25 mg per square meter of body-surface area) followed by gemcitabine (1000 mg per square meter on days 1 and 8, every 3 weeks for eight cycles) or gemcitabine alone (1000 mg per square meter on days 1, 8, and 15, every 4 weeks for six cycles) for up to 24 weeks. The primary end point was overall survival.
After a median follow-up of 8.2 months and 327 deaths, the median overall survival was 11.7 months among the 204 patients in the cisplatin-gemcitabine group and 8.1 months among the 206 patients in the gemcitabine group (hazard ratio, 0.64; 95% confidence interval, 0.52 to 0.80; P<0.001). The median progression-free survival was 8.0 months in the cisplatin-gemcitabine group and 5.0 months in the gemcitabine-only group (P<0.001). In addition, the rate of tumor control among patients in the cisplatin-gemcitabine group was significantly increased (81.4% vs. 71.8%, P=0.049). Adverse events were similar in the two groups, with the exception of more neutropenia in the cisplatin-gemcitabine group; the number of neutropenia-associated infections was similar in the two groups.
As compared with gemcitabine alone, cisplatin plus gemcitabine was associated with a significant survival advantage without the addition of substantial toxicity. Cisplatin plus gemcitabine is an appropriate option for the treatment of patients with advanced biliary cancer. (ClinicalTrials.gov number, NCT00262769.)
The activation of protease-activated receptor (PAR)-2 by factor Xa (fXa) promotes the release of tissue factor-positive microvesicles (TF
MV), and contributes to proliferation in cancer cells. This ...study examined the ability of direct oral anticoagulants (DOACs), apixaban and rivaroxaban, to inhibit the release of TF
MV from two cell lines (MDA-MB-231 and AsPC-1) as well as cell proliferation.Activation of the cells with fXa (10 nM) enhanced the release of TF
MV but was suppressed in the presence of either DOAC. These MVs were found to contain fVIIa, but not fXa. Incubation of cell lines with apixaban (1.8 µM) but not rivaroxaban (1.8 µM), in the absence of fXa decreased the release of TF
MV below that of resting cells, in a PAR2-dependent manner. Furthermore, incubation with apixaban reduced the proliferation rate in both cells lines. Incubation of purified fVIIa with apixaban but not rivaroxaban resulted in complete inhibition of fVIIa proteolytic activity as measured using two fVIIa chromogenic substrates. Pre-incubation of the cells with an inhibitory anti-fVIIa antibody, with apixaban or the blocking of PAR2 suppressed the release of TF
MV to a comparable level, and reduced cell proliferation but the effect was not cumulative.This study has established that the activation of PAR2 by TF-fVIIa complex is the principal mediator in augmenting the release of TF
MV as well as cancer cell proliferation. Importantly, for the first time we have shown that apixaban selectively inhibits the proteolytic activity of fVIIa as well as the signalling arising from the TF-fVIIa complex.
Tissue factor (TF) signalling has been associated with alterations in Akt activity influencing cellular survival and proliferation. TF is also shown to induce signalling through activation of the ...protease activated receptor (PAR)2. Seven cell lines were exposed to recombinant-TF (rec-TF), or activated using a PAR2-agonist peptide and the phosphorylation state of PTEN, and the activities of PTEN and Akt measured. Furthermore, by measuring the association of PTEN with MAGI proteins a mechanism for the induction of signalling by TF was proposed. Short term treatment of cells resulted in de-phosphorylation of PTEN, increased lipid-phosphatase activity and reduced Akt kinase activity in most of the cell lines examined. In contrast, continuous exposure to rec-TF up to 14 days, resulted in lower PTEN antigen levels, enhanced Akt activity and increased rate of cell proliferation. To explore the mechanism of activation of PTEN by TF, the association of "membrane-associated guanylate kinase-with inverted configuration" (MAGI)1-3 proteins with PTEN was assessed using the proximity ligation assay and by co-immunoprecipitation. The interaction of PTEN with all three MAGI proteins was transiently reduced following PAR2 activation and explains the changes in PTEN activity. Our data is first to show that PAR2 activation directly, or through exposure of cells to TF releases PTEN from MAGI proteins and is concurrent with increases in PTEN phosphatase activity. However, prolonged exposure to TF results in the reduction in PTEN antigen with concurrent increase in Akt activity which may explain the aberrant cell survival, proliferation and invasion associated with TF during chronic diseases.
