Cediranib or placebo in combination with cisplatin and gemcitabine chemotherapy for patients with advanced biliary tract cancer (ABC-03): a randomised phase 2 trial.

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/m(2) cisplatin and 1000 mg/m(2) 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.

Biomarkers for assessment of pharmacologic activity for a vascular endothelial growth factor (VEGF) receptor inhibitor, PTK787/ZK 222584 (PTK/ZK): translation of biological activity in a mouse melanoma metastasis model to phase I studies in patients with advanced colorectal cancer with liver metastases.

PTK/ZK is a novel, oral angiogenesis inhibitor that specifically targets all 3 vascular endothelial growth factor (VEGF) receptor tyrosine kinases and is currently in phase III clinical trials. In early clinical trials, PTK/ZK demonstrated a dose-dependent reduction in tumor vascular parameters as measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and an acute increase in plasma VEGF levels. The reduction in tumor vascularity was significantly correlated with improved clinical outcome in patients with advanced colorectal cancer and liver metastases. To assess the predictive value of a mouse model of tumor metastases, comparisons were performed for the biological activity of PTK/ZK in the mouse model and in patients with liver metastases in the clinical phase I trials. An orthotopic, syngeneic mouse model was used: C57BL/6 mice injected in the ear with murine B16/BL6 melanoma cells which metastases to the cervical lymph-nodes. The primary tumor and spontaneous metastases express VEGF and VEGF receptors and respond to treatment with VEGFR tyrosine kinase inhibitors. PTK/ZK was administered orally, with assessments by DCE-MRI of the metastases and plasma VEGF taken predose and at 3 days posttreatment and efficacy determined at 7 days posttreatment. Dose-ranging studies in naive mice provided preclinical pharmacokinetic data, while two dose-escalation phase I studies provided clinical pharmacokinetic data. An exposure-response relationship was observed both for mouse metastases (measured as % tumor weight treated/control) and for human liver metastases (measured as % regression). In the B16/BL6 model, the active dose of 50 mg/kg PTK/ZK yielded 62.4 (+/- 16.0) h microM plasma exposure, which is comparable to the plasma area under the concentration time curve (AUC) achieved by the 1000 mg dose of PTK/ZK used in clinical trials. At this exposure level in clinical trials, DCE-MRI showed a reduction in the area under the enhancement curve (IAUC) to 47% of baseline. At a similar exposure in the PTK/ZK-treated mice, a reduction in IAUC to 75% of baseline was observed. Furthermore, at doses of 50 mg/kg PTK/ZK and above, an increase in plasma VEGF level 10 h after drug administration was observed in mice which was consistent with findings from the clinical trials. In conclusion, the preclinical pharmacodynamics of PTK/ZK correlate well with clinical activity in phase I trials over comparable exposures to the drug. Thus, data from this preclinical model proved to be consistent with and thus predictive of the biologic effects of PTK/ZK in phase I/II clinical trials.

Hypoxia and angiogenesis in pancreatic cancer.

BACKGROUND: Pancreatic cancer remains one of the most lethal of all solid tumours of the gastrointestinal tract. It is characterized by late diagnosis, aggressive local invasion, early metastasis and resistance to chemoradiotherapy. Increasing knowledge regarding the molecular events behind the growth and invasion of pancreatic cancer may lead to new targets for intervention. METHODS: A search of Pubmed and Medline databases was undertaken using the keywords pancreatic cancer, gastrointestinal cancer, hypoxia, angiogenesis and anti-angiogenesis therapy. RESULTS: Hypoxia is the driving force behind angiogenesis in pancreatic cancers. Research into angiogenesis has shown many different sites that can be targeted by agents such as tyrosine kinase inhibitors. CONCLUSION: Anti-angiogenic therapy could be an important adjunct to conventional chemotherapy treatment of gastrointestinal neoplasia.

Resveratrol--a prostate cancer chemopreventive agent?

The incidence of prostate cancer in Western countries continues to rise. Whilst opinion remains divided on the best treatment for localized disease, intervention for metastatic, hormone-independent cancer remains extremely limited. The concept of chemoprevention is gaining popularity as an effective means of reducing the burden of prostate cancer on the population, and many compounds with putative chemopreventive activity are currently under investigation. Resveratrol is a plant-derived polyphenolic compound which has a wide spectrum of biological activity. It has anti-oxidant and anti-inflammatory properties, and may induce apoptosis as well as modulate the function of the androgen receptor in prostate cancer cell lines. Further studies to evaluate the use of this compound as a chemopreventive agent in prostate cancer are warranted.

Chemoprevention of gastrointestinal malignancies.

BACKGROUND: There has been considerable interest in the use of chemical or dietary agents to suppress or inhibit the development of tumours in the early stages of carcinogenesis. This concept is known as chemoprevention and although the potential for such agents is tremendous, evaluating their clinical benefit is beset with difficulties. AIMS: Using selected agents, such as curcumin and indole-3-carbinol, as examples, the present review will discuss the possible mechanisms of chemoprevention and the problems encountered in developing these agents into clinical drugs. METHODS: A review of the published literature from 1985 to the present day was performed using Medline and Web of Science search engines. Key words used were 'gastrointestinal cancer' and 'chemoprevention'. CONCLUSION: A huge number of agents with possible chemopreventive action has been identified. Pilot trials using molecular signatures of cancer activity can be used to select which agents should be included in large-scale phase III clinical trials. Publications concerning chemoprevention are concentrated in the scientific and oncological literature but surgeons with their greater exposure to premalignant gastrointestinal disease need to be aware of current concepts in this rapidly expanding field. This knowledge would allow collaboration between oncologists and surgeons in clinical trials to further evaluate chemopreventive compounds and ascertain their clinical impact.

