Paul Ross - Academia.edu (original) (raw)

Papers by Paul Ross

Targeted oncology, Feb 1, 2017

Activating KRAS mutations are reported in up to 90% of pancreatic cancers. Refametinib potently i... more Activating KRAS mutations are reported in up to 90% of pancreatic cancers. Refametinib potently inhibits MEK1/2, part of the MAPK signaling pathway. This phase I/II study evaluated the safety and efficacy of refametinib plus gemcitabine in patients with advanced pancreatic cancer. Phase I comprised dose escalation, followed by phase II expansion. Refametinib and gemcitabine plasma levels were analyzed for pharmacokinetics. KRAS mutational status was determined from circulating tumor DNA. Ninety patients overall received treatment. The maximum tolerated dose was refametinib 50 mg twice daily plus standard gemcitabine (1000 mg/m(2) weekly). The combination was well tolerated, with no pharmacokinetic interaction. Treatment-emergent toxicities included thrombocytopenia, fatigue, anemia, and edema. The objective response rate was 23% and the disease control rate was 73%. Overall response rate, disease control rate, progression-free survival, and overall survival were higher in patients w...

Targeted oncology, Feb 1, 2017

Activating KRAS mutations are reported in up to 90% of pancreatic cancers. Refametinib potently i... more Activating KRAS mutations are reported in up to 90% of pancreatic cancers. Refametinib potently inhibits MEK1/2, part of the MAPK signaling pathway. This phase I/II study evaluated the safety and efficacy of refametinib plus gemcitabine in patients with advanced pancreatic cancer. Phase I comprised dose escalation, followed by phase II expansion. Refametinib and gemcitabine plasma levels were analyzed for pharmacokinetics. KRAS mutational status was determined from circulating tumor DNA. Ninety patients overall received treatment. The maximum tolerated dose was refametinib 50 mg twice daily plus standard gemcitabine (1000 mg/m(2) weekly). The combination was well tolerated, with no pharmacokinetic interaction. Treatment-emergent toxicities included thrombocytopenia, fatigue, anemia, and edema. The objective response rate was 23% and the disease control rate was 73%. Overall response rate, disease control rate, progression-free survival, and overall survival were higher in patients w...

Journal of Hepatocellular Carcinoma

Combined hepatocellular cholangiocarcinoma (CC) is a rare and aggressive primary hepatic malignan... more Combined hepatocellular cholangiocarcinoma (CC) is a rare and aggressive primary hepatic malignancy with significant histological and biological heterogeneity. It presents with more aggressive behavior and worse survival outcomes than either hepatocellular carcinoma or CC and remains a diagnostic challenge. An accurate diagnosis is crucial for its optimal management. Major hepatectomy with hilar node resection remains the mainstay of treatment in operable cases. Advances in the genetic and molecular characterization of this tumor will contribute to the better understanding of its pathogenesis and shape its future management.

PloS one, 2018

Fluoropyrimidines, including 5-fluororacil (5FU) and its pro-drug Capecitabine, are the common tr... more Fluoropyrimidines, including 5-fluororacil (5FU) and its pro-drug Capecitabine, are the common treatment for colorectal, breast, neck and head cancers-either as monotherapy or in combination therapy. Adverse reactions (ADRs) to the treatment are common and often result in treatment discontinuation or dose reduction. Factors contributing to ADRs, including genetic variation, are poorly characterized. We performed exome array analysis to identify genetic variants that contribute to adverse reactions. Our final dataset consisted of 504 European ancestry individuals undergoing fluoropyrimidine-based therapy for gastrointestinal cancer. A subset of 254 of these were treated with Capecitabine. All individuals were genotyped on the Illumina HumanExome Array. Firstly, we performed SNP and gene-level analyses of protein-altering variants on the array to identify novel associations the following ADRs, which were grouped into four phenotypes based on symptoms of diarrhea, mucositis, and neutro...

Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 27, 2018

Refametinib, an oral MEK inhibitor, has demonstrated antitumor activity in combination with soraf... more Refametinib, an oral MEK inhibitor, has demonstrated antitumor activity in combination with sorafenib in patients with -mutated hepatocellular carcinoma (HCC). Two phase II studies evaluated the efficacy of refametinib monotherapy and refametinib plus sorafenib in patients with -mutant unresectable or metastatic HCC. Eligible patients with mutations of cell-free circulating tumor DNA (ctDNA) determined by beads, emulsion, amplification, and magnetics technology received twice-daily refametinib 50 mg ± sorafenib 400 mg. Potential biomarkers were assessed in ctDNA via next-generation sequencing (NGS). Of 1318 patients screened, 59 (4.4%) had a mutation, of whom 16 received refametinib and 16 received refametinib plus sorafenib. With refametinib monotherapy, the objective response rate (ORR) was 0%, the disease control rate (DCR) was 56.3%, overall survival (OS) was 5.8 months, and progression-free survival (PFS) was 1.9 months. With refametinib plus sorafenib, the ORR was 6.3%, the DC...

British journal of cancer, Jan 21, 2018

Advanced biliary tract cancer (ABC) has a poor prognosis. Cediranib, in addition to cisplatin/gem... more Advanced biliary tract cancer (ABC) has a poor prognosis. Cediranib, in addition to cisplatin/gemcitabine [CisGem], improved the response rate, but did not improve the progression-free survival (PFS) in the ABC-03 study. Minimally invasive biomarkers predictive of cediranib benefit may improve patient outcomes. Changes in 15 circulating plasma angiogenesis or inflammatory-related proteins and cytokeratin-18 (CK18), measured at baseline and during therapy until disease progression, were correlated with overall survival (OS) using time-varying covariate Cox models (TVC). Samples were available from n = 117/124 (94%) patients. Circulating Ang1&2, FGFb, PDGFbb, VEGFC, VEGFR1 and CK18 decreased as a result of the therapy, independent of treatment with cediranib. Circulating VEGFR2 and Tie2 were preferentially reduced by cediranib. Patients with increasing levels of VEGFA at any time had a worse PFS and OS; this detrimental effect was attenuated in patients receiving cediranib. TVC analys...

Future Oncology

Hepatocellular carcinoma is one of the fastest growing causes of cancer-related mortality worldwi... more Hepatocellular carcinoma is one of the fastest growing causes of cancer-related mortality worldwide. Sorafenib was the first and only drug to improve survival for patients with advanced disease, and has been the cornerstone of treatment for nearly a decade. Regorafenib is a multikinase inhibitor that has recently been shown to significantly improve survival in patients who have progressed on first-line sorafenib. In this review, we discuss the pharmacokinetic and pharmacodynamics properties of regorafenib and its efficacy and tolerability in patients with advanced hepatocellular carcinoma.

Virchows Archiv : an international journal of pathology, Jan 13, 2017

Combined hepatocellular-cholangiocarcinoma (cHCC-CC) is a rare and aggressive primary liver cance... more Combined hepatocellular-cholangiocarcinoma (cHCC-CC) is a rare and aggressive primary liver cancer with both hepatocellular and cholangiocellular differentiation. Due to its bi-phenotypic component, cHCC-CC is a heterogeneous tumour and histopathological analysis of metastatic deposits is poorly characterized. In this retrospective study, we describe four patients in whom the histology from resected specimens of both primary and recurrent and/or metastatic tumour was available for comparison and immunohistochemical characterization. Our study shows that recurrent or metastatic deposits replicate the heterogeneity of the primary cHCC-CC, that even originally small foci of divergent differentiation can become predominant later on and that hepatocellular and cholangiocellular components can show different tropism in distant organs. In our experience, the behaviour of recurrent/metastatic cHCC-CC is unpredictable and histological examination is necessary to guide treatment options at pr...