Low molecular weight heparins have demonstrated superiority over coumarins in the extended treatment of cancer-associated thrombosis and are recommended as first-line therapy in clinical guidelines. ...Non-vitamin K oral antagonists are yet to be evaluated against low molecular weight heparin for this indication. Nevertheless, a perception that patients favor oral anticoagulants over injections may lead to an increased prescribing of warfarin or non-vitamin K oral antagonists despite the evidence gap. There has been no evaluation of cancer patient preferences for anticoagulants and whether such an evidence gap is an acceptable trade-off for patients prescribed orals. We conducted a study to assess what features are most important to CAT patients regarding their choice of anticoagulant. Two modules were applied: Initial in-depth interviews with 9 patients diagnosed with cancer-associated thrombosis, and thereafter quantitative research, where a further 100 patients completed a choice-based-conjoint exercise, where 15 different scenarios were presented to identify the most important attributes of an anticoagulant. Seventy percent of the patients were treated with injected medication (low molecular weight heparin) and 30% with oral medications. Patients most valued an anticoagulant with minimal interference with their cancer treatment (39%), low thrombosis recurrence rate (24%), and low risk of major bleed (19%). Preference for oral administration over injection had moderate importance (13%). The results show that patients prefer an anticoagulant that does not interfere with their cancer treatment, suggesting the primacy of the cancer disease over venous thromboembolism in these patients. Patients also favor efficacy and safety over convenience of route of administration.
The diagnosis of symptomatic cancer-associated thrombosis often causes distress and alarm for patients, especially for those unaware of the risk, or the signs and symptoms to look out for. There are ...few data about cancer patients' experiences of incidentally diagnosed pulmonary embolism (IPE), where lack of warning (recognised signs, symptoms) may cause delayed diagnosis and aggravate distress. To explore cancer patients' experience of the diagnosis of and living with incidental pulmonary embolism treated with anticoagulation. A qualitative study using modified grounded theory approach. Semi-structured interviews were conducted as part of a mixed- methods prospective observational survey study of consenting patients with IPE. Data were subjected to thematic analysis. The qualitative findings are presented. Eleven participants were interviewed (mean age 68.3 years, range 38-82 years; various forms of cancer and stages). Three major themes and one cross-cutting theme were generated. Theme (1): IPE is experienced in the context of cancer and concomitant comorbidities. Issues are understood in the shadow of-and often overshadowed by-current serious illness. Theme (2): Being diagnosed with IPE. Misattribution to cancer or other comorbidities caused delay in help-seeking and diagnosis. Theme (3): Coping with anticoagulation. Participants' incorporated anticoagulation treatment and its effects into their daily routine with acceptance and stoicism. Finally, the cross-cutting theme relates to a lack of information and uncertainty, contributing to distress throughout the experience. The diagnosis of IPE was upsetting and unexpected. Expert and timely information was valued by those with IPE. Education called for about the increased risk of cancer-associated thrombosis and the signs and symptoms to be aware of.
Background:
Cancer patients have a four- to fivefold greater risk of thrombosis than the general population. Recommended treatment for cancer-associated thrombosis is 3–6 months of ...low-molecular-weight heparin. The ‘select-d’ trial is an open-label, randomised, multi-centre pilot trial in patients with cancer-associated thrombosis, utilising dalteparin (low-molecular-weight heparin) versus rivaroxaban (a direct oral anticoagulant), to assess effectiveness and safety.
Aim:
To explore patient and informal carers’ experiences of cancer-associated thrombosis and their experience and understanding of the risk–benefit of thrombosis treatment.
