Thromboxane biosynthesis in cancer patients and its inhibition by aspirin: a sub-study of the Add-Aspirin trial

BACKGROUND: Pre-clinical models demonstrate that platelet activation is involved in the spread of malignancy. Ongoing clinical trials are assessing whether aspirin, which inhibits platelet activation, can prevent or delay metastases. METHODS: Urinary 11-dehydro-thromboxane B2 (U-TXM), a biomarker of in vivo platelet activation, was measured after radical cancer therapy and correlated with patient demographics, tumour type, recent treatment, and aspirin use (100 mg, 300 mg or placebo daily) using multivariable linear regression models with log-transformed values. RESULTS: In total, 716 patients (breast 260, colorectal 192, gastro-oesophageal 53, prostate 211) median age 61 years, 50% male were studied. Baseline median U-TXM were breast 782; colorectal 1060; gastro-oesophageal 1675 and prostate 826 pg/mg creatinine; higher than healthy individuals (~500 pg/mg creatinine). Higher levels were associated with raised body mass index, inflammatory markers, and in the colorectal and gastro-oesophageal participants compared to breast participants (P < 0.001) independent of other baseline characteristics. Aspirin 100 mg daily decreased U-TXM similarly across all tumour types (median reductions: 77-82%). Aspirin 300 mg daily provided no additional suppression of U-TXM compared with 100 mg. CONCLUSIONS: Persistently increased thromboxane biosynthesis was detected after radical cancer therapy, particularly in colorectal and gastro-oesophageal patients. Thromboxane biosynthesis should be explored further as a biomarker of active malignancy and may identify patients likely to benefit from aspirin

Thromboxane biosynthesis in cancer patients and its inhibition by aspirin: a sub-study of the Add-Aspirin trial

Background: Pre-clinical models demonstrate that platelet activation is involved in the spread of malignancy. Ongoing clinical trials are assessing whether aspirin, which inhibits platelet activation, can prevent or delay metastases. Methods: Urinary 11-dehydro-thromboxane B2 (U-TXM), a biomarker of in vivo platelet activation, was measured after radical cancer therapy and correlated with patient demographics, tumour type, recent treatment, and aspirin use (100 mg, 300 mg or placebo daily) using multivariable linear regression models with log-transformed values. Results: In total, 716 patients (breast 260, colorectal 192, gastro-oesophageal 53, prostate 211) median age 61 years, 50% male were studied. Baseline median U-TXM were breast 782; colorectal 1060; gastro-oesophageal 1675 and prostate 826 pg/mg creatinine; higher than healthy individuals (~500 pg/mg creatinine). Higher levels were associated with raised body mass index, inflammatory markers, and in the colorectal and gastro-oesophageal participants compared to breast participants (P < 0.001) independent of other baseline characteristics. Aspirin 100 mg daily decreased U-TXM similarly across all tumour types (median reductions: 77–82%). Aspirin 300 mg daily provided no additional suppression of U-TXM compared with 100 mg. Conclusions: Persistently increased thromboxane biosynthesis was detected after radical cancer therapy, particularly in colorectal and gastro-oesophageal patients. Thromboxane biosynthesis should be explored further as a biomarker of active malignancy and may identify patients likely to benefit from aspirin

Real world outcomes in platinum sensitive relapsed ovarian, fallopian tube, or peritoneal cancer treated in routine clinical practice in the United Kingdom prior to poly-ADP ribose polymerase inhibitors

