Sorafenib for the Treatment of Advanced Hepatocellular Cancer - a UK Audit.

AIMS: Sorafenib is the current standard treatment for advanced hepatocellular carcinoma. We carried out a national audit of UK patients treated with sorafenib as standard-of-care and those treated with systemic therapy in first-line trials. MATERIALS AND METHODS: Sorafenib-treated and trial-treated patients were identified via the Cancer Drugs Fund and local databases. Data were collected retrospectively from medical records according to a standard case report form. The primary outcome measure was overall survival, estimated by the Kaplan-Meier method. RESULTS: Data were obtained for 448 sorafenib-treated patients from 15 hospitals. The median age was 68 years (range 17-89) and 75% had performance status ≤ 1. At baseline, 77% were Child-Pugh A and 16.1% Child-Pugh B; 38% were albumin-bilirubin grade 1 (ALBI-1) and 48% ALBI-2; 23% were Barcelona Clinic Liver Classification B (BCLC-B) and 72% BCLC-C. The median time on sorafenib was 3.6 months, with a mean daily dose of 590 mg. The median overall survival for 448 evaluable sorafenib-treated patients was 8.5 months. There were significant differences in overall survival comparing Child-Pugh A versus Child-Pugh B (9.5 versus 4.6 months), ALBI-1 versus ALBI-2 (12.9 versus 5.9 months) and BCLC-B versus BCLC-C (13.0 versus 8.3 months). For trial-treated patients (n=109), the median overall survival was 8.1 months and this was not significantly different from the sorafenib-treated patients. CONCLUSION: For Child-Pugh A patients with good performance status, survival outcomes were similar to those reported in global randomised controlled trials. Patients with ALBI grade > 1, Child-Pugh B or poor performance status seem to derive limited benefit from sorafenib treatment.

Diagnostic and prognostic markers in gliomas - an update.

Gliomas are the most common primary central nervous system tumour seen in adults. There have been many advances over the last two decades as we widen our search for a molecular basis of gliomagenesis. Many biomarkers have been discovered to be important in the management of gliomas, including 1p19q co-deletion, MGMT promoter methylation, BRAF and IDH1 mutations. In this review, we attempt to summarise the available literature on these biomarkers and their use in the diagnosis and management of gliomas. We pay special attention to the recently discovered IDH1 mutation, which is already proving to be a valuable new marker for favourable prognosis and may also indicate a greater response to therapy. 1p19q co-deletions have been shown to delineate a clinically distinct tumour type and are now routinely tested for in certain situations and can help direct treatment. MGMT promoter methylation is one of the most commonly studied biomarkers in gliomas. It has been shown to be a strong positive prognostic marker in gliomas, with positive tumours being more sensitive to chemotherapy. However, a lack of alternatives means that it is not yet a routine mutation tested for clinically. BRAF mutations are new markers found in pilocytic astrocytomas. Although the prognostic value of such mutations is not yet known, they may play a significant role in the diagnosis and treatment of such tumours. IDH1 mutations are 'the new kid on the block' and seem to play a central role in the pathogenesis of gliomas. They represent an independent and favourable prognostic marker and are a new molecular marker for disease diagnosis. Its role in determining response to chemotherapy is still controversial but with further study, IDH1 mutations may prove to be an invaluable marker in the management of gliomas.

A randomised study evaluating the use of pyridoxine to avoid capecitabine dose modifications.

BACKGROUND: Pyridoxine is frequently used to treat capecitabine-induced hand-foot syndrome (HFS), although the evidence of benefit is lacking. We performed a randomised placebo-controlled trial to determine whether pyridoxine could avoid the need for capecitabine dose modifications and improve outcomes. METHODS: A total of 106 patients planned for palliative single-agent capecitabine (53 in each arm, 65%/35% colorectal/breast cancer) were randomised to receive either concomitant pyridoxine (50 mg po) or matching placebo three times daily. RESULTS: Compared with placebo, pyridoxine use was associated with an increased rate of avoiding capecitabine dose modifications (37% vs 23%, relative risk 0.59, 95% CI 0.29, 1.20, P=0.15) and fewer grade 3/4 HFS-related adverse events (9% vs 17%, odds ratio 0.51, 95% CI 0.15-1.6, P=0.26). Use of pyridoxine did not improve response rate or progression-free survival. CONCLUSION: Pyridoxine may reduce the need for capecitabine dose modifications and the incidence of severe HFS, but does not impact on antitumour effect.

Metabolic response at repeat PET/CT predicts pathological response to neoadjuvant chemotherapy in oesophageal cancer.

OBJECTIVES: Reports have suggested that a reduction in tumour 18F-fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET) examination during or after neoadjuvant chemotherapy may predict pathological response in oesophageal cancer. Our aim was to determine whether metabolic response predicts pathological response to a standardised neoadjuvant chemotherapy regimen within a prospective clinical trial. METHODS: Consecutive patients staged with potentially curable oesophageal cancer who underwent treatment within a non-randomised clinical trial were included. A standardised chemotherapy regimen (two cycles of oxaliplatin and 5-fluorouracil) was used. PET/CT was performed before chemotherapy and repeated 24-28 days after the start of cycle 2. RESULTS: Forty-eight subjects were included: mean age 65 years; 37 male. Using the median percentage reduction in SUV(max) (42%) to define metabolic response, pathological response was seen in 71% of metabolic responders (17/24) compared with 33% of non-responders (8/24; P = 0.009, sensitivity 68%, specificity 70%). Pathological response was seen in 81% of subjects with a complete metabolic response (13/16) compared with 38% of those with a less than complete response (12/32; P = 0.0042, sensitivity 52%, specificity 87%). There was no significant histology-based effect. CONCLUSIONS: There was a significant association between metabolic response and pathological response; however, accuracy in predicting pathological response was relatively low.