International journal of cancer, Sep 2, 2017

Metabolic syndrome (MetS) is associated with non-alcoholic fatty liver disease, which may progres... more Metabolic syndrome (MetS) is associated with non-alcoholic fatty liver disease, which may progress to cirrhosis, a significant risk factor of hepatocellular carcinoma (HCC), the commonest malignant primary liver cancer (PLC). We investigated the association between the individual components of MetS (lipids, apolipoproteins, raised glucose, diabetes and obesity), PLC and cirrhosis. A total of 509,436 participants from the Swedish AMORIS cohort, recruited between January 1985 to December 1996 (end-date December 2011), aged ≥20 with baseline triglycerides (TG), total cholesterol (TC), glucose and liver enzymes were included. Those with baseline benign liver tumours, PLC or cirrhosis were excluded. Multivariate Cox regression, adjusted for age, gender, socio-economic status, liver disease (excluding cirrhosis) and MetS factors were used to estimate the association with PLC and cirrhosis. There were 766 PLC and 2,775 cirrhosis cases over 13-years. Raised TG, low TC, raised glucose, diabe...

The Lancet. Oncology, Apr 1, 2017

Erlotinib is an EGFR tyrosine kinase inhibitor that has shown a significant but only marginally i... more Erlotinib is an EGFR tyrosine kinase inhibitor that has shown a significant but only marginally improved median overall survival when combined with gemcitabine in patients with locally advanced and metastatic pancreatic cancer. Vandetanib is a novel tyrosine kinase inhibitor of VEGFR2, RET, and EGFR, all of which are in involved in the pathogenesis of pancreatic cancer. We investigated the clinical efficacy of vandetanib when used in combination with gemcitabine in patients with advanced pancreatic cancer. The Vandetanib in Pancreatic Cancer (ViP) trial was a phase 2 double-blind, multicentre, randomised placebo-controlled trial in previously untreated adult patients (aged ≥18 years) diagnosed with locally advanced or metastatic carcinoma of the pancreas confirmed by cytology or histology. Patients had to have an Eastern Cooperative Oncology Group (ECOG) score of 0-2 and a documented life expectancy of at least 3 months. Patients were randomly assigned 1:1 to receive vandetanib plus...

Lancet (London, England), Jan 5, 2016

There are no systemic treatments for patients with hepatocellular carcinoma (HCC) whose disease p... more There are no systemic treatments for patients with hepatocellular carcinoma (HCC) whose disease progresses during sorafenib treatment. We aimed to assess the efficacy and safety of regorafenib in patients with HCC who have progressed during sorafenib treatment. In this randomised, double-blind, parallel-group, phase 3 trial done at 152 sites in 21 countries, adults with HCC who tolerated sorafenib (≥400 mg/day for ≥20 of last 28 days of treatment), progressed on sorafenib, and had Child-Pugh A liver function were enrolled. Participants were randomly assigned (2:1) by a computer-generated randomisation list and interactive voice response system and stratified by geographical region, Eastern Cooperative Oncology Group performance status, macrovascular invasion, extrahepatic disease, and α-fetoprotein level to best supportive care plus oral regorafenib 160 mg or placebo once daily during weeks 1-3 of each 4-week cycle. Investigators, patients, and the funder were masked to treatment as...

Diseases, 2015

Hepatocellular carcinoma (HCC) is a lethal cancer with limited systemic therapeutic options. Live... more Hepatocellular carcinoma (HCC) is a lethal cancer with limited systemic therapeutic options. Liver carcinogenesis is a complex procedure and various pathways have been found to be deregulated which are potential targets for novel treatments. Aberrant signalling through FGF19 and its receptor FGFR4 seems to be the oncogenic driver for a subset of HCCs and is associated with poor prognosis. Inhibition of the pathway in preclinical models has shown antitumour activity and has triggered further evaluation of this strategy to in vivo models. This review aims to describe the role of the FGF19/FGFR4 pathway in hepatocellular carcinoma and its role as a potential predictive biomarker for novel targeted agents against FGF19/FGFR4 signalling.

