Tumour pharmacodynamics and circulating cell free DNA in patients with refractory colorectal carcinoma treated with regorafenib.

BACKGROUND: Regorafenib, a multi-kinase inhibitor, is used in the treatment of patients with metastatic colorectal cancer refractory to standard therapy. However, this benefit was limited to 1.4 months improvement in overall survival, with more than half of patients experiencing grade 3 to 4 adverse events. We aim to elucidate the pharmacodynamic effects of regorafenib in metastatic colorectal cancer and discover potential biomarkers that may predict clinical benefit. METHODS: Patients with metastatic colorectal adenocarcinoma refractory to standard therapy with tumours amenable to biopsy were eligible for the study. Regorafenib was administered orally at 160 mg daily for 3 out of 4 weeks with tumour assessment every 2 cycles. Metabolic response was assessed by FDG PET-CT scans (pre-treatment and day 15); paired tumour biopsies (pre-treatment and day 21 post-treatment) were sampled for immunohistochemistry and proteomic profiling analyses. Plasma circulating cell free DNA was quantified serially before and after treatment. RESULTS: There were 2(6%) partial responses out of 35 patients, and 8(23%) patients had stable disease for more than 7 months. Adverse event profile was similar to reported data. Recurrent somatic mutations in K-RAS, PIK3CA and BRAF were detected in plasma circulating cell free DNA in 14 patients; some mutations were not found in archival tumour. Total plasma circulating cell free DNA inversely correlated with progression free survival (PFS), and presence of KRAS mutations associated with shorter PFS. Immunohistochemistry of pre- and post- treatment biopsies showed majority of patients had downregulation of phosphorylated-VEGFR2, podoplanin, phosphorylated-AKT, Ki-67 and upregulation of the MEK-ERK axis, phosphorylated-C-MET, phosphorylated-SRC, phosphorylated-STAT3 and phosphorylated-JUN. Proteomic analysis of fine needle tumour aspirates showed down-regulation of PI3K was associated with longer PFS. CONCLUSION: Plasma circulating cell free DNA may yield potential predictive biomarkers of regorafenib treatment. Downregulation of the PI3K-AKT axis may be an important predictor of clinical benefit.

Evaluation of hypertension and proteinuria as markers of efficacy in antiangiogenic therapy for metastatic colorectal cancer.

BACKGROUND: The vascular endothelial growth factor pathway is strongly implicated in cancer-related angiogenesis. Antiangiogenic agents such as bevacizumab commonly cause hypertension (HTN) and proteinuria (PTN), which may be biomarkers of response and clinical outcome. STUDY: We conducted a retrospective analysis of patients with histologically proven metastatic colorectal cancer (mCRC) treated with either bevacizumab or a tyrosine kinase inhibitor in combination with chemotherapy at The Christie Hospital from January 2006 to September 2009. RESULTS: Of 90 patients evaluated, 50 were eligible. Seventeen (34%), 4 (8%), and 3 (6%) patients developed Common Toxicity Criteria (v 3.0) grades 1, 2, and 3 HTN, respectively. Response rates were 42% for patients with grades 0 to 1 HTN compared with 86% for patients with ≥grade 2 HTN (P=0.043). Median overall survival was 21.6 months for patients with grades 0 to 1 HTN and 25.2 months for patients with ≥grade 2 HTN (P=0.270). Twelve patients (24%) developed grade 1 PTN and 4 patients (8%) developed ≥grade 2 PTN. Median overall survival was 23.9 months for patients with grades 0 to 1 PTN and 4.2 months for those with ≥grade 2 PTN (P=0.028). CONCLUSIONS: To our knowledge, this is the first study to demonstrate the utility of PTN as a surrogate marker of outcome in antiangiogenic therapy for metastatic colorectal cancer. Although HTN is predictive of a significantly higher response rate, the development of PTN during treatment with bevacizumab or tyrosine kinase inhibitor portends poorer survival and should be evaluated prospectively.

Pharmacologic modulation strategies to reduce dose requirements of anticancer therapy while preserving clinical efficacy.

Drug interactions may be exploited to overcome pharmacokinetic issues in order to improve the therapeutic index of a drug, with clinical goals of reducing the dose of the active drug while preserving efficacy or reducing toxicity. This strategy has been used in infectious disease and transplant medicine, and, more recently, in oncology. Pharmacologic modulation strategies range from coadministration of either a drug that inhibits a metabolizing enzyme that would inactivate the drug of interest, a drug that induces an enzyme that activates the drug of interest or a drug that inhibits transporters that affect the uptake or elimination of the drug of interest. This review will discuss pharmacologic modulation strategies that have been tested clinically in order to increase systemic drug exposure. Important examples include ketoconazole inhibition of hepatic CYP3A4 in order to increase systemic exposure to docetaxel, irinotecan and etoposide, and cyclosporine inhibition of intestinal ATP-binding cassette transporters in order to decrease the toxicity of irinotecan and increase the bioavailability of oral docetaxel, paclitaxel and topotecan.

Unusual Merkel cell carcinoma of the eyelid.

Merkel cell carcinoma of the eyelid is a rare tumor with less than 100 reported cases worldwide. We describe an unusual presentation of Merkel cell carcinoma of the eyelid in a 60 year old Asian male. He presented with multiple left lower lid conjunctival nodules, intense conjunctival erythema, as well as ipsilateral cervical lymphadenopathy. An incisional biopsy diagnosed him with Merkel cell carcinoma with a PET scan showing distant metastatic disease. He was then treated with chemotherapy. The combination of a presentation of conjunctival nodules and erythema, location in the lower eyelid and the conjunctiva, the presence of metastatic disease on diagnosis as well as an unusual immunohistochemical profile make this an unusual case.