Design:
Qualitative substudy of the select-d trial, using semi-structured interviews. Interviews were audio-recorded and transcribed. Data were analysed using Framework Analysis.
Participants:
Participants were purposively sampled (n = 37 patients; 46% male; age 40–89; 9 with carer present).
Results:
Three themes were found: experience of cancer-associated thrombosis, experience of anticoagulation and risk–benefit balance of the two modes of administration. Some were shocked by their thrombosis diagnosis (most were unaware of their risk), but others found it insignificant compared with cancer. Most patients found tablets more convenient, but injections were acceptable in the context of having cancer. While most were happy to follow medical advice, others weighed preference on the basis of effectiveness.
Conclusion:
Lack of awareness of thrombosis risk is concerning; cancer patients must be informed to enable prompt help-seeking. Tablets could provide a welcome choice for patients if there is equivalent risk–benefit to injected anticoagulants. Patients trust their clinicians to tailor their treatment. Future research could explore the effect of routine information giving about the risk of thrombosis.
Several independent risk factors have been reported to influence viral shedding following COVID-19 infection, but the influence of host-related molecular factors has not yet been described. We report ...a case of a cancer patient with Lynch syndrome (hereditary nonpolyposis colorectal cancer, HNPCC) who manifested SARS-CoV-2 PCR (polymerase chain reaction) positivity for at least 54 days after contracting mild COVID-19 illness. We propose that deficient mismatch repair (MMR) may play a role in the prolonged SARS-CoV-2 RNA shedding. The importance of understanding the scientific basis of extended viral shedding during the COVID-19 pandemic is now centre-stage in the establishment of robust track and trace services to allow the recovery and function of societies and economies. This patient with Lynch syndrome recovered from infection but had prolonged viral positivity, which might merit further investigation to better understand the effect of this condition on infection duration and outcome.
Diarrhea (with or without colitis) is an immune-related adverse event (irAE) associated with ipilimumab. A randomized, double-blind, placebo-controlled, multicenter, multinational phase II trial was ...conducted to determine whether prophylactic budesonide (Entocort EC), a nonabsorbed oral steroid, reduced the rate of grade >or=2 diarrhea in ipilimumab-treated patients with advanced melanoma.
Previously treated and treatment-naïve patients (N = 115) with unresectable stage III or IV melanoma received open-label ipilimumab (10 mg/kg every 3 weeks for four doses) with daily blinded budesonide (group A) or placebo (group B) through week 16. The first scheduled tumor evaluation was at week 12; eligible patients received maintenance treatment starting at week 24. Diarrhea was assessed using Common Terminology Criteria for Adverse Events (CTCAE) 3.0. Patients kept a diary describing their bowel habits.
Budesonide did not affect the rate of grade >or=2 diarrhea, which occurred in 32.7% and 35.0% of patients in groups A and B, respectively. There were no bowel perforations or treatment-related deaths. Best overall response rates were 12.1% in group A and 15.8% in group B, with a median overall survival of 17.7 and 19.3 months, respectively. Within each group, the disease control rate was higher in patients with grade 3 to 4 irAEs than in patients with grade 0 to 2 irAEs, although many patients with grade 1 to 2 irAEs experienced clinical benefit. Novel patterns of response to ipilimumab were observed.
Ipilimumab shows activity in advanced melanoma, with encouraging survival and manageable adverse events. Budesonide should not be used prophylactically for grade >or=2 diarrhea associated with ipilimumab therapy.
