Chris Verslype

Phase III Trial of Gemcitabine Plus Tipifarnib Compared With Gemcitabine Plus Placebo in Advanced Pancreatic Cancer

PURPOSE To determine whether addition of the farnesyltransferase inhibitor tipifarnib (Zarnestra, R115777; Johnson and Johnson Pharmaceutical Research and Development, Beerse, Belgium) to standard gemcitabine therapy improves overall survival in advanced pancreatic cancer. PATIENTS AND METHODS This randomized, double-blind, placebo-controlled study compared gemcitabine + tipifarnib versus gemcitabine + placebo in patients with advanced pancreatic adenocarcinoma previously untreated with systemic therapy. Tipifarnib was given at 200 mg bid orally continuously; gemcitabine was given at 1,000 mg/m(2) intravenously weekly x 7 for 8 weeks, then weekly x 3 every 4 weeks. The primary end point was overall survival; secondary end points included 6-month and 1-year survival rates, progression-free survival, response rate, safety, and quality of life. RESULTS Six hundred eighty-eight patients were enrolled. Baseline characteristics were well balanced between the two treatment arms. No statistically significant differences in survival parameters were observed. The median overall survival for the experimental arm was 193 v 182 days for the control arm (P =.75); 6-month and 1-year survival rates were 53% and 27% v 49% and 24% for the control arm, respectively; median progression-free survival was 112 v 109 days for the control arm. Ten drug-related deaths were reported for the experimental arm and seven for the control arm. Neutropenia and thrombocytopenia grade > or = 3 were observed in 40% and 15% in the experimental arm versus 30% and 12% in the control arm. Incidences of nonhematologic adverse events were similar in two groups. CONCLUSION The combination of gemcitabine and tipifarnib has an acceptable toxicity profile but does not prolong overall survival in advanced pancreatic cancer compared with single-agent gemcitabine.

Clinicopathological study on cholangiolocellular carcinoma suggesting hepatic progenitor cell origin

Cholangiolocellular carcinoma (CLC), a subtype of cholangiocellular carcinoma (CC), is thought to originate from the ductules/canals of Hering, where hepatic progenitor cells (HPCs) are located. We investigated the clinicopathological features of 30 CLCs and their relationship to HPCs. We evaluated the expression of hepatocytic markers (hepatocyte paraffin‐1, canalicular polyclonal carcinoembryonic antigen, and CD10), biliary/HPC markers (keratin [K]7, K19, and neural cell adhesion molecule), the adenosine triphosphate binding cassette transporters: multidrug resistance protein 1, multidrug resistance‐associated protein (MRP)1, MRP3, and breast cancer resistance protein, using immunohistochemistry and electron microscopy. In addition, gene expression profiling of CLC was performed and compared with the profile of hepatocellular carcinoma (HCC) with or without HPC features (K19 expression). In surrounding nontumoral tissue, K7‐positive and K19‐positive HPCs/ductular reaction were observed. More than 90% of the tumor was composed of CLC areas that showed small monotonous and/or anastomosing glands, strongly positive for K7 and K19. Especially at the tumor boundary, all cases showed a HCC‐like trabecular area characterized by canalicular CD10/polyclonal carcinoembryonic antigen expression, and submembranous K7 expression, similar to intermediate hepatocytes. K7‐positive/K19‐positive HPCs were also seen. Out of 30 cases, 19 showed papillary and/or clear glandular formation with mucin production, representing CC areas. These three different areas showed transitional zones with each other. We observed an increased expression of MRP1, MRP3, and breast cancer resistance protein in the tumor. Electron microscopy findings in HCC‐like trabecular areas confirmed the presence of HPCs and intermediate hepatocytes. HPC markers, K7, K19, prominin‐1, receptor for stem cell factor c‐kit, octamer‐4 transcription factor, and leukemia inhibitory factor were upregulated (P < 0.05), while albumin was downregulated in CLC (P = 0.007) toward K19‐negative HCCs. Comparison of CLC with K19‐positive HCCs indicated a high homology. Conclusion: All these findings highly suggest a progenitor cell origin of CLC. (HEPATOLOGY 2008.)

