Biomedical subjects

G C Jayson

Publications and source records attributed to G C Jayson.

At least 19 recordsLinked to original sources

PubMed2007

DCE-MRI biomarkers in the clinical evaluation of antiangiogenic and vascular disrupting agents.

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is now frequently used in early clinical trial assessment of antiangiogenic and vascular disrupting compounds. Evidence of drug efficacy and dose-dependent response has been demonstrated with some angiogenesis inhibitors. This review highlights the critical issues that influence T(1)-weighted DCE-MRI data acquisition and analysis, identifies important areas for future development and reviews the clinical trial findings to date.

Angiogenesis Inhibitors↗

PubMed2006

The interval from surgery to chemotherapy in the treatment of advanced epithelial ovarian carcinoma.

BACKGROUND: To study the effect of the interval between surgery and the start of chemotherapy in the treatment of patients with advanced ovarian cancer. METHODS: We stratified patients according to the start of platinum-based chemotherapy in group 1 (within 4 weeks from surgery), group 2 (between 4 and 8 weeks) and group 3 (between 8 and 12 weeks). RESULTS: Three hundred and ninty-four stage III ovarian cancer patients were analysed. In the multivariate analysis there were no differences in survival according to the interval between surgery and chemotherapy among the three groups. The independent prognostic variables were type of procedure (p = 0.014), performance status (p = 0.040) and post-chemotherapy CA-125 (p < 0.0001). CONCLUSIONS: The interval between surgery and chemotherapy does not affect outcome.

Adult↗

PubMed2006

SCOTROC 2B: feasibility of carboplatin followed by docetaxel or docetaxel-irinotecan as first-line therapy for ovarian cancer.

The feasibility of combination irinotecan, carboplatin and docetaxel chemotherapy as first-line treatment for advanced epithelial ovarian carcinoma was assessed. One hundred patients were randomised to receive four 3-weekly cycles of carboplatin (area under the curve (AUC) 7) followed by four 3-weekly cycles of docetaxel 100 mg m(-2) (arm A, n=51) or docetaxel 60 mg m(-2) with irinotecan 200 mg m(-2) (arm B, n=49). Neither arm met the formal feasibility criterion of an eight-cycle treatment completion rate that was statistically greater than 60% (arm A 71% (90% confidence interval (CI) 58-81%; P=0.079; arm B 67% (90% CI 55-78%; P=0.184)). Median-dose intensities were >85% of planned dose for all agents. In arms A and B, 15.6 and 12.2% of patients, respectively, withdrew owing to treatment-related toxicity. Grade 3-4 sensory neurotoxicity was more common in arm A (1.9 vs 0%) and grade 3-4 diarrhoea was more common in arm B (0.6 vs 3.5%). Of patients with radiologically evaluable disease at baseline, 50 and 48% responded to therapy in arms A and B, respectively; at median 17.1 months' follow-up, median progression-free survival was 17.1 and 15.9 months, respectively. Although both arms just failed to meet the formal statistical feasibility criteria, the observed completion rates of around 70% were reasonable. The addition of irinotecan to first-line carboplatin and docetaxel chemotherapy was generally well tolerated although associated with increased gastrointestinal toxicity. Further exploratory studies of topoisomerase-I inhibitors in this setting may be warranted.

Adult↗

PubMed2005

The clinical potential of antiangiogenic fragments of extracellular matrix proteins.

Neovasculature development is a crucial step in the natural history of a cancer. While much emphasis has been placed on proangiogenic growth factors such as VEGF, it is clear that endogenous angiogenesis inhibitors also have critical roles in the regulation of this process. Recent research has identified several cryptic fragments of extracellular matrix/vascular basement membrane proteins that have potent antiangiogenic properties in vivo. It has become apparent that many of these fragments signal via interactions with endothelial integrins, although multiple downstream effector pathways have been implicated and endostatin, the first non-collagenous domain of collagen XVIII, influences an intricate signalling network. The activity of these molecules in animal models suggests that they may have significant clinical activity; however, results of phase I/II trials with endostatin were disappointing. Many possible reasons can be found for the failure of these studies. Weaknesses in trial design, endostatin administration regimen and patient selection are identifiable, and importantly the lack of a clearly defined antiangiogenic mechanism for endostatin hindered assessment of biologically effective dose. Additionally, in vivo immunological and proteolytic function-neutralising mechanisms may have negated endostatin's actions. Lessons learned from these studies will aid the future clinical development of other antiangiogenic extracellular matrix protein fragments.