Summary Background Cisplatin and gemcitabine is the standard first-line chemotherapy regimen for patients with advanced biliary tract cancer; expression of VEGF and its receptors is associated with ...adverse outcomes. We aimed to assess the effect of the addition of cediranib (an oral inhibitor of VEGF receptor 1, 2, and 3) to cisplatin and gemcitabine on progression-free survival. Methods In this multicentre, placebo-controlled, randomised phase 2 study, we recruited patients aged 18 years or older with histologically confirmed or cytologically confirmed advanced biliary tract cancer from hepatobiliary oncology referral centres in the UK. Patients were eligible if they had an ECOG performance status of 0–1 and an estimated life expectancy of longer than 3 months. Patients were given first-line cisplatin and gemcitabine chemotherapy (25 mg/m2 cisplatin and 1000 mg/m2 gemcitabine on days 1 and 8 every 21 days, for up to eight cycles) with either 20 mg oral cediranib or placebo once a day until disease progression. We randomly assigned patients (1:1) with a minimisation algorithm, incorporating the stratification factors: extent of disease, primary disease site, previous treatment, ECOG performance status, and centre. The primary endpoint was progression-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov , number NCT00939848 , and was closed on Sept 30, 2014; results of the final analysis for the primary endpoint are presented. Findings Between April 5, 2011, and Sept 28, 2012, we enrolled 124 patients (62 in each group). With a median follow-up of 12·2 months (IQR 7·3–18·5), median progression-free survival was 8·0 months (95% CI 6·5–9·3) in the cediranib group and 7·4 months (5·7–8·5) in the placebo group (HR 0·93, 80% CI 0·74–1·19, 95% CI 0·65–1·35; p=0·72). Patients who received cediranib had more grade 3–4 toxic effects than did patients who received placebo: hypertension (23 37% vs 13 21%; p=0·05), diarrhoea (eight 13% vs two 3%; p=0·05); platelet count decreased (ten 16% vs four 6%; p=0·09), white blood cell decreased (15 24% vs seven 11%; p=0·06) and fatigue (16 24% vs seven 11%; p=0·04). Interpretation Cediranib did not improve the progression-free survival of patients with advanced biliary tract cancer in combination with cisplatin and gemcitabine, which remains the standard of care. Although patients in the cediranib group had more adverse events, we recorded no unexpected toxic effects. The role of VEGF inhibition in addition to chemotherapy for patients with advanced biliary tract cancer remains investigational. Funding Cancer Research UK and AstraZeneca Pharmaceuticals.
Venous thromboembolism (VTE) is often cited as a major cause of death and morbidity in cancer patients. Even a non-lethal VTE causes distress and is commonly perceived by patients as a set-back in ...the cancer journey and a threat to the cancer treatment. It is also known that the risk of VTE varies between cancers (cancer-related risk factors), between patients (patient-related risk factors), and also within the cancer journey of a single patient. Risk can increase during treatments like surgery and chemotherapy and decline during remission. Neither the low molecular weight heparins nor the vitamin K analogues have gained an established role in thromboprevention guidance other than in ‘the high risk’ patient, who remains a rather ambiguous entity. The recently published randomised studies of rivaroxaban and apixaban in moderate- to high-risk thrombosis patients, assigned by the Khorana Risk Score, has seen the inclusion of direct oral anticoagulants (DOACs) in recent guidelines (e.g. the American Society of Clinical Oncology 2019 guidelines) for this indication. The ease of administration and the demonstrated greater patient adherence to oral agents has heightened the expectation that a practice-changing thromboprevention study in cancer patients should be realizable. However, key unmet needs that pose familiar challenges remain and as yet do not have satisfactory solutions. Anticoagulants carry risks of bleeding that are higher in the cancer population. There is therefore the challenge of sufficient risk reduction of VTE from the intervention balanced against the number of patients that may be harmed from bleeding. There is also the challenge of penetrating the risk threshold beyond which oncologists would deem thromboprevention a clinically meaningful praxis. Thus, identifying the high-risk groups of patients or targeting the length or timing of the thromboprevention to when the risks are highest are major questions that remain the subject of ongoing research. Notably all this is taking place against a backdrop of changing therapeutics for many cancers (e.g. targeted agents, checkpoint inhibitors and combinations) and their assorted impact on VTE incidence. In this review, past data for the ambulatory cancer patient are summarised, the latest evidence for the direct oral anticoagulants apixaban and rivaroxaban are analysed and the challenges of identifying the high-risk patients that have the greater chance of benefiting from thromboprophylaxis are discussed.
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