Introduction: The introduction of poly-ADP ribose polymerase inhibitors in ovarian cancer has demonstrated significantly improved progression free survival in four randomized controlled clinical trials in patients with platinum sensitive relapsed ovarian cancer. While overall survival data remain immature, this real world evidence study sets a baseline for future evaluation of poly-ADP ribose polymerase inhibitors. Methods: A retrospective chart review was undertaken to investigate real world survival outcomes across 13 National Health Service Trusts in England, Wales, and Scotland. Patients were included if they had platinum sensitive relapsed high grade serous ovarian cancer and had responded to secondline platinum based chemotherapy. Clinical data were collected retrospectively from electronic prescribing records and chart notes. The index date for overall survival analysis was defined as the later of (1) day 1 of the final secondline platinum based treatment or (2) date of response to secondline treatment. The primary objective was overall survival from the index date. Secondary objectives included progression free survival and overall survival by subsequent line of treatment. BRCA mutation status was collected where available. Quality of life questionnaires were not assessed within this study. Results: 233 patients were identified who met the study inclusion criteria. Patient characteristics were consistent with other published data, with a median age of 61 years (range 35–85). Sensitivity analysis of the primary objective demonstrated that the earliest point poly-ADP ribose polymerase inhibitors may be initiated (following completion of secondline chemotherapy) is associated with a median overall survival of 19.8 months. Secondline median overall survival and progression free survival from the index date were 19.3±2.4 months and 7.3±1.2 months, respectively. 144 patients were treated with thirdline chemotherapy with median overall survival and progression free survival from the index date (either date of last cycle of thirdline treatment or date of response to thirdline treatment) of 8.3±2.6 and 4.4±1.8 months, respectively. Conclusion: Overall survival was shown to be shorter in this real world study compared with randomized clinical trials, and underlines the differences in clinical outcomes of patients in a real life setting. This baseline real world study has demonstrated poor survival outcomes in this patient group prior to availability of poly-ADP ribose polymerase inhibitors

Can localised 19F magnetic resonance spectroscopy pharmacokinetics of 5FU in colorectal metastases predict clinical response?

Background 5-Fluorouracil remains widely used in colorectal cancer treatment more than 40 years after its development. 19F magnetic resonance spectroscopy can be used in vivo to measure 5FU’s half-life and metabolism to cytotoxic fluoronucleotides. Previous studies have shown better survival associated with longer 5FU tumour half-life. This work investigated 5FU pharmacokinetics in liver metastases of colorectal cancer. Methods A total of 32 subjects with colorectal cancer undergoing 5FU treatment, 15 of whom had liver metastases, were examined in a 1.5T MRI scanner, using a large coil positioned over the liver. Non-localised spectra were acquired in 1-min blocks for 32 min after injection of a 5FU bolus. The 5FU half-life was measured in each subject, and averaged spectra were examined for the presence of fluoronucleotides. Associations with progression-free survival were assessed. Results No association was observed between 5FU halflife, tumour burden and survival. Half-lives were all shorter than those associated with improved survival in the literature. Remarkably, in the group with liver metastases, high levels of fluoronucleotides were associated with poorer survival; this counterintuitive result may be due to the higher levels of fluoronucleotides (whose level is higher in tumour tissue than in normal liver) in patients with higher tumour burdens. Conclusions It is recommended that future studies use chemical shift imaging at higher field strengths to better resolve tumour from normal liver. Non-localised spectroscopy retains prognostic potential by enabling straightforward detection of fluoronucleotides, which are present at very low concentrations distributed throughout the tissue

Longitudinal quality of life and quality adjusted survival in a randomised controlled trial comparing six months of bolus fluorouracil/leucovorin vs. twelve weeks of protracted venous infusion fluorouracil as adjuvant chemotherapy for colorectal cancer

Longitudinal quality of life (QOL) assessment is infrequently made in adjuvant therapy for colorectal cancer (CRC). This analysis aims to assess QOL and quality adjusted survival (QAS) in patients receiving adjuvant 5-FU for stage II and III CRC. We performed a multicentre study in which 801 patients were randomised to 6 months of bolus 5-FU/leucovorin (LV n = 404) or 12 weeks of protracted venous infusion (PVI) 5-FU (n = 397). There were significant differences in the deterioration of QOL scores at week 2 with bolus 5-FU/LV compared to PVI 5-FU (P &lt; 0.001), coinciding with toxicity peak during the first cycle. Following week 12, global QOL recovered to baseline when PVI 5-FU was stopped but this was delayed with bolus 5-FU/LV until completion at week 24. QOL scores significantly improved in both arms during follow-up (P &lt; 0.001) and reached a plateau by year 1 without incremental improvement between years 2 and 5. There was a trend towards better QAS with PVI 5-FU. Twelve weeks of adjuvant PVI 5-FU was associated with significantly better QOL during treatment and faster time to recovery compared to 6 months of bolus 5-FU/LV. <br/