Angiogenesis Inhibitors↗

PubMed2005

Impact of laparotomy and liver resection on the peritoneal concentrations of fibroblast growth factor 2, vascular endothelial growth factor and hepatocyte growth factor.

PURPOSE: Some data have suggested that major surgery is associated with the post-operative growth of residual tumour masses but the mechanism of this is unknown. This study was designed to determine the relationship between intraperitoneal (IP) cytokine levels, and laparotomy in benign and malignant settings. METHODS: Intraperitoneal fluid specimens were obtained at the start and at the end of laparotomy in patients with benign conditions (n=10) and in others undergoing resection of hepatic metastases from colorectal cancer (n=10). Using ELISA the concentration of the angiogenic cytokines, HGF, VEGF-A, VEGF-C, VEGF-D and FGF-2 was determined. RESULTS: The data show that in 16 of 20 patients there was a significant increase (P=0.006) in the IP concentration of hepatocyte growth factor (HGF) but not in the other growth factors by the end of the operation. The mean increase in HGF concentration was 821.5 pg/ml (95% CI: 11.0-6,426.0). Neither the groups (malignant and non-malignant) nor the length of operation correlated with greater or lesser increases in HGF. CONCLUSION: The observation that the increase in HGF occurred in both the cancer and non-cancer groups suggests that it is the surgery rather than the disease that is associated with the increased cytokine concentration. As HGF is a potent endothelial, epithelial and mesenchymal mitogen the data highlight HGF as a potential target for anti-cancer treatments in the peri-operative period. However, investigators should closely monitor wound healing as this may be compromised by this new class of drugs.

Ascitic Fluid↗

PubMed2005

Phase II trial of tamoxifen and goserelin in recurrent epithelial ovarian cancer.

Endocrine therapy is a recognised option in the treatment of chemo-resistant ovarian cancer. We conducted a nonrandomised phase II evaluation of combination endocrine therapy with tamoxifen and goserelin in patients with advanced ovarian cancer that had recurred following chemotherapy. In total, 26 patients entered the study, of which 17 had platinum-resistant disease. The median age was 63 years and enrolled patients had received a median of three chemotherapy regimens prior to trial entry. Patients were given oral tamoxifen 20 mg twice daily on a continuous basis and subcutaneous goserelin 3.6 mg once a month until disease progression. Using the definition of endocrine response that included patients with stable disease (SD) of 6 months or greater, the overall response rate (clinical benefit rate) was 50%. This included one complete response (CR) (3.8%), two partial responses (PR) (7.7%) and 10 patients with SD (38.5%). The median progression-free interval (PFI) was 4 months (95% CI 2.4-9.6) while the median overall survival (OS) was 13.6 months (95% CI 5.5-30.6). Four patients received treatment for more than 2 years (range 1-31) and one of them is still on treatment. In none of the four patients was there any evidence of recurrent or cumulative treatment related toxicity. Treatment-limiting toxicity was not seen in any of the study population. Endocrine data demonstrated a marked suppression of luteinising hormone (LH) and follicle-stimulating hormone (FSH) to less than 4% of baseline values. No consistent correlation could be established between LH/FSH suppression and tumour response. Likewise no relationship was observed between Inhibin A/B and pro-alpha C levels and tumour response. Inhibin is unlikely to be a useful surrogate marker for response in locally advanced or metastatic ovarian cancer. Combination endocrine therapy with tamoxifen and goserelin is an active regimen in platinum-resistant ovarian cancer patients. Hormonal therapy is advantageous in its relative lack of toxicity, ease of administration and tolerability, thus making it suitable for patients with heavily pretreated disease, compromised bone marrow function and other comorbid conditions that contraindicate cytotoxic therapy as well as in patients with indolent disease.

Aged↗

PubMed2005

The assessment of antiangiogenic and antivascular therapies in early-stage clinical trials using magnetic resonance imaging: issues and recommendations.

Vascular and angiogenic processes provide an important target for novel cancer therapeutics. Dynamic contrast-enhanced magnetic resonance imaging is being used increasingly to noninvasively monitor the action of these therapeutics in early-stage clinical trials. This publication reports the outcome of a workshop that considered the methodology and design of magnetic resonance studies, recommending how this new tool might best be used.

Angiogenesis Inhibitors↗

PubMed2005

Pre-operative plasma levels of vascular endothelial growth factor A, C and D in patients with colorectal cancer.