Outcomes after multiple lines of chemotherapy for platinum-resistant epithelial cancers of the ovary, peritoneum, and fallopian tube.

BACKGROUND: Platinum-resistant and refractory cancers of the ovary, fallopian tube, and peritoneum have a poor prognosis, yet in some cases, they can respond to multiple lines of chemotherapy. Uncertainty remains over optimal drug choice and when therapeutic focus should be switched from active therapy to supportive care. METHODS: A retrospective case note review was performed on 274 women treated for platinum-resistant/refractory ovarian, fallopian tube, or peritoneal carcinoma at the Christie Hospital between 2004 and 2008. Baseline data at onset of platinum resistance and outcomes from subsequent lines of therapy were recorded. RESULTS: A total of 689 lines of therapy were administered with a median overall survival from initiation of first-line therapy for platinum-resistant disease of 61 weeks. Twenty-eight percent of women commenced cytotoxic therapy in the last 3 months of life. Treatment efficacy declined rapidly with successive lines of therapy particularly if disease progression occurred during first-line therapy. Factors independently associated with worse overall survival at recognition of platinum resistance were performance status, presence of stage IV disease, elevated cancer antigen 125, and platinum-refractory disease. CONCLUSIONS: A significant proportion of women who were treated received therapy within the last few months of life with little clinical benefit. Disease progression on 2 consecutive lines of therapy should be used as a guide to discontinue cytotoxic treatment. A subset of patients with poor prognosis at the onset of platinum resistance, who may have little gain from anticancer treatment, can be identified.

Pharmacogenetics-Guided Phase I Study of Capecitabine on an Intermittent Schedule in Patients with Advanced or Metastatic Solid Tumours.

The FDA-approved starting dosage of capecitabine is 1,250 mg/m(2), and market research indicates that U.S. physicians routinely prescribe 1,000 mg/m(2). Retrospective analyses however report reduced toxicity and efficacy in a subset of patients with the 3R/3R genotype of the thymidylate synthase gene enhancer region (TSER). This study sought to develop TSER genotype-specific guidelines for capecitabine dosing. Capecitabine was dose-escalated in advanced and/or metastatic cancer patients with TSER 3R/3R (Group A; N = 18) or 2R/2R + 2R/3R (Group B; N = 5) from 1,250 to 1,625 mg/m(2) b.i.d., every 2 weeks on/1 week off for up to 8 cycles. Parent and metabolites pharmacokinetics, adverse events, and tumour response were assessed. The maximum tolerated and recommended doses in 3R/3R patients are 1,625 mg/m(2) and 1,500 mg/m(2). At 1,500 mg/m(2), one in nine 3R/3R patients experienced a dose-limiting toxicity. Dosing guidelines for 2R/2R + 2R/3R remain undetermined due to poor accrual. The results indicate that 3R/3R patients may be amenable to 1,500 mg/m(2) b.i.d. on an intermittent schedule, and is the first to prospectively validate the utility of TSER pharmacogenetic-testing before capecitabine treatment.

Glucuronidation by UGT1A1 is the dominant pathway of the metabolic disposition of belinostat in liver cancer patients.

UNLABELLED: Belinostat is a hydroxamate class HDAC inhibitor that has demonstrated activity in peripheral T-cell lymphoma and is undergoing clinical trials for non-hematologic malignancies. We studied the pharmacokinetics of belinostat in hepatocellular carcinoma patients to determine the main pathway of metabolism of belinostat. The pharmacokinetics of belinostat in liver cancer patients were characterized by rapid plasma clearance of belinostat with extensive metabolism with more than 4-fold greater relative systemic exposure of major metabolite, belinostat glucuronide than that of belinostat. There was significant interindividual variability of belinostat glucuronidation. The major pathway of metabolism involves UGT1A1-mediated glucuronidation and a good correlation has been identified between belinostat glucuronide formation and glucuronidation of known UGT1A1 substrates. In addition, liver microsomes harboring UGT1A1*28 alleles have lower glucuronidation activity for belinostat compared to those with wildtype UGT1A1. The main metabolic pathway of belinostat is through glucuronidation mediated primarily by UGT1A1, a highly polymorphic enzyme. The clinical significance of this finding remains to be determined. TRIAL REGISTRATION: ClinicalTrials.gov NCT00321594.

Imaging angiogenesis of genitourinary tumors.

Angiogenesis is a key process in the growth and metastasis of cancer, and genitourinary tumors are no exception. The evolution of angiogenesis as an important target for novel anticancer therapeutics has brought with it new challenges for in vivo imaging. Most imaging techniques quantify physiological parameters, such as blood volume and capillary endothelial permeability. Although CT, PET and ultrasonography have shown promise, MRI is the most common method used to evaluate angiogenesis in clinical trials of genitourinary tumors. Pilot studies of MRI, CT and ultrasonography in patients with renal cancer have produced promising results; reductions in vascular permeability and blood flow have been correlated with progression-free survival. The vascular characteristics of prostate cancer have been evaluated by MRI, and this has been suggested as a means of assessing tumor response to hormone deprivation therapy. Current evidence highlights the potential of angiogenesis imaging in the diagnosis, staging and possibly response monitoring of bladder cancer. In the future, assessment of the angiogenic process at the structural, functional and molecular levels, before, during and after antiangiogenic therapy will undoubtedly be integrated into wider clinical practice.