ABSTRACT
INTRODUCTION: Colorectal cancer is the fourth most common cancer in the UK. There remains a need for improved risk stratification following curative resection. Circulating-tumour DNA (ctDNA) has gained particular interest as a cancer biomarker in recent years. We performed a systematic review to assess the utility of ctDNA in identifying minimal residual disease in colorectal cancer. METHODS: Studies were included if ctDNA was measured following curative surgery and long-term outcomes were assessed. Studies were excluded if the manuscript could not be obtained from the British Library or were not available in English. RESULTS: Thirty-seven studies met the inclusion criteria, involving 3002 patients. Hazard ratios (HRs) for progression-free survival (PFS) were available in 21 studies. A meta-analysis using a random effects model demonstrated poorer PFS associated with ctDNA detection at the first liquid biopsy post-surgery [HR: 6.92 CI: 4.49-10.64 p < 0.00001]. This effect was also seen in subgroup analysis by disease extent, adjuvant chemotherapy and assay type. DISCUSSION: Here we demonstrate that ctDNA detection post-surgery is associated with a greater propensity to disease relapse and is an independent indicator of poor prognosis. Prior to incorporation into clinical practice, consensus around timing of measurements and assay methodology are critical. PROTOCOL REGISTRATION: The protocol for this review is registered on PROSPERO (CRD42021261569).
Subject(s)
Colorectal Neoplasms , Neoplasm Recurrence, Local , Humans , Neoplasm, Residual/genetics , Neoplasm Recurrence, Local/pathology , Chemotherapy, Adjuvant , Colorectal Neoplasms/diagnosis , Colorectal Neoplasms/genetics , Colorectal Neoplasms/surgery , Biomarkers, Tumor/geneticsABSTRACT
Colorectal cancer (CRC) is the second leading cause of cancer death in the UK. Novel therapeutic prevention strategies to inhibit the development and progression of CRC would be invaluable. Potential contenders include low toxicity agents such as dietary-derived agents or repurposed drugs. However, in vitro and in vivo models used in drug development often do not take into account the heterogeneity of tumours or the tumour microenvironment. This limits translation to a clinical setting. Our objectives were to develop an ex vivo method utilizing CRC and adenoma patient-derived explants (PDEs) which facilitates screening of drugs, assessment of toxicity, and efficacy. Our aims were to use a multiplexed immunofluorescence approach to demonstrate the viability of colorectal tissue PDEs, and the ability to assess immune cell composition and interactions. Using clinically achievable concentrations of curcumin, we show a correlation between curcumin-induced tumour and stromal apoptosis (P < .001) in adenomas and cancers; higher stromal content is associated with poorer outcomes. B cell (CD20+ve) and T cell (CD3+ve) density of immune cells within tumour regions in control samples correlated with curcumin-induced tumour apoptosis (P < .001 and P < .05, respectively), suggesting curcumin-induced apoptosis is potentially predicted by baseline measures of immune cells. A decrease in distance between T cells (CD3+ve) and cytokeratin+ve cells was observed, indicating movement of T cells (CD3+ve) towards the tumour margin (P < .001); this change is consistent with an immune environment associated with improved outcomes. Concurrently, an increase in distance between T cells (CD3+ve) and B cells (CD20+ve) was detected following curcumin treatment (P < .001), which may result in a less immunosuppressive tumour milieu. The colorectal tissue PDE model offers significant potential for simultaneously assessing multiple biomarkers in response to drug exposure allowing a greater understanding of mechanisms of action and efficacy in relevant target tissues, that maintain both their structural integrity and immune cell compartments.
Subject(s)
Adenoma , Colorectal Neoplasms , Humans , Adenoma/drug therapy , Colorectal Neoplasms/drug therapy , Tumor MicroenvironmentABSTRACT
BACKGROUND: Gastroesophageal adenocarcinoma (GOA) has poor clinical outcomes and lacks reliable blood markers. Here we present circulating tumour DNA (ctDNA) as an emerging biomarker. METHODS: Forty patients (17 palliative and 23 curative) were followed by serial plasma monitoring. Primary tumour DNA was analysed by targeted next-generation sequencing to identify somatic single-nucleotide variants (SNVs), and Nanostring nCounter® to detect copy number alterations (CNAs). Patient-specific SNVs and CNA amplifications (CNAamp) were analysed in plasma using digital droplet PCR and quantitative PCR, respectively. RESULTS: Thirty-five patients (13 palliative, 22 curative) had ≥1 SNVs and/or CNAamp detected in primary tumour DNA suitable for tracking in plasma. Eighteen of 35 patients (nine palliative, nine curative) had ≥1 ctDNA-positive plasma sample. Detection of postoperative ctDNA predicted short RFS (190 vs 934 days, HR = 3.7, p = 0.028) and subsequent relapse (PPV for relapse 0.83). High ctDNA levels (>60.5 copies/ml) at diagnosis of metastatic disease predicted poor OS (90 vs 372 days, HR = 11.7 p < 0.001). CONCLUSION: Sensitive ctDNA detection allows disease monitoring and prediction of short OS in metastatic patients. Presence of ctDNA postoperatively predicts relapse and defines a 'molecular relapse' before overt clinical disease. This lead time defines a potential therapeutic window for additional anticancer therapy.