A phase 1b dose-escalation trial of erlotinib, capecitabine and oxaliplatin in metastatic colorectal cancer (MCRC) patients

3585 Background: Epidermal growth factor receptor (HER1/EGFR) overexpression occurs in 45-80% of CRC patients (pts). Erlotinib (Tarceva™) is a potent HER1/EGFR inhibitor. Capecitabine and oxaliplatin have proven activity in MCRC pts. This trial determined the safety, the maximum tolerated dose (MTD) and pharmacokinetics (PK) of erlotinib in combination with capecitabine and oxaliplatin. METHODS MCRC pts were previously untreated or had received first-line treatment with 5-FU ± irinotecan. Patients were to receive escalating doses of daily oral erlotinib, capecitabine (days 1-14) (100mg + 1,650mg/m2 [Cohort 1]; 100mg + 2,000mg/m2 [Cohort 2]; 150mg + 2,000mg/m2 [Cohort 3]) and i.v. oxaliplatin 130mg/m2, every 21 days. Dose-limiting toxicity (DLT) was defined according to NCI-CTC criteria (2.0) in cycle 1 or 2. The MTD was the dose below which >1/3 pts had a DLT. RESULTS The first 6 pts in Cohort 1 had no DLTs. In Cohort 2, 2/6 pts had DLTs: one with G3 diarrhea and G3 intolerable rash; one with G3 diarrhea. Cohort 2 was expanded to 11 pts and two more pts experienced DLTs: one pt had G4 diarrhea and one pt had G3 pruritic rash. As 4/11 pts had DLTs, this cohort exceeded the definition of MTD. Thus, Cohort 1 was expanded to 12 pts and there were no DLTs in the additional pts. The most common adverse events (AEs) were diarrhea and rash. Preliminary evidence of antitumor activity was seen in both cohorts. Overall, 5 pts had a partial response (PR) and 14 had stable disease (SD). There was no evidence of PK interaction between erlotinib, capecitabine and oxaliplatin. CONCLUSIONS These data indicate that capecitabine 1,650mg/m2 and oxaliplatin 130mg/m2 in combination with erlotinib 100mg/d is the recommended dose for phase II trials in MCRC pts. [Figure: see text] [Table: see text].

Sorafenib-Induced Liver Failure: A Case Report and Review of the Literature

In patients with hepatocellular carcinoma characterized by vascular invasion and/or extrahepatic disease, Sorafenib is considered treatment of choice. Although mild liver test abnormalities were reported in less than 1% of the patients in the two large randomized, controlled phase III trials, four cases of severe acute Sorafenib-induced hepatitis have been described. One of these four cases died from liver failure. In this paper, a patient with HCC with lung metastases developed high fever and a severe hepatitis that rapidly evolved into liver coma and death, two weeks after the initiation of Sorafenib. Biochemical parameters pointed to a hepatocellular type of injury. Clinical and biochemical presentations were compatible with a drug-induced hypersensitivity syndrome such as it has mainly been described for aromatic anticonvulsants, sulphonamides, and allopurinol. We hypothesize that an underlying cytochrome P450 dysfunction with the presence of reactive drug metabolites might lead to this potentially fatal Sorafenib-induced severe liver dysfunction.

Combining bevacizumab and chemoradiation in rectal cancer. Translational results of the AXEBeam trial.

Background:This study characterises molecular effect of bevacizumab, and explores the relation of molecular and genetic markers with response to bevacizumab combined with chemoradiotherapy (CRT).Methods:From a subset of 59 patients of 84 rectal cancer patients included in a phase II study combining bevacizumab with CRT, tumour and blood samples were collected before and during treatment, offering the possibility to evaluate changes induced by one dose of bevacizumab. We performed cDNA microarrays, stains for CD31/CD34 combined with α-SMA and CA-IX, as well as enzyme-linked immunosorbent assay (ELISA) for circulating angiogenic proteins. Markers were related with the pathological response of patients.Results:One dose of bevacizumab changed the expression of 14 genes and led to a significant decrease in microvessel density and in the proportion of pericyte-covered blood vessels, and a small but nonsignificant increase in hypoxia. Alterations in angiogenic processes after bevacizumab delivery were only detected in responding tumours. Lower PDGFA expression and PDGF-BB levels, less pericyte-covered blood vessels and higher CA-IX expression were found after bevacizumab treatment only in patients with pathological complete response.Conclusions:We could not support the ‘normalization hypothesis’ and suggest a role for PDGFA, PDGF-BB, CA-IX and α-SMA. Validation in larger patient groups is needed.