AIMS: Vascular endothelial growth factor (VEGF)-C and VEGF-D are angiogenic and lymphangiogenic members of the VEGF family of growth factors. Increased VEGF-C or VEGF-D expression in human tumours may be associated with lymph-node metastasis and lymphatic invasion. Circulating plasma levels of VEGF-A, VEGF-C and VEGF-D were measured in patients with colorectal cancer, and assessed for their usefulness as a diagnostic tool for determining lymph-node metastasis. MATERIALS AND METHODS: One hundred and twenty patients with colorectal cancer and 50 healthy control patients were included in the study. Plasma growth-factor levels were assessed by enzyme-linked immunosorbent assays. RESULTS: No significant differences in plasma VEGF-C or VEGF-D levels were seen between patients subgrouped by clinicopathological variables. In particular, there were no differences in median plasma VEGF-C or VEGF-D level in patients with and without lymph-node involvement (VEGF-C: 11.2 U/ml [range, 4.9-51.9] vs 9.9 U/ml [4.4-93.4 U/ml]; P = 0.90; VEGF-D: 335 pg/ml [113-1102] vs 316.5 pg/ml [0-1343]; P = 0.68). CONCLUSIONS: Circulating plasma levels of VEGF-C and VEGF-D do not allow pre-operative identification of lymph-node status in patients with colorectal cancer.

Adult↗

PubMed2004

Blockade of platelet-derived growth factor receptor-beta by CDP860, a humanized, PEGylated di-Fab', leads to fluid accumulation and is associated with increased tumor vascularized volume.

PURPOSE: CDP860 is an engineered Fab' fragment-polyethylene glycol conjugate, which binds to and blocks the activity of the beta-subunit of the platelet-derived growth factor receptor (PDGFR-beta). Studies in animals have suggested that PDGFR-beta inhibition reduces tumor interstitial fluid pressure, and thus increases the uptake of concomitantly administered drugs. The purpose of this study was to determine whether changes in tumor vascular parameters could be detected in humans, and to assess whether CDP860 would be likely to increase the uptake of a concurrently administered small molecule in future studies. PATIENTS AND METHODS: Patients with advanced ovarian or colorectal cancer and good performance status received intravenous infusions of CDP860 on days 0 and 28. Patients had serial dynamic contrast-enhanced magnetic resonance imaging studies to measure changes in tumor vascular parameters. RESULTS: Three of eight patients developed significant ascites, and seven of eight showed evidence of fluid retention. In some patients, the ratio of vascular volume to total tumor volume increased significantly (P < .001) within 24 hours following CDP860 administration, an effect suggestive of recruitment of previously non-functioning vessels. CONCLUSION: These observations suggest that inhibition of PDGFR-beta might improve delivery of a concurrently administered therapy. However, in cancer patients, further exploration of the dosing regimen of CDP860 is required to dissociate adverse effects from beneficial effects. The findings challenge the view that inhibition of PDGF alone is beneficial, and confirm that effects of PDGFR kinase inhibition mediate, to some extent, the fluid retention observed in patients treated with mixed tyrosine kinase inhibitors.

Adult↗

PubMed2004

A phase IIA study of the topoisomerase I inhibitor, exatecan mesylate (DX-8951f), administered at two different dose schedules in patients with platinum- and taxane-resistant/refractory ovarian cancer.

OBJECTIVES: There is an urgent need for new agents with activity in platinum- and taxane-resistant epithelial ovarian cancer. Exatecan mesylate is a novel topoisomerase I inhibitor with potent activity against ovarian cancer in vitro. A multicentre phase IIA study was conducted in patients with platinum- and taxane-resistant epithelial ovarian cancer. PATIENTS AND METHODS: Fifty-seven patients with bidimensionally measurable ovarian cancer, previously exposed to platinum and taxanes, whose disease had relapsed within 6 months of platinum-containing chemotherapy were randomised to one of two intravenous schedules of exatecan mesylate; 0.3 mg/m(2) daily for 5 days every 3 weeks (Arm A) or 2.1 mg/m(2) weekly for 3 weeks out of 4 (Arm B). RESULTS: There were no responses in the weekly arm and a radiological response rate of 5.3% (95% CI 0.3-21.8%) in the daily arm. Principal toxicities were myelosuppression and emesis. Grade 3/4 neutropenia occurred in 29% of patients in Arm A and 6% patients in Arm B. Seventy-one percent of patients in Arm A required red cell transfusions while on treatment. CONCLUSIONS: Exatecan is well tolerated in this poor prognosis group of patients but only has modest single agent activity when administered in a daily regimen.

Adult↗

PubMed2004

Quantitative angiogenesis assays in vivo--a review.