Subject(s)
Adenocarcinoma/genetics , Circulating Tumor DNA/blood , Esophageal Neoplasms/genetics , Neoplasm Recurrence, Local/genetics , Stomach Neoplasms/genetics , Adenocarcinoma/mortality , Aged , Aged, 80 and over , DNA Copy Number Variations , Esophageal Neoplasms/mortality , High-Throughput Nucleotide Sequencing , Humans , Longitudinal Studies , Middle Aged , Prognosis , Stomach Neoplasms/mortalityABSTRACT
Curcumin has been investigated extensively for cancer prevention, but it has been proposed that long-term treatments may promote clonal evolution and gain of cellular resistance, potentially rendering cancer cells less sensitive to future therapeutic interventions. Here, we used long-term, low-dose treatments to determine the potential for adverse effects in non-small cell lung cancer (NSCLC) cells. IC50s for curcumin, cisplatin, and pemetrexed in A549, PC9, and PC9ER NSCLC cells were evaluated using growth curves. IC50s were subsequently re-assessed following long-term, low-dose curcumin treatment and a three-month treatment withdrawal period, with a concurrent assessment of oncology-related protein expression. Doublet cisplatin/pemetrexed-resistant cell lines were created and the IC50 for curcumin was determined. Organotypic NSCLC-fibroblast co-culture models were used to assess the effects of curcumin on invasive capacity. Following long-term treatment/treatment withdrawal, there was no significant change in IC50s for the chemotherapy drugs, with chemotherapy-resistant cell lines exhibiting similar sensitivity to curcumin as their non-resistant counterparts. Curcumin (0.25-0.5 µM) was able to inhibit the invasion of both native and chemo-resistant NSCLC cells in the organotypic co-culture model. In summary, long-term curcumin treatment in models of NSCLC neither resulted in the acquisition of pro-carcinogenic phenotypes nor caused resistance to chemotherapy agents.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Curcumin/pharmacology , Animals , Antineoplastic Agents, Phytogenic/administration & dosage , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Curcumin/administration & dosage , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Resistance, Neoplasm/drug effects , Fibroblasts , Humans , Immunohistochemistry , Mice , Time Factors , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND: Curcumin is the main active ingredient of the spice turmeric, investigated extensively for putative anticancer properties. OBJECTIVES: This phase IIa open-labelled randomized controlled trial aimed to assess safety, efficacy, quality of life, neurotoxicity, curcuminoids, and C-X-C-motif chemokine ligand 1 (CXCL1) in patients receiving folinic acid/5-fluorouracil/oxaliplatin chemotherapy (FOLFOX) compared with FOLFOX + 2 g oral curcumin/d (CUFOX). METHODS: Twenty-eight patients aged >18 y with a histological diagnosis of metastatic colorectal cancer were randomly assigned (1:2) to receive either FOLFOX or CUFOX. Safety was assessed by Common Toxicity Criteria-Adverse Event reporting, and efficacy via progression-free survival (PFS) and overall survival (OS). Quality of life and neurotoxicity were assessed using questionnaires (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 and Functional Assessment of Cancer Treatment-Gynecologic Oncology Group-Neurotoxicity). Plasma curcuminoids were determined with liquid chromatography (LC) electrospray ionization tandem mass spectrometry and CXCL1 by ELISA. RESULTS: Addition of daily oral curcumin to FOLFOX chemotherapy was safe and tolerable (primary outcome). Similar adverse event profiles were observed for both arms. In the intention-to-treat population, the HR for PFS was 0.57 (95% CI: 0.24, 1.36; P = 0.2) (median of 171 and 291 d for FOLFOX and CUFOX, respectively) and for OS was 0.34 (95% CI: 0.14, 0.82; P = 0.02) (median of 200 and 502 d for FOLFOX and CUFOX, respectively). There was no significant difference between arms for quality of life (P = 0.248) or neurotoxicity (P = 0.223). Curcumin glucuronide was detectable at concentrations >1.00 pmol/mL in 15 of 18 patients receiving CUFOX. Curcumin did not significantly alter CXCL1 over time (P = 0.712). CONCLUSION: Curcumin is a safe and tolerable adjunct to FOLFOX chemotherapy in patients with metastatic colorectal cancer. This trial was registered at clinicaltrials.gov as NCT01490996 and at www.clinicaltrialsregister.eu as EudraCT 2011-002289-19.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/drug therapy , Curcumin/therapeutic use , Administration, Oral , Aged , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Colorectal Neoplasms/pathology , Curcumin/administration & dosage , Female , Fluorouracil/administration & dosage , Fluorouracil/therapeutic use , Humans , Leucovorin/administration & dosage , Leucovorin/therapeutic use , Male , Middle Aged , Neoplasm Metastasis , Organoplatinum Compounds/administration & dosage , Organoplatinum Compounds/therapeutic use , Treatment OutcomeABSTRACT