Cancer Chemother Pharmacol, 2010

Purpose The Xuoropyrimidines have been extensively used for almost Wve decade worldwide for the t... more Purpose The Xuoropyrimidines have been extensively used for almost Wve decade worldwide for the treatment of solid cancers. However, severe toxicity is a major clinical problem and has been reported in association with deleterious sequence variants in dihydropyrimidine dehydrogenase (DPD) coding-gene (DPYD), causing DPD deWciency. Genetic DPD deWciency has previously been considered to be insigniWcant in the British population. The study aim was to assess the contribution of deleterious DPYD sequence variants to Xuoropyrimidine toxicity amongst British cancer patients. Methods Sequencing of the coding region of DPYD was undertaken in 47 patients (27 female, mean age 61 years), mainly with GI malignancy, experiencing grade 3 or 4 toxicity on Xuoropyrimidines according to CTCAE criteria. Results Myelotoxicity (37.5%) and diarrhoea (37.5%) were the most frequent toxicities followed by mucositis (19.6%), hand-foot syndrome (3.6%) and neurotoxicity (1.8%). 4 of 47 (8.5%) patients carried the 1905+1G>A splice site variant. All 4 cases were female and 3 of 4 suVered severe diarrhoea. A further Wve cases carried other sequence variants (2846A>T n = 4, 1679T>G n = 1). In total, 9 (19%) patients carried deWciency associated DPYD sequence variants. Conclusions Contrary to previous estimates for a UK population, genetic DPD deWciency accounts for around 19% of cases of severe Xuoropyrimidine toxicity. The inXuence of DPD deWciency is such that toxicity can be avoided by prior testing and appropriate 5-FU dose/regimen alteration.

Eur J Cancer, 1995

21 patients with squamous oesophageal carcinoma were treated with a new regimen designed in our u... more 21 patients with squamous oesophageal carcinoma were treated with a new regimen designed in our unit and effective in treating gastric adenocarcinoma, consisting of continuous venous infusion of 5-fluorouracil for up to 24 weeks (200 mg/m*/day) with epirubicin (50 mg/m*) and cisplatin (60 mg/m*) every 3 weeks. 12 patients (57%) had an objective response. The median relapse free period was 7 months, median survival from start of chemotherapy 8.4 months, and median survival from diagnosis, 14 months. Symptomatic improvements were reported by lo/11 patients with pain (91%), 8/9 with anorexia (89O/,), 8/10 with reflux (80%) and lo/14 with dysphagia (71%). Grade 3 or 4 toxicity was reported by 11 patients: 5 had haematological toxicity, 3 vomiting, 2 infection and 1 diarrhoea. One patient developed peripheral neuropathy, 1 renal impairment and another peripheral vascular disease. Following chemotherapy, surgery was attempted in 5 patients. One remains well 3 years on, 2 had macroscopic clearance of tumour but died of postoperative complications. In 2, disease was irresectable. This regimen of moderate toxicity is effective at improving symptoms in the majority of patients. In some patients, tumours are briefly downstaged so that inoperable tumours may become operable.

European Journal of Cancer, 1996

Introduction of new agents on to hospital drug formularies requires the demonstration of efficacy... more Introduction of new agents on to hospital drug formularies requires the demonstration of efficacy, safety and cost advantages. An audit of the total monthly costs of'Tomudex,TM* (raltitrexed; administered every 3 weeks), a drug recently introduced for the treatment of advanced colorectal cancer, and three 5-fluorouracil-based regimens [5-day daily bolus (Mayo); continuous ambulatory pump; 48-h continuous infusion (De Gramont)] was undertaken. Patient-specific costs associated with fluids, concomitant medication and consumables were largely negligible, but chemotherapy was the main cost driver in the raltitrexed and De Gramont groups. Fixed inpatient costs were highest for the patients receiving the De Gramont regimen which required more inpatient stays each month. Total costs (patient-specific plus fixed costs) were lowest in patients on the Mayo regimen (mean £954.03; median £659.68), followed by patients in the ambulatory pump (mean £1207.61; median £749.19), raltitrexed [mean £1256.93; median £1087.14 (mean £1117.85; median £959.34 when costs of protocol-driven visits were excluded)], and De Gramont groups (mean £2028.52; median £1775.66). The pattern of costs varied considerably between regimens, such that high drug costs, for example those associated with raltitrexed therapy, were partially offset by reductions in hospital visits and stays.