Venous thromboembolism at time of diagnosis of ovarian cancer: Survival differs in symptomatic and asymptomatic cases

Objectives To determine the impact on survival of symptomatic and asymptomatic venous thromboembolism (VTE) at time of diagnosis of primary ovarian malignancy. Materials and methods The clinical records of 397 consecutive cases of primary ovarian malignancy were studied. Clinical, pathological and survival data were obtained. Results and conclusions Of 397 cases, 19 (4.8%) were found to have VTE at diagnosis, of which 63.2% (n = 12) were asymptomatic. VTE was significantly associated with reduced overall median survival (28 vs. 45 months, p = 0.004). Decreased survival was associated with symptomatic VTE compared to patients with asymptomatic VTE (21 vs. 36 months, p = 0.02) whose survival was similar to that of patients without VTE. Decreased survival remained significant in symptomatic patients after controlling for stage of disease at diagnosis, cytoreductive status and adjuvant chemotherapy use. Overall these data suggest for the first time that symptomatic but not asymptomatic VTE prior to primary treatment of ovarian cancer is an independent adverse prognostic factor

Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer

Background: a regimen of epirubicin, cisplatin, and infused fluorouracil (ECF) improves survival among patients with incurable locally advanced or metastatic gastric adenocarcinoma. We assessed whether the addition of a perioperative regimen of ECF to surgery improves outcomes among patients with potentially curable gastric cancer. Methods: we randomly assigned patients with resectable adenocarcinoma of the stomach, esophagogastric junction, or lower esophagus to either perioperative chemotherapy and surgery (250 patients) or surgery alone (253 patients). Chemotherapy consisted of three preoperative and three postoperative cycles of intravenous epirubicin (50 mg per square meter of body-surface area) and cisplatin (60 mg per square meter) on day 1, and a continuous intravenous infusion of fluorouracil (200 mg per square meter per day) for 21 days. The primary end point was overall survival. Results: ECF-related adverse effects were similar to those previously reported among patients with advanced gastric cancer. Rates of postoperative complications were similar in the perioperative-chemotherapy group and the surgery group (46 percent and 45 percent, respectively), as were the numbers of deaths within 30 days after surgery. The resected tumors were significantly smaller and less advanced in the perioperative-chemotherapy group. With a median follow-up of four years, 149 patients in the perioperative-chemotherapy group and 170 in the surgery group had died. As compared with the surgery group, the perioperative-chemotherapy group had a higher likelihood of overall survival (hazard ratio for death, 0.75; 95 percent confidence interval, 0.60 to 0.93; P=0.009; five-year survival rate, 36 percent vs. 23 percent) and of progression-free survival (hazard ratio for progression, 0.66; 95 percent confidence interval, 0.53 to 0.81; P&lt;0.001). Conclusions: in patients with operable gastric or lower esophageal adenocarcinomas, a perioperative regimen of ECF decreased tumor size and stage and significantly improved progression-free and overall survival

Common variation near CDKN1A, POLD3 and SHROOM2 influences colorectal cancer risk

We performed a meta-analysis of five genome-wide association studies to identify common variants influencing colorectal cancer (CRC) risk comprising 8,682 cases and 9,649 controls. Replication analysis was performed in case-control sets totaling 21,096 cases and 19,555 controls. We identified three new CRC risk loci at 6p21 (rs1321311, near CDKN1A; P = 1.14 × 10 -10), 11q13.4 (rs3824999, intronic to POLD3; P = 3.65 × 10 -10) and Xp22.2 (rs5934683, near SHROOM2; P = 7.30 × 10 -10) This brings the number of independent loci associated with CRC risk to 20 and provides further insight into the genetic architecture of inherited susceptibility to CRC.</p