OBJECTIVE: Colorectal cancer (CRC) leads to significant morbidity/mortality worldwide. Defining critical research gaps (RG), their prioritisation and resolution, could improve patient outcomes. DESIGN: RG analysis was conducted by a multidisciplinary panel of patients, clinicians and researchers (n=71). Eight working groups (WG) were constituted: discovery science; risk; prevention; early diagnosis and screening; pathology; curative treatment; stage IV disease; and living with and beyond CRC. A series of discussions led to development of draft papers by each WG, which were evaluated by a 20-strong patient panel. A final list of RGs and research recommendations (RR) was endorsed by all participants. RESULTS: Fifteen critical RGs are summarised below: RG1: Lack of realistic models that recapitulate tumour/tumour micro/macroenvironment; RG2: Insufficient evidence on precise contributions of genetic/environmental/lifestyle factors to CRC risk; RG3: Pressing need for prevention trials; RG4: Lack of integration of different prevention approaches; RG5: Lack of optimal strategies for CRC screening; RG6: Lack of effective triage systems for invasive investigations; RG7: Imprecise pathological assessment of CRC; RG8: Lack of qualified personnel in genomics, data sciences and digital pathology; RG9: Inadequate assessment/communication of risk, benefit and uncertainty of treatment choices; RG10: Need for novel technologies/interventions to improve curative outcomes; RG11: Lack of approaches that recognise molecular interplay between metastasising tumours and their microenvironment; RG12: Lack of reliable biomarkers to guide stage IV treatment; RG13: Need to increase understanding of health related quality of life (HRQOL) and promote residual symptom resolution; RG14: Lack of coordination of CRC research/funding; RG15: Lack of effective communication between relevant stakeholders. CONCLUSION: Prioritising research activity and funding could have a significant impact on reducing CRC disease burden over the next 5 years.
Subject(s)
Biomedical Research/methods , Colorectal Neoplasms/therapy , Colorectal Neoplasms/diagnosis , Colorectal Neoplasms/genetics , Early Detection of Cancer/methods , Evidence-Based Medicine/methods , Gene-Environment Interaction , Genetic Predisposition to Disease , Humans , Risk FactorsABSTRACT
BACKGROUND: There is limited evidence assessing the effects of omega-3 polyunsaturated fatty acids (PUFAs) on oesophageal adenocarcinoma, both in vitro and in vivo. We evaluated the effects of the omega-3 PUFA and oxaliplatin on OE33 and OE19 cells. METHOD: The two oesophageal cells were treated with Omegaven® (fish oil emulsion), EPA, DHA and oxaliplatin and incubated for up to 144 h. RESULTS: The following inhibitory effects were observed on OE33 cells: EPA reduced cell growth by 39% (p = 0.001), DHA by 59% (p < 0.000) and Oxaliplatin by 77% (p < 0.000). For OE19 cells, the EPA reduced growth by 1% (p = 0.992), DHA by 26% (p = 0.019) and oxaliplatin by 76% (p < 0.000). For both cells, Omegaven® resulted in reduced cell growth at intermediate concentrations (20-40 µM) and increased cell growth at low (10 µM) and high (50 µM) concentrations. DHA, Omegaven® and oxaliplatin were associated with significant downregulation of VEGF and p53 protein, and upregulation of p21 protein. DHA, Omegaven® and Oxaliplatin also led to significant downregulation of the total ERK1/2 and Akt proteins. CONCLUSION: DHA, Omegaven® and oxaliplatin were associated with downregulation of p53 and VEGF in both cells. Of the PUFAs studied, DHA alone or in combination (Omegaven®) had greater in vitro anti-cancer effects than EPA alone.
Subject(s)
Adenocarcinoma/drug therapy , Esophageal Neoplasms/drug therapy , Fatty Acids, Omega-3/pharmacology , Fish Oils/pharmacology , Organoplatinum Compounds/pharmacology , Signal Transduction/drug effects , Adenocarcinoma/metabolism , Adenocarcinoma/physiopathology , Aged , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Cell Proliferation/drug effects , Cytokines/drug effects , Docosahexaenoic Acids/pharmacology , Docosahexaenoic Acids/therapeutic use , Down-Regulation , Eicosapentaenoic Acid/pharmacology , Eicosapentaenoic Acid/therapeutic use , Esophageal Neoplasms/metabolism , Esophageal Neoplasms/physiopathology , Fatty Acids, Omega-3/therapeutic use , Female , Fish Oils/therapeutic use , Gene Expression Regulation, Neoplastic , Humans , Male , Organoplatinum Compounds/therapeutic use , Oxaliplatin , Triglycerides , Tumor Suppressor Protein p53/drug effects , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Vascular Endothelial Growth Factors/drug effects , Vascular Endothelial Growth Factors/genetics , Vascular Endothelial Growth Factors/metabolismABSTRACT
BACKGROUND: Asymmetries in knowledge and competence in the medical encounter often mean that doctor-patient communication can be compromised. This study explores this issue and examines whether the likelihood of patient question asking is increased following the delivery of diagnostic test results. It also examines whether that likelihood is related to the way in which the test results are delivered. OBJECTIVE: To examine when and how patients initiate questions following diagnostic news announcements. METHODS: We audio-recorded oncology consultations (n = 47) consisting of both first consultations and follow-up consultations with patients with different types of cancer, at a leading UK teaching hospital. From the primary sample, we identified 30 consultations based on a basic count of the frequency of patient questions and their positioning in relation to diagnostic announcements. This subset of 30 consultations consisted of a mix of first and follow-up consultations. RESULTS: Our data demonstrate how the design and delivery of diagnostic news announcements can either discourage or provide the opportunity for a patient-initiated question in the next turn of talk. We identified two types of announcement. Q+ generally provided for a patient-initiated question as a relevant next turn following the news announcement, whereas Q- did not. Q+ was sometimes followed up with the explanation of test results, which appeared to encourage further patient questions. CONCLUSION: The design and delivery of diagnostic news announcements can make a patient-initiated question more or less appropriate, in the next turn of talk. In addition, showing and explaining test results can encourage further opportunities for patients' questions.