Crit Rev Oncol Hematol, 1999

Targeted oncology, Feb 1, 2017

Activating KRAS mutations are reported in up to 90% of pancreatic cancers. Refametinib potently i... more Activating KRAS mutations are reported in up to 90% of pancreatic cancers. Refametinib potently inhibits MEK1/2, part of the MAPK signaling pathway. This phase I/II study evaluated the safety and efficacy of refametinib plus gemcitabine in patients with advanced pancreatic cancer. Phase I comprised dose escalation, followed by phase II expansion. Refametinib and gemcitabine plasma levels were analyzed for pharmacokinetics. KRAS mutational status was determined from circulating tumor DNA. Ninety patients overall received treatment. The maximum tolerated dose was refametinib 50 mg twice daily plus standard gemcitabine (1000 mg/m(2) weekly). The combination was well tolerated, with no pharmacokinetic interaction. Treatment-emergent toxicities included thrombocytopenia, fatigue, anemia, and edema. The objective response rate was 23% and the disease control rate was 73%. Overall response rate, disease control rate, progression-free survival, and overall survival were higher in patients w...

Targeted oncology, Feb 1, 2017

Activating KRAS mutations are reported in up to 90% of pancreatic cancers. Refametinib potently i... more Activating KRAS mutations are reported in up to 90% of pancreatic cancers. Refametinib potently inhibits MEK1/2, part of the MAPK signaling pathway. This phase I/II study evaluated the safety and efficacy of refametinib plus gemcitabine in patients with advanced pancreatic cancer. Phase I comprised dose escalation, followed by phase II expansion. Refametinib and gemcitabine plasma levels were analyzed for pharmacokinetics. KRAS mutational status was determined from circulating tumor DNA. Ninety patients overall received treatment. The maximum tolerated dose was refametinib 50 mg twice daily plus standard gemcitabine (1000 mg/m(2) weekly). The combination was well tolerated, with no pharmacokinetic interaction. Treatment-emergent toxicities included thrombocytopenia, fatigue, anemia, and edema. The objective response rate was 23% and the disease control rate was 73%. Overall response rate, disease control rate, progression-free survival, and overall survival were higher in patients w...

Journal of Hepatocellular Carcinoma

Combined hepatocellular cholangiocarcinoma (CC) is a rare and aggressive primary hepatic malignan... more Combined hepatocellular cholangiocarcinoma (CC) is a rare and aggressive primary hepatic malignancy with significant histological and biological heterogeneity. It presents with more aggressive behavior and worse survival outcomes than either hepatocellular carcinoma or CC and remains a diagnostic challenge. An accurate diagnosis is crucial for its optimal management. Major hepatectomy with hilar node resection remains the mainstay of treatment in operable cases. Advances in the genetic and molecular characterization of this tumor will contribute to the better understanding of its pathogenesis and shape its future management.

PloS one, 2018

Fluoropyrimidines, including 5-fluororacil (5FU) and its pro-drug Capecitabine, are the common tr... more Fluoropyrimidines, including 5-fluororacil (5FU) and its pro-drug Capecitabine, are the common treatment for colorectal, breast, neck and head cancers-either as monotherapy or in combination therapy. Adverse reactions (ADRs) to the treatment are common and often result in treatment discontinuation or dose reduction. Factors contributing to ADRs, including genetic variation, are poorly characterized. We performed exome array analysis to identify genetic variants that contribute to adverse reactions. Our final dataset consisted of 504 European ancestry individuals undergoing fluoropyrimidine-based therapy for gastrointestinal cancer. A subset of 254 of these were treated with Capecitabine. All individuals were genotyped on the Illumina HumanExome Array. Firstly, we performed SNP and gene-level analyses of protein-altering variants on the array to identify novel associations the following ADRs, which were grouped into four phenotypes based on symptoms of diarrhea, mucositis, and neutro...

Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 27, 2018

Refametinib, an oral MEK inhibitor, has demonstrated antitumor activity in combination with soraf... more Refametinib, an oral MEK inhibitor, has demonstrated antitumor activity in combination with sorafenib in patients with -mutated hepatocellular carcinoma (HCC). Two phase II studies evaluated the efficacy of refametinib monotherapy and refametinib plus sorafenib in patients with -mutant unresectable or metastatic HCC. Eligible patients with mutations of cell-free circulating tumor DNA (ctDNA) determined by beads, emulsion, amplification, and magnetics technology received twice-daily refametinib 50 mg ± sorafenib 400 mg. Potential biomarkers were assessed in ctDNA via next-generation sequencing (NGS). Of 1318 patients screened, 59 (4.4%) had a mutation, of whom 16 received refametinib and 16 received refametinib plus sorafenib. With refametinib monotherapy, the objective response rate (ORR) was 0%, the disease control rate (DCR) was 56.3%, overall survival (OS) was 5.8 months, and progression-free survival (PFS) was 1.9 months. With refametinib plus sorafenib, the ORR was 6.3%, the DC...

British journal of cancer, Jan 21, 2018

Advanced biliary tract cancer (ABC) has a poor prognosis. Cediranib, in addition to cisplatin/gem... more Advanced biliary tract cancer (ABC) has a poor prognosis. Cediranib, in addition to cisplatin/gemcitabine [CisGem], improved the response rate, but did not improve the progression-free survival (PFS) in the ABC-03 study. Minimally invasive biomarkers predictive of cediranib benefit may improve patient outcomes. Changes in 15 circulating plasma angiogenesis or inflammatory-related proteins and cytokeratin-18 (CK18), measured at baseline and during therapy until disease progression, were correlated with overall survival (OS) using time-varying covariate Cox models (TVC). Samples were available from n = 117/124 (94%) patients. Circulating Ang1&2, FGFb, PDGFbb, VEGFC, VEGFR1 and CK18 decreased as a result of the therapy, independent of treatment with cediranib. Circulating VEGFR2 and Tie2 were preferentially reduced by cediranib. Patients with increasing levels of VEGFA at any time had a worse PFS and OS; this detrimental effect was attenuated in patients receiving cediranib. TVC analys...

Future Oncology

Hepatocellular carcinoma is one of the fastest growing causes of cancer-related mortality worldwi... more Hepatocellular carcinoma is one of the fastest growing causes of cancer-related mortality worldwide. Sorafenib was the first and only drug to improve survival for patients with advanced disease, and has been the cornerstone of treatment for nearly a decade. Regorafenib is a multikinase inhibitor that has recently been shown to significantly improve survival in patients who have progressed on first-line sorafenib. In this review, we discuss the pharmacokinetic and pharmacodynamics properties of regorafenib and its efficacy and tolerability in patients with advanced hepatocellular carcinoma.

Virchows Archiv : an international journal of pathology, Jan 13, 2017

Combined hepatocellular-cholangiocarcinoma (cHCC-CC) is a rare and aggressive primary liver cance... more Combined hepatocellular-cholangiocarcinoma (cHCC-CC) is a rare and aggressive primary liver cancer with both hepatocellular and cholangiocellular differentiation. Due to its bi-phenotypic component, cHCC-CC is a heterogeneous tumour and histopathological analysis of metastatic deposits is poorly characterized. In this retrospective study, we describe four patients in whom the histology from resected specimens of both primary and recurrent and/or metastatic tumour was available for comparison and immunohistochemical characterization. Our study shows that recurrent or metastatic deposits replicate the heterogeneity of the primary cHCC-CC, that even originally small foci of divergent differentiation can become predominant later on and that hepatocellular and cholangiocellular components can show different tropism in distant organs. In our experience, the behaviour of recurrent/metastatic cHCC-CC is unpredictable and histological examination is necessary to guide treatment options at pr...