The development of agents that target tumour vasculature is ultimately dependent on the availability of appropriate preclinical screening assays. Several quantitative angiogenesis assays exist, each with its own unique characteristics and disadvantages. In this review we discuss some of the commonly used assays, their methodological pitfalls and current use. The corneal micropocket and the CAM assay are well established. However, the matrix-implant assays have the potential advantage of replicating the hypoxic tumour microenvironment, thus making them suitable for the study of tumour angiogenesis. The ideal quantitative angiogenesis assay does not exist and the use of two complimentary quantitative assays, such as a matrix implant assay and a microcirculatory preparation like the CAM or corneal micropocket assay, provides the best compromise. Newer models like the hollow-fibre assay are being developed and older ones refined. Assay systems should reflect distinct disease processes. Thus it is appropriate to develop assays that study exclusively pro- or anti-angiogenic compounds or anti-vascular agents. Criticisms of currently available screening systems are that the predictive value of current screening systems remains to be established as anti-angiogenic agents are still in clinical development. Anti-angiogenic agents are likely to be most effective as chronic therapy for remission maintenance in the metastatic setting or as adjuvant therapy in patients at high risk of relapse, an important clinical aspect not addressed in animal models of tumour angiogenesis. Histological analysis still provides the most detailed information on in vivo angiogenesis. However, angiogenesis is a dynamic process and assays that permit continuous monitoring of the angiogenic response and provide information on the physiological characteristics of new vessels will be distinctly advantageous over older systems. The development of non-invasive techniques for quantitation of angiogenesis will greatly facilitate this process.

Animals↗

PubMed2004

Resistance to anti-VEGF agents.

The number of anti-angiogenic agents developed for clinical use has risen greatly over the past decade. Currently, more than 80 are in trials ranging from phase I through to phase III studies and many more are in preclinical evaluation. Much hope was envisaged for these new agents to become the panacea of anti-tumoural treatment. Unfortunately the single agent activity to date has proven to be disappointing although one trial has recently reported a survival advantage when chemotherapy was administered with anti-VEGF antibodies in the setting of advanced colorectal cancer. To an extent, this may be due to great expectations of cytostatic compounds, but recently many factors have been examined to explain the differences between clinical and experimental findings. In this review, some of the factors responsible for the discrepancy are examined, with a specific focus on inhibitors of VEGF. The key factors responsible for the lack of activity are tumour heterogeneity and redundancy in the VEGF signalling system. An increased understanding of these factors is critical to the development of effective anti-angiogenic agents and need to be taken into account as new generations of drugs emerge.

Animals↗

PubMed2003

A phase II trial of bryostatin-1 administered by weekly 24-hour infusion in recurrent epithelial ovarian carcinoma.

Bryostatin-1 is a macrocyclic lactone whose main mechanism of action is protein kinase C modulation. We investigated its activity as a weekly 24-h infusion in recurrent ovarian carcinoma. In all, 17 patients were recruited and 11 had chemotherapy-resistant disease as defined by disease progression within 4 months of last cytotoxic therapy. All were evaluable for toxicity and 14 for response. There were no disease responses and the main toxicity was myalgia.

Adult↗

PubMed2003

Vascular endothelial growth factors C and D and lymphangiogenesis in gastrointestinal tract malignancy.

Vascular endothelial growth factor-C (VEGF-C) and VEGF-D are members of the VEGF family of cytokines and have angiogenic and lymphangiogenic actions. In gastric adenocarcinoma, VEGF-C mRNA and tissue protein expression correlate with lymphatic invasion, lymph node metastasis and in some reports, venous invasion and reduced 5-year survival. Patients with gastric adenocarcinomas containing high levels of VEGF-C expression have significantly reduced 5-year survival rates, and VEGF-C expression is an independent prognostic risk factor for death. The role of VEGF-C in oesophageal squamous and colorectal cancer and VEGF-D in colorectal cancer is not clear, with conflicting reports in the published literature. In order to exploit potential therapeutic applications, further research is necessary to define the precise roles of these cytokines in health and disease.

Adenocarcinoma↗

PubMed2003

Oral melphalan as a treatment for platinum-resistant ovarian cancer.