Subject(s)
Communication , Neoplasms/diagnosis , Physician-Patient Relations , Referral and Consultation , Female , Health Knowledge, Attitudes, Practice , Humans , Male , Medical Oncology/methods , United KingdomABSTRACT
This note presents a comparison of the use of saliva versus leukocytes for the determination of Pt-DNA adducts obtained from patients undergoing platinum-based chemotherapy. Samples of both blood and saliva were taken pre- and post-treatment and were analysed via sector-field inductively coupled plasma mass spectrometry (SF-ICP-MS) to determine the level of Pt-DNA adducts formed. As expected, significant inter-patient variability was seen; however, a lack of correlation between the levels of adducts observed in saliva and blood samples was also observed (Pearson correlation coefficient r = -0.2598). A high yield of DNA was obtained from saliva samples, but significant difficulties were experienced in obtaining patient adherence to the saliva sampling procedure. In both leukocyte and saliva samples, not only was Pt from previous chemotherapy cycles detected, but the rapid appearance of Pt in the DNA was noted in both sample types 1 h after treatment.
Subject(s)
Antineoplastic Agents/pharmacology , Cisplatin/pharmacology , DNA Adducts/analysis , Organoplatinum Compounds/pharmacology , Platinum/analysis , Saliva/chemistry , Humans , Leukocytes/chemistry , Leukocytes/drug effects , Mass Spectrometry , Neoplasms/chemistry , Neoplasms/drug therapy , Oxaliplatin , Saliva/drug effectsABSTRACT
OBJECTIVES: To determine whether early switch to oral antibiotic treatment in adults with neutropenic sepsis at low risk of complications is non-inferior to switching later. METHODS: This non-inferiority, parallel-group, randomized, open-label clinical trial enrolled UK adults hospitalized with neutropenic sepsis. Participants were randomly assigned to either switch to oral ciprofloxacin plus co-amoxiclav within 12-24 hours or to continue intravenous treatment for at least 48 hours. The primary outcome was a composite measure of treatment failure, 14 days after randomization. The non-inferiority margin was 15%. RESULTS: There were 129 participants from 16 centres and 125 were assessed for the primary outcome. Of these, 113 patients completed protocolized treatment and comprised the per-protocol population. In total, 9 (14.1%) of 64 patients in the standard care arm met the primary end point, compared with 15 (24.6%) of 61 in the early switch arm, giving a risk difference of 10.5% (1-sided 95% CI, -∞% to 22%; p 0.14). In the per-protocol population, 8 (13.3%) of the 60 patients in the standard care arm met the primary end point, compared with 9 (17%) of 53 in the intervention arm giving a risk difference of 3.7% (one-sided 95% CI, -∞% to 14.8%; p 0.59). Duration of hospital stay was shorter in the intervention arm (median 2 [inter-quartile range (IQR) 2-3] vs. 3 days [IQR 2-4]; p 0.002). DISCUSSION: Although non-inferiority of early oral switch was found in the per-protocol population, the intervention was not non-inferior in the intent-to-treat population.