International journal of cancer, Sep 2, 2017

Metabolic syndrome (MetS) is associated with non-alcoholic fatty liver disease, which may progres... more Metabolic syndrome (MetS) is associated with non-alcoholic fatty liver disease, which may progress to cirrhosis, a significant risk factor of hepatocellular carcinoma (HCC), the commonest malignant primary liver cancer (PLC). We investigated the association between the individual components of MetS (lipids, apolipoproteins, raised glucose, diabetes and obesity), PLC and cirrhosis. A total of 509,436 participants from the Swedish AMORIS cohort, recruited between January 1985 to December 1996 (end-date December 2011), aged ≥20 with baseline triglycerides (TG), total cholesterol (TC), glucose and liver enzymes were included. Those with baseline benign liver tumours, PLC or cirrhosis were excluded. Multivariate Cox regression, adjusted for age, gender, socio-economic status, liver disease (excluding cirrhosis) and MetS factors were used to estimate the association with PLC and cirrhosis. There were 766 PLC and 2,775 cirrhosis cases over 13-years. Raised TG, low TC, raised glucose, diabe...

The Lancet. Oncology, Apr 1, 2017

Erlotinib is an EGFR tyrosine kinase inhibitor that has shown a significant but only marginally i... more Erlotinib is an EGFR tyrosine kinase inhibitor that has shown a significant but only marginally improved median overall survival when combined with gemcitabine in patients with locally advanced and metastatic pancreatic cancer. Vandetanib is a novel tyrosine kinase inhibitor of VEGFR2, RET, and EGFR, all of which are in involved in the pathogenesis of pancreatic cancer. We investigated the clinical efficacy of vandetanib when used in combination with gemcitabine in patients with advanced pancreatic cancer. The Vandetanib in Pancreatic Cancer (ViP) trial was a phase 2 double-blind, multicentre, randomised placebo-controlled trial in previously untreated adult patients (aged ≥18 years) diagnosed with locally advanced or metastatic carcinoma of the pancreas confirmed by cytology or histology. Patients had to have an Eastern Cooperative Oncology Group (ECOG) score of 0-2 and a documented life expectancy of at least 3 months. Patients were randomly assigned 1:1 to receive vandetanib plus...

Lancet (London, England), Jan 5, 2016

There are no systemic treatments for patients with hepatocellular carcinoma (HCC) whose disease p... more There are no systemic treatments for patients with hepatocellular carcinoma (HCC) whose disease progresses during sorafenib treatment. We aimed to assess the efficacy and safety of regorafenib in patients with HCC who have progressed during sorafenib treatment. In this randomised, double-blind, parallel-group, phase 3 trial done at 152 sites in 21 countries, adults with HCC who tolerated sorafenib (≥400 mg/day for ≥20 of last 28 days of treatment), progressed on sorafenib, and had Child-Pugh A liver function were enrolled. Participants were randomly assigned (2:1) by a computer-generated randomisation list and interactive voice response system and stratified by geographical region, Eastern Cooperative Oncology Group performance status, macrovascular invasion, extrahepatic disease, and α-fetoprotein level to best supportive care plus oral regorafenib 160 mg or placebo once daily during weeks 1-3 of each 4-week cycle. Investigators, patients, and the funder were masked to treatment as...

Diseases, 2015

Hepatocellular carcinoma (HCC) is a lethal cancer with limited systemic therapeutic options. Live... more Hepatocellular carcinoma (HCC) is a lethal cancer with limited systemic therapeutic options. Liver carcinogenesis is a complex procedure and various pathways have been found to be deregulated which are potential targets for novel treatments. Aberrant signalling through FGF19 and its receptor FGFR4 seems to be the oncogenic driver for a subset of HCCs and is associated with poor prognosis. Inhibition of the pathway in preclinical models has shown antitumour activity and has triggered further evaluation of this strategy to in vivo models. This review aims to describe the role of the FGF19/FGFR4 pathway in hepatocellular carcinoma and its role as a potential predictive biomarker for novel targeted agents against FGF19/FGFR4 signalling.