A large number of drugs have been used to treat recurrent ovarian cancer, yet there are few data that guide the physician's choice. Typically, the decision to re-treat with platinum-based therapy depends on the progression-free interval. However, the optimum agent for the treatment of platinum-resistant or refractory disease is not defined. In this study, we investigated the efficacy of oral melphalan in patients who have platinum refractory or resistant disease. A retrospective analysis was performed on 22 patients with ovarian carcinomas who had relapsed within 6 months of their platinum-based chemotherapy and were treated with oral melphalan. No objective responses were seen and the median overall survival was 3 months from commencement of therapy. Although the treatment was generally well tolerated, only two of the 22 patients managed to complete the planned six cycles of treatment. At the time of analysis, only two patients were alive. Other nonplatinum compounds have demonstrated response rates in the region of 20% in similar patient populations and it is unlikely that any positive responses could have been missed by chance (95% CI 0-15.4). The results of this study serve to eliminate oral melphalan as a treatment option in patients with platinum-resistant or refractory ovarian carcinoma.

Administration, Oral↗

PubMed2003

Carcinosarcoma of the ovary.

We report our experience in the management of patients with carcinosarcoma of the ovary, a rare but aggressive variant of ovarian cancer. Forty patients were treated at a single centre, which is the largest reported series. The median age at diagnosis was 65 years (range 45-86) and the median Karnofsky performance (KP) status was 70. Thirty-two patients (80%) presented with FIGO stage III or IV disease. Twenty-four had heterologous and 14 homologous carcinosarcoma on review of histopathology, but there was no significant difference in survival between these groups (P=0.28). Twenty-seven of the 40 patients had bulk residual disease present after surgery and this was associated with a worse prognosis (P=0.045). Chemotherapy was given to 32 patients (80%) of whom 26 (81%) received platinum-based regimens. Of these 32 patients, three (9.4%) achieved a complete response (CR), 10 (31%) a partial response (PR), five (16%) had stable disease, 10 (31%) had progressive disease and four were not assessable. Of the 19 patients who had a CR, PR or stable disease after chemotherapy or were unevaluable (stage Ic), the median survival was 29.6 months. Currently, seven patients are still alive although one has cancer. The overall censored median survival was 8.7 months after a median follow-up of 34 months, and the 1- and 5-year survival were 40 and 7.5%, respectively.

Aged↗

PubMed2003

The current and future management of malignant ascites.

Malignant ascites occurs in association with a variety of neoplasms. It is a frequent cause of morbidity and presents significant problems for which there are no clear management guidelines. In this article we discuss various modalities which are available including diuretic therapy, paracentesis, peritoneovenous shunts and intraperitoneal chemotherapy. There are no randomized trials of diuretic drugs to assess their efficacy in malignant ascites. Phase II data suggest that they are effective in approximately one-third of patients with malignancy, and their efficacy may be determined by plasma renin/aldosterone concentrations. Paracentesis provides relief in up to 90% of patients; because of varying reports of hypovolaemia, some advocate simultaneous intravenous fluid infusion. Permanent percutaneous drains may prevent the need for repeated paracentesis, although there is potential for infection. A peritoneovenous shunt also prevents the need for repeated paracenteses, whilst maintaining normal serum albumin concentrations. Blockage occurs in 25% of shunts, which are contraindicated in the presence of heavily bloodstained ascites because of the risk of occlusion. The preclinical and clinical experience with anti-angiogenic agents such as the matrix metalloproteinase inhibitors and the VEGF antagonists suggests that these agents may have a role in the treatment of malignant ascites.

Antineoplastic Agents↗

PubMed2003

Reproducibility of quantitative dynamic contrast-enhanced MRI in newly presenting glioma.

We have investigated the reproducibility of dynamic contrast enhanced imaging techniques in nine patients with cerebral glioma. Patients were imaged twice with a 2 day interval between scans. Maps were produced of the time taken to achieve 90% enhancement (T90), the maximal intensity change per time interval ratio (MITR), the volume transfer coefficient between plasma and the extravascular extracellular space (K(trans)) and the extravascular extracellular contrast distribution volume, v(e). Measurements of K(trans) greater than 1.2 min(-1) were used to exclude pixels where first pass perfusion effects dominated the measurement. Measures of the test-retest coefficient of variation (CoV) and intraclass correlation coefficients were used to assess reproducibility for measurements from a volume of interest containing enhancing tissue from the whole tumour. MITR showed poor reproducibility (mean CoV 17.9%, 95% confidence limits for group comparisons 20.2%). T90 showed good reproducibility (mean CoV 7.1%, 95% confidence limits for group comparisons 5.2%). Calculated values of K(trans) and v(e) also showed good reproducibility (mean CoV 7.7% and 6.2% respectively, 95% confidence limits for group comparisons 6.2% and 4.8%, respectively). We conclude that the measurements of K(trans) and v(e) derived from pharmacokinetic analysis are sufficiently reproducible to support their use as a biological markers in therapeutic trials.

Aged↗