Subject(s)
Neutropenia , Sepsis , Adult , Humans , Anti-Bacterial Agents , Ciprofloxacin/therapeutic use , Sepsis/drug therapy , Sepsis/chemically induced , Neutropenia/complications , Treatment OutcomeABSTRACT
AIM: Patients with loco-regional right-sided colorectal tumors have a worse overall survival (OS). Here we investigate the difference in disease free survival (DFS) between colorectal patients with right and left sided tumors in the SCOT study. METHODS: The SCOT study showed 3-months of oxaliplatin-containing adjuvant chemotherapy (OxFp) is non-inferior to 6-months for patients with stage III and high-risk stage II colorectal cancer. We divided the cohort into patients with left and right sided tumors, and evaluated the effect on DFS and the principle 3 versus 6-months analysis. RESULTS: 6088 patients with Stage III/high risk Stage II colorectal cancers were randomized between 27th March 2008 and 29th November 2013 from 244 centers internationally. In February 2017 (3-years FU) information on sidedness was available for 3309 patients (1238 R-sided, 2071 L-sided). Patients with right-sided tumors had a significantly worse DFS (3-year DFS right: 73.3% (se = 1.3%), left: 80.2% (se = 0.9%) HR 1.423 (95% CI 1.237-1.637; P < .0001). Adjusting for T and N-stage reduced the HR to 1.230 (95% CI 1.066-1.420, P = .005). The data did not suggest that sidedness affected the impact of chemotherapy duration on 3-year DFS (R: HR 1.024 [0.831-1.261], L: HR 0.944 [0.783-1.139]). Test for heterogeneity, P = .571. Further sub-set analysis was limited due to cohort size. CONCLUSIONS: This is the first study to show that unselected patients with right-sided tumors had a worse DFS compared to left-sided tumors. Tumor sidedness did not impact upon the 3-months versus 6-months comparison in SCOT.
Subject(s)
Colorectal Neoplasms , Humans , Disease-Free Survival , Prognosis , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/pathology , Oxaliplatin/therapeutic use , Chemotherapy, Adjuvant , Neoplasm Staging , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Retrospective StudiesABSTRACT
Platinum-containing drugs are widely used to treat cancer in a variety of clinical settings. Their mode of action involves the formation of DNA adducts, which facilitate apoptosis in cancer cells. Cisplatin binds to the N7 position of the purine DNA bases forming intrastrand cross-links between either two adjacent guanines [cis-Pt(NH(3))(2)d(pGpG), 1,2-GG] or an adjacent adenine and guanine [cis-Pt(NH(3))(2)d(pApG), 1,2-AG)]. The cytotoxic efficacy for each of the different types of DNA adducts and the relationship between adduct levels in tumor cells and blood are not well understood. By using these Pt-containing adduct species as biomarkers, information on a patient's response to chemotherapy would be directly related to the mode of action of the drug. This type of analysis requires the most sensitive and specific methods available, to facilitate detection limits sufficient to measure the DNA adduct in the limited sample quantities available from patients. This was achieved in the current study by coupling a highly specific enzyme-based adduct isolation method with a sensitive detection system based on HPLC coupled to inductively coupled plasma mass spectrometry to measure the 1,2-GG cisplatin adducts formed in DNA. The method was developed and validated using calf thymus DNA and two different adenocarcinoma cell lines. The values for the limit of detection (LOD) and the limit of quantitation determined for the 1,2-GG cisplatin adduct were 0.21 and 0.67 fmol per microg DNA, respectively. This corresponds to an absolute LOD of 0.8 pg as Pt for the 1,2-GG adduct. Cisplatin-sensitive (H23) and -resistant (A549) tumor cells were exposed to the drug, and the 1,2-GG adduct levels were measured over a 24 h time period. The results showed a statistically significant (P < 0.05) higher concentration in the sensitive cells as compared to the resistant cells after repair for 7 h. Although the adduct concentration present fell at subsequent time points (12 and 24 h), the levels in each cell line were broadly similar. The protocol was then applied to the analysis of patient samples taken before and then 1 h after treatment. The 1,2-GG cisplatin adduct was present in the range from 113 to 1245 fg Pt per microg DNA in all of the patient samples taken after treatment. Although the adduct was not present at levels greater than the LOD in the initial pretreatment samples, trace amounts were discernible in some patient samples on their third treatment cycle.
Subject(s)
Antineoplastic Agents/analysis , Cisplatin/analysis , DNA Adducts/analysis , DNA Adducts/chemistry , Guanine/chemistry , Leukocytes/metabolism , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cattle , Cell Line, Tumor , Cell Survival/drug effects , Chromatography, High Pressure Liquid , Cisplatin/chemistry , Cisplatin/pharmacology , DNA/chemistry , DNA/drug effects , DNA Adducts/pharmacology , DNA, Neoplasm/drug effects , DNA, Neoplasm/genetics , Drug Screening Assays, Antitumor , Humans , Leukocytes/cytology , Leukocytes/drug effects , Mass Spectrometry , Sensitivity and SpecificityABSTRACT
BACKGROUND: In cancer, platelets may facilitate metastatic spread by a number of mechanisms as well as contribute to thrombotic complications. Ticagrelor, a platelet antagonist- that blocks adenosine diphosphate activation of platelet P2Y12 receptors, is widely used in the treatment of cardiovascular disease, but its efficacy in cancer remains unknown. OBJECTIVES: This study sought to evaluate the effect of aspirin and ticagrelor monotherapy, as well as dual antiplatelet therapy, on platelet activation in cancer. METHODS: This study consisted of 2 phases: first, an in vitro study of human platelet-tumor cell interaction; and second, a randomized crossover clinical trial of 22 healthy donors and 16 patients with metastatic breast or colorectal cancer. Platelet activation and inhibition were measured by aggregometry and flow cytometry. RESULTS: In vitro, tumor cells induced cellular clusters that were predominantly platelet-platelet aggregates. Ticagrelor significantly inhibited formation of large tumor cell-induced platelet-platelet aggregates: 65.4 ± 4.8% to 50.9 ± 5.9% (p = 0.002) and 62.3 ± 3.1% to 48.3 ± 7.3% (p = 0.014) for MCF-7 and HT-29-induced aggregation, respectively. Supporting this finding, cancer patients on ticagrelor had significantly reduced levels of spontaneous platelet aggregation and activation compared with baseline; 14.8 ± 2.7% at baseline to 7.8 ± 2.3% with ticagrelor (p = 0.012). CONCLUSIONS: Our findings suggested that P2Y12 inhibition with ticagrelor might reduce spontaneous platelet aggregation and activation in patients with metastatic cancer and merits further investigation in patients at high risk of cancer-associated thrombosis. (Ticagrelor-Oncology [TICONC] Study; EudraCT: 2014-004049-29).