Cancer Chemother Pharmacol, 2010

Purpose The Xuoropyrimidines have been extensively used for almost Wve decade worldwide for the t... more Purpose The Xuoropyrimidines have been extensively used for almost Wve decade worldwide for the treatment of solid cancers. However, severe toxicity is a major clinical problem and has been reported in association with deleterious sequence variants in dihydropyrimidine dehydrogenase (DPD) coding-gene (DPYD), causing DPD deWciency. Genetic DPD deWciency has previously been considered to be insigniWcant in the British population. The study aim was to assess the contribution of deleterious DPYD sequence variants to Xuoropyrimidine toxicity amongst British cancer patients. Methods Sequencing of the coding region of DPYD was undertaken in 47 patients (27 female, mean age 61 years), mainly with GI malignancy, experiencing grade 3 or 4 toxicity on Xuoropyrimidines according to CTCAE criteria. Results Myelotoxicity (37.5%) and diarrhoea (37.5%) were the most frequent toxicities followed by mucositis (19.6%), hand-foot syndrome (3.6%) and neurotoxicity (1.8%). 4 of 47 (8.5%) patients carried the 1905+1G>A splice site variant. All 4 cases were female and 3 of 4 suVered severe diarrhoea. A further Wve cases carried other sequence variants (2846A>T n = 4, 1679T>G n = 1). In total, 9 (19%) patients carried deWciency associated DPYD sequence variants. Conclusions Contrary to previous estimates for a UK population, genetic DPD deWciency accounts for around 19% of cases of severe Xuoropyrimidine toxicity. The inXuence of DPD deWciency is such that toxicity can be avoided by prior testing and appropriate 5-FU dose/regimen alteration.

Eur J Cancer, 1995

21 patients with squamous oesophageal carcinoma were treated with a new regimen designed in our u... more 21 patients with squamous oesophageal carcinoma were treated with a new regimen designed in our unit and effective in treating gastric adenocarcinoma, consisting of continuous venous infusion of 5-fluorouracil for up to 24 weeks (200 mg/m*/day) with epirubicin (50 mg/m*) and cisplatin (60 mg/m*) every 3 weeks. 12 patients (57%) had an objective response. The median relapse free period was 7 months, median survival from start of chemotherapy 8.4 months, and median survival from diagnosis, 14 months. Symptomatic improvements were reported by lo/11 patients with pain (91%), 8/9 with anorexia (89O/,), 8/10 with reflux (80%) and lo/14 with dysphagia (71%). Grade 3 or 4 toxicity was reported by 11 patients: 5 had haematological toxicity, 3 vomiting, 2 infection and 1 diarrhoea. One patient developed peripheral neuropathy, 1 renal impairment and another peripheral vascular disease. Following chemotherapy, surgery was attempted in 5 patients. One remains well 3 years on, 2 had macroscopic clearance of tumour but died of postoperative complications. In 2, disease was irresectable. This regimen of moderate toxicity is effective at improving symptoms in the majority of patients. In some patients, tumours are briefly downstaged so that inoperable tumours may become operable.

European Journal of Cancer, 1996

Introduction of new agents on to hospital drug formularies requires the demonstration of efficacy... more Introduction of new agents on to hospital drug formularies requires the demonstration of efficacy, safety and cost advantages. An audit of the total monthly costs of'Tomudex,TM* (raltitrexed; administered every 3 weeks), a drug recently introduced for the treatment of advanced colorectal cancer, and three 5-fluorouracil-based regimens [5-day daily bolus (Mayo); continuous ambulatory pump; 48-h continuous infusion (De Gramont)] was undertaken. Patient-specific costs associated with fluids, concomitant medication and consumables were largely negligible, but chemotherapy was the main cost driver in the raltitrexed and De Gramont groups. Fixed inpatient costs were highest for the patients receiving the De Gramont regimen which required more inpatient stays each month. Total costs (patient-specific plus fixed costs) were lowest in patients on the Mayo regimen (mean £954.03; median £659.68), followed by patients in the ambulatory pump (mean £1207.61; median £749.19), raltitrexed [mean £1256.93; median £1087.14 (mean £1117.85; median £959.34 when costs of protocol-driven visits were excluded)], and De Gramont groups (mean £2028.52; median £1775.66). The pattern of costs varied considerably between regimens, such that high drug costs, for example those associated with raltitrexed therapy, were partially offset by reductions in hospital visits and stays.

Crit Rev Oncol Hematol, 1999