Pancreatic stellate cells and pancreas cancer: current perspectives and future strategies.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant disease with a very poor prognosis. To date patient outcomes have not improved principally due to the limited number of patients suitable for surgical resections and the radiation and chemotherapy resistance of these tumours. In the last decade, a failure of conventional therapies has forced researchers to re-examine the environment of PDAC. The tumour environment has been demonstrated to consist of an abundance of stroma containing many cells but predominantly pancreatic stellate cells (PSCs). Recent research has focused on understanding the interaction between PSCs and PDAC cells in vitro and in vivo. It is believed that the interaction between these cells is responsible for supporting tumour growth, invasion and metastasis and creating the barrier to delivery of chemotherapeutics. Novel approaches which focus on the interactions between PDAC and PSCs which sustain the tumour microenvironment may achieve significant patient benefits. This manuscript reviews the current evidence regarding PSCs, their interaction with PDAC cells and the potential implication this may have for future therapies. METHODS: A PubMed search was carried out for the terms 'pancreas cancer' OR 'pancreatic cancer', AND 'pancreatic stellate cells', NOT 'hepatic stellate cells'. All studies were screened and assessed for their eligibility and manuscripts exploring the relationship between PSCs and PDAC were included. The studies were subdivided into in vitro and in vivo groups. RESULTS: One hundred and sixty-six manuscripts were identified and reduced to seventy-three in vitro and in vivo studies for review. The manuscripts showed that PDAC cells and PSCs interact with each other to enhance proliferation, reduce apoptosis and increase migration and invasion of cancer cells. The pathways through which they facilitate these actions provide potential targets for future novel therapies. CONCLUSION: There is accumulating evidence supporting the multiple roles of PSCs in establishing the tumour microenvironment and supporting the survival of PDAC. To further validate these findings there is a need for greater use of physiologically relevant models of pancreatic cancer in vitro such as three dimensional co-cultures and the use of orthotopic and genetically engineered murine (GEM) models in vivo.

Surgical bypass vs. endoscopic stenting for pancreatic ductal adenocarcinoma.

BACKGROUND: The majority of patients with pancreatic cancer are non-resectable and jaundiced at presentation. Methods of palliation in such patients with locally advanced disease comprise endoscopic placement of a biliary endoprosthesis or surgical bypass. METHODS: This retrospective study compared morbidity, mortality, hospital stay, readmission rate and survival in consecutive patients with incurable locally advanced pancreatic ductal adenocarcinoma. RESULTS: We identified a total of 56 patients, of whom 33 underwent endoscopic stenting and 23 underwent a surgical bypass consisting of a hepaticojejunostomy-en-Y and a gastrojejunostomy. There were no significant differences in complication or mortality rates between patients undergoing palliative stenting and those undergoing palliative surgery. However, after excluding admissions for chemotherapy-related problems, the number of readmissions expressed as a percentage of the group population size was greater in stented patients compared with biliary bypass patients (39.4% vs. 13.0%, respectively; P < 0.05). Overall survival amongst patients undergoing palliative bypass was significantly greater than in stented patients (382 days vs. 135 days, respectively; P < 0.05). CONCLUSIONS: On analysis of these data and the published literature, we conclude that surgical bypass represents an effective method of palliation for patients with locally advanced pancreatic cancer. Patients need to be carefully selected with regard to both operative risk and perceived overall survival.

Improving and predicting radiosensitivity in muscle invasive bladder cancer.

PURPOSE: Muscle invasive bladder cancer is a common urological malignancy with a relatively poor prognosis and 5-year survival rates ranging from 20% to 90%. We review methods of improving the outcome of this condition, with particular emphasis on the principal bladder preserving treatment modality of radiation therapy. MATERIALS AND METHODS: We performed a literature search using MEDLINE and the ISI Web of Science using the keywords radiotherapy, radiosensitization and bladder neoplasia to ascertain the current status of radiation therapy and radiosensitizing agents in the treatment of muscle invasive bladder cancer. RESULTS: Several methods aimed at improving outcome following radiation therapy for muscle invasive bladder cancer are described. These methods range from modifications in the application of radiation therapy to use of conventional radiosensitizing agents, such as accelerated radiotherapy with carbon dioxide, oxygen and nicotinamide, and finally to use of more novel agents that interact with oncogenic products. The use of assays that predict tumor sensitivity on an individual basis represents an additional potential method to improve prognosis following radiation therapy. CONCLUSIONS: The ability to predict tumor radiosensitivity and the subsequent implementation of radiosensitizing techniques are likely to improve the results of treatment centered on radiation therapy, suggesting that bladder sparing approaches will remain a treatment option for muscle invasive bladder cancer.