ABSTRACT
BACKGROUND: Neutropenic sepsis remains a common treatment complication for patients receiving systemic anti-cancer treatment. The UK National Institute for Health and Care Excellence have not recommended switching from empirical intravenous antibiotics to oral antibiotics within 48 h for patients assessed as low risk for septic complications because of uncertainty about whether this would achieve comparable outcomes to using intravenous antibiotics for longer. The UK National Institute for Health Research funded the EASI-SWITCH trial to tackle this uncertainty. METHODS: The trial is a pragmatic, randomised, non-inferiority trial that aims to establish the clinical and cost-effectiveness of early switching from intravenous to oral antibiotics in cancer patients with low-risk neutropenic sepsis. Patients ≥ 16 years, receiving systemic anti-cancer treatment (acute leukaemics/stem cell transplants excluded), with a temperature of > 38 °C, neutrophil count ≤ 1.0 × 109/L, MASCC (Multinational Association of Supportive Care in Cancer) score ≥ 21 and receiving IV piperacillin/tazobactam or meropenem for less than 24 h are eligible to participate. Patients are randomised 1:1 either (i) to switch to oral ciprofloxacin and co-amoxiclav within 12-24 h of commencing intravenous antibiotics, completing at least 5 days total antibiotics (intervention), or (ii) to continue intravenous antibiotics for at least 48 h, with ongoing antibiotics being continued at the physician's discretion (control). Patients are discharged home when their physician deems it appropriate. The primary outcome measure is a composite of treatment failures as assessed at day 14. The criteria for treatment failure include fever persistence or recurrence 72 h after starting intravenous antibiotics, escalation from protocolised antibiotics, hospital readmission related to infection/antibiotics, critical care support or death. Based on a 15% treatment failure rate in the control group and a 15% non-inferiority margin, the recruitment target is 230 patients. DISCUSSION: If the trial demonstrates non-inferiority of early switching to oral antibiotics, with potential benefits for patient quality of life and resource savings, this finding will have significant implications for the routine clinical management of those with low-risk neutropenic sepsis. TRIAL REGISTRATION: ISRCTN: 84288963. Registered on the 1 July 2015. https://doi.org/10.1186/ISRCTN84288963. EudraCT: 2015-002830-35.
Subject(s)
Anti-Bacterial Agents/administration & dosage , Neoplasms/complications , Neutropenia/drug therapy , Sepsis/drug therapy , Administration, Intravenous , Administration, Oral , Amoxicillin-Potassium Clavulanate Combination , Anti-Bacterial Agents/adverse effects , Ciprofloxacin , Cost-Benefit Analysis/economics , Drug Administration Schedule , Equivalence Trials as Topic , Humans , Meropenem , Multicenter Studies as Topic , Piperacillin , Pragmatic Clinical Trials as Topic , Quality of Life , Tazobactam , Treatment OutcomeABSTRACT
BACKGROUND/AIM: Previous studies have shown anti-proliferative and anti-apoptotic effects of omega-3 fatty acids (Omegaven®) in vitro and in vivo. Whether this effect can be exploited in patients with advanced esophago-gastric adenocarcinoma is unknown. The present study intended to determine the tumour radiological response and toxicity profile of intravenous omega-3 fish oil infusion when combined with standard palliative chemotherapy, and present the effects of this treatment on plasma cytokine biomarkers. MATERIALS AND METHODS: Participants with advanced esophago-gastric adenocarcinoma were enrolled in a phase II single-arm clinical trial of palliative chemotherapy (epirubicin, oxaliplatin, and capecitabine; EOX) coupled with weekly infusion of Omegaven®. Outcomes were compared to those observed in 37 historical control patients who had received EOX alone. Toxicity was graded using the CTCAE v4.03 and radiological response was assessed using RECIST v1.1. Plasma cytokine levels of IL-1, IL-2, IL-6, TNF-α, and VEGF were evaluated by ELISA. RESULTS: Twenty participants were included in the analysis. Radiological responses were as follows: partial response (EOX plus omega-3 group 73% vs. EOX alone 39%, p=0.03), stable disease (EOX plus omega-3 21% vs. EOX alone 39%, p=0.24), and progressive disease (EOX plus omega-3 7% vs. EOX alone 18%, p=0.34). Grade 3 or 4 toxicity was less common (thromboembolism & gastrointestinal) in those who received EOX plus omega-3. This translated into fewer hospital admissions. There were significant reductions in the concentrations of IL-2 (p=0.009), TNF-α (p<0.0001) and VEGF (p=0.002) following each treatment. CONCLUSION: The treatment with supplementary omega-3 fatty acids reduced chemotherapy-related toxicity and resulted in better radiological responses. The combination treatment resulted in a shift towards a favourable anti-inflammatory cytokine profile. These findings should be evaluated in a randomised clinical trial.