Oxford experience with neoadjuvant chemotherapy and surgical resection for esophageal adenocarcinomas and squamous cell tumors.

The Medical Research Council trial for oesophageal cancer (OEO2) trial demonstrated a clear survival benefit from neoadjuvant chemotherapy in resectable esophageal carcinoma. Since February 2000 it has been our practice to offer this chemotherapy regime to patients with T2 and T3 or T1N1 tumors. We analyzed prospectively collected data of patients who received neoadjuvant chemotherapy prior to esophageal resection under the care of a single surgeon. Complications of treatment and overall outcomes were evaluated. A total of 194 patients had cisplatin and 5-fluorouracil prior to esophageal resection. Six patients (5.7%) had progressive disease and were inoperable (discovered in four at surgery). During chemotherapy one patient died and one perforated (operated immediately). Complications including severe neutropenia, coronary artery spasm, renal impairment and pulmonary edema led to the premature cessation of chemotherapy in 12 patients (6.2%). A total of 182 patients with a median age of 63 (range 30-80), 41 squamous and 141 adenocarcinomas underwent surgery. Operations were 91 left thoracoabdominal (50%), 45 radical transhiatal (25%), 40 Ivor-Lewis (22%) and six stage three (3%), and 78.6% had microscopically complete (R0) resections. Median survival was 28 months with 77.3% surviving for 1 year and 57.7% for 2 year. In hospital mortality was 5.5% and anastomotic leak rate 7.7%. A radical surgical approach to the primary tumor in combination with OEO2 neoadjuvant chemotherapy has led to a high R0 resection rate and good survival with acceptable morbidity and mortality.

Phase II study to evaluate combining gemcitabine with flutamide in advanced pancreatic cancer patients.

A phase II study was undertaken to determine the safety of combining flutamide with gemcitabine, with response rate being the primary end point. Twenty-seven patients with histologically proven, previously untreated, unresectable pancreatic adenocarcinoma received gemcitabine, 1 g m(-2) intravenously on days 1, 8 and 15 of a 28 day cycle, and flutamide 250 mg given orally three times daily. Treatment was halted if there was unacceptable toxicity, or evidence of disease progression. Toxicity was documented every cycle. Tumour assessment was undertaken after cycles 2 and 4, and thereafter at least every additional four cycles. One hundred and seventeen cycles of treatment were administered, median four cycles per patient (range 1-18). Gemcitabine combined with flutamide was well tolerated, with most toxicities being recorded as grade 1 or 2 and only nine treatment cycles associated with grade 3 toxicity. The most frequent toxicity was myelosuppression. One case of transient jaundice was recorded. The commonest symptomatic toxicity was nausea and vomiting. The response rate was 15% (four partial responses), median survival 6 months and 22% of patients were alive at 1 year. These results suggest antitumour activity of the combination therapy to be equivalent to single agent gemcitabine.

Simultaneous gas chromatographic-mass spectrophotometric determination of alpha-fluoro-beta-alanine and 5-fluorouracil in plasma.

A gas chromatographic-mass spectrometric (GC-MS) method is reported for simultaneous determination of alpha-fluoro-beta-alanine (FBA), the major end metabolite of 5-fluorouracil (5-FU), and 5-FU in plasma samples isolated from cancer patients. 5-Chlorouracil (5-CIU, 1 micrograms/ml) is added to samples as an internal standard. The method relies on protein precipitation of the plasma sample followed by derivatisation with pentafluorobenzyl bromide. Following sample purification with Sep-pak C18 columns the derivatives are analysed by GC-MS, with FBA, 5-FU and 5-CIU being determined at 36.96-37.03, 46.91-46.98 and 51.99-52.13 min, respectively. The ions measured in each case had m/z of 390, 490 and 506, respectively. The method showed good reproducibility with coefficients of variation between 3 and 10%, with a detection limit of < 1 ng/ml for 5-FU and < 5 ng FBA/ml plasma. The possibility of sensitive determination of FBA without the use of radioisotopes should permit routine estimation of rates of 5-FU metabolism in individual patients.

Intra-hepatic arterial drug delivery.

In this review, the pharmacokinetic rationale for hepatic arterial drug therapy is discussed, along with techniques that have been developed in order to try to enhance the regional advantage accrued from this route of administration. Clinical trials of hepatic arterial therapy in patients with primary hepatocellular carcinoma and with liver metastases from colorectal carcinoma are discussed. Although clinical response rates are significantly better with regional as compared with systemic therapy, survival is not prolonged. This is mainly due to the development of extrahepatic metastases. A treatment strategy using high dose hepatic arterial 5-fluorouracil (5-FU) infusion with the deliberate aim of achieving maximum tolerated systemic drug levels has entered phase III clinical trial. Monitoring of in vivo tumour pharmacokinetics using 19F magnetic resonance spectroscopy and 18F-5-FU positron emission tomography (PET) demonstrate elegantly how target drug uptake may be assessed. We plan to use PET to monitor intra-tumoral viral transduction and 5-flucytosine conversion rates to active 5-FU in our hepatic arterial pro-drug gene therapy programme soon to enter clinical trial.