Subject(s)
Adenocarcinoma/drug therapy , Esophageal Neoplasms/drug therapy , Fish Oils/therapeutic use , Stomach Neoplasms/drug therapy , Adenocarcinoma/pathology , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Apoptosis , Biomarkers, Tumor/metabolism , Capecitabine/administration & dosage , Capecitabine/therapeutic use , Cell Proliferation , Cytokines/metabolism , Dietary Supplements , Epirubicin/administration & dosage , Epirubicin/therapeutic use , Esophageal Neoplasms/pathology , Esophagogastric Junction/pathology , Fatty Acids, Omega-3/therapeutic use , Feasibility Studies , Female , Fish Oils/administration & dosage , Humans , Male , Middle Aged , Oxaliplatin/administration & dosage , Oxaliplatin/therapeutic use , Palliative Care , Pilot Projects , Prospective Studies , Stomach Neoplasms/pathology , Treatment Outcome , TriglyceridesABSTRACT
BACKGROUND: Jejunostomy feeding tubes (JFTs) can be used to provide nutrition support to patients who have had surgery for esophagogastric cancer. Although previous research reports how patients cope with a gastrostomy tube, little is known about the impact of having a JFT. The aim of this qualitative study was to explore how patients and their informal caregivers experience living with a JFT in the first months following surgery. METHODS: Participants were purposively sampled from a cohort of patients recruited to a trial investigating home enteral nutrition vs standard care after esophagogastric surgery for cancer. The sampling framework considered age, sex, and marital status. Informal caregivers were also invited to participate. Interviews were audio recorded, transcribed verbatim, and anonymized. Inductive thematic analysis was used to identify key themes related to living with a JFT. RESULTS: Fifteen patient interviews were conducted; 8 also included a family caregiver. Analysis of the data resulted in 2 main themes: "challenges" and "facilitators" when living with a JFT. While "physical effects," "worries" and "impact on routine" were the main challenges, "support," "adaptation" and "perceived benefit" were what motivated continuation of the intervention. CONCLUSION: Findings suggest that participants coped well with a JFT, describing high levels of compliance with stoma care and the feeding regimen. Nonetheless, disturbed sleep patterns and stoma-related problems proved troublesome. A better understanding of these practical challenges, from the patient and family caregiver perspective, should guide healthcare teams in providing proactive support to avoid preventable problems.
Subject(s)
Adaptation, Psychological , Caregivers/psychology , Enteral Nutrition , Esophageal Neoplasms/therapy , Jejunostomy , Stomach Neoplasms/therapy , Aged , Body Mass Index , Cohort Studies , Esophageal Neoplasms/psychology , Esophageal Neoplasms/surgery , Female , Humans , Male , Middle Aged , Pilot Projects , Qualitative Research , Socioeconomic Factors , Stomach Neoplasms/psychology , Stomach Neoplasms/surgeryABSTRACT
Familial adenomatous polyposis coli (FAP) is an autosomal dominant condition caused by a germline mutation in the adenomatous polyposis coli gene. Colonic adenomas form and almost all patients will develop colorectal cancer if they are not managed at an early stage. The safest preventive strategy is surgical resection of the colon, most commonly performed in late teenage years. There is a paucity of trials investigating the use of primary chemoprevention to delay polyp formation in paediatric FAP. There are extensive preclinical and early clinical data demonstrating that curcumin may be a safe and effective chemotherapeutic agent in reducing the polyp burden in this disease. We ultimately proposed to design and conduct a clinical study to assess whether curcumin treatment delays the need for surgery and/or prevents cancer in young patients with FAP. Research into clinical trial protocols has demonstrated that assessing patients' perceptions at the initial stage leads to better outcomes. We therefore conducted a questionnaire study of patients and parents of children affected by FAP to gain information to aid the protocol design. Results demonstrated that there are some FAP patients for whom this study is relevant and desirable. Those with a personal history of curcumin use reported that it was well tolerated. However, the response rate was poor (25%), indicating that there are potential difficulties ensuring adequate recruitment to the proposed trial. This report draws on lessons learnt from prior trials and the findings from the questionnaire to outline the challenges faced in designing such a study.
Subject(s)
Adenomatous Polyposis Coli/drug therapy , Antineoplastic Agents/therapeutic use , Colorectal Neoplasms/prevention & control , Research Design/standards , Adolescent , Adult , Aged , Chemoprevention , Child , Child, Preschool , Female , Follow-Up Studies , Humans , Male , Middle Aged , Prognosis , Surveys and Questionnaires , Young AdultABSTRACT
INTRODUCTION: Gastroesophageal adenocarcinoma (GOA) is a frequently occurring cancer worldwide with a poor clinical outcome. Adenocarcinomas of the esophagus and gastroesophageal junction have shown a recent increase in frequency, therefore there is need to increase our understanding of GOA in order to improve our ability to detect, monitor and treat the disease. Areas covered: The authors discuss the current classification of GOA in the context of recent changes in incidence. The authors also discuss developments in the understanding of disease biology and recent discoveries from whole genome and whole exome sequencing, and studies in immunotherapy. Finally, the authors discuss the recent developments in the use of circulating tumour DNA (ctDNA). PubMed search terms were in English including 'esophageal/gastric adenocarcinoma', 'gastroesophageal junctional tumour', 'whole genome/exome sequencing', 'immunotherapy' and 'circulating tumour DNA'. Expert commentary: Shared biological and genetic changes in GOA suggest it can be investigated as a single disease entity with different molecular subtypes. A number of genes are recurrently mutated including TP53, SMAD4, PIK3CA and there are frequent somatic copy number alterations and high levels of chromosomal instability. A subset of these genetic alterations have been detected in ctDNA and may provide an important avenue of research for detecting minimal residual disease and response to chemo- and immunotherapies.
Subject(s)
Adenocarcinoma , DNA, Neoplasm/genetics , Esophageal Neoplasms , Stomach Neoplasms , Adenocarcinoma/diagnosis , Adenocarcinoma/genetics , Esophageal Neoplasms/diagnosis , Esophageal Neoplasms/genetics , Humans , Stomach Neoplasms/diagnosis , Stomach Neoplasms/geneticsABSTRACT
PURPOSE: PTK787/ZK 222584 (PTK/ZK) is an oral angiogenesis inhibitor targeting all known vascular endothelial growth factor (VEGF) receptor tyrosine kinases, including VEGFR-1/Flt-1, VEGFR-2/KDR, VEGFR-3/Flt-4, the platelet-derived growth factor receptor tyrosine kinase, and the c-kit protein tyrosine kinase. In this phase I dose-escalating study, PTK/ZK was administered bid to exploit the theoretical advantage of maintaining constant drug levels above a threshold known from preclinical data to interfere with VEGF receptor signaling. PATIENTS AND METHODS: Forty-three patients with advanced cancers received single-agent PTK/ZK at doses of 150 to 1,000 mg orally bid. Assessments for safety and pharmacokinetics were performed. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used as a pharmacodynamic marker of response. RESULTS: At 1,000 mg bid, the dose-limiting toxicity of reversible grade 3 lightheadedness was observed. Dose-related grade 3 fatigue and vomiting were observed but these were not dose-limiting. Pharmacokinetic data confirmed that PTK/ZK exposure increased with increasing dose up to 500 mg bid and appeared to plateau at higher doses. A greater than 40% reduction in the DCE-MRI bidirectional transfer constant (K(i)) at day 2 predicted for nonprogression of disease. CONCLUSION: The maximum-tolerated oral dose of PTK/ZK is 750 mg orally bid. DCE-MRI and pharmacokinetic data indicate that PTK/ZK >/= 1,000 mg total daily dose is the biologically active dose.
Subject(s)
Angiogenesis Inhibitors/pharmacology , Angiogenesis Inhibitors/pharmacokinetics , Neoplasms/drug therapy , Phthalazines/pharmacology , Phthalazines/pharmacokinetics , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/pharmacokinetics , Pyridines/pharmacology , Pyridines/pharmacokinetics , Administration, Oral , Adult , Aged , Angiogenesis Inhibitors/administration & dosage , Area Under Curve , Chi-Square Distribution , Chromatography, High Pressure Liquid , Disease Progression , Female , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Phthalazines/administration & dosage , Protein Kinase Inhibitors/administration & dosage , Pyridines/administration & dosage , Statistics, Nonparametric , Treatment OutcomeABSTRACT
Diet has been linked to an overwhelming proportion of cancers. Current chemotherapy and targeted therapies are limited by toxicity and the development of resistance against these treatments results in cancer recurrence or progression. In vitro evidence indicates that a number of dietary-derived agents have activity against a highly tumorigenic, chemoradiotherapy resistant population of cells within a tumour. This population is associated with cancer recurrence and is therefore clinically significant. Targeting this subpopulation, termed cancer stem-like cells with dietary-derived agents provides a potentially low toxicity strategy to enhance current treatment regimens. In addition, dietary-derived compounds also provide a novel approach to cancer prevention strategies. This review focusses on selected diet-derived agents that have been shown to specifically target cancer stem-like cells using in vivo models, or in clinical trials. Furthermore, the potential limitations of these studies are discussed, and areas of research that need to be addressed to allow successful translation of dietary-derived agents to the clinical arena are highlighted.