Kurt Possinger

Double-Blind, Randomized Placebo Controlled Trial of Fulvestrant Compared With Exemestane After Prior Nonsteroidal Aromatase Inhibitor Therapy in Postmenopausal Women With Hormone Receptor–Positive, Advanced Breast Cancer: Results From EFECT

PURPOSE The third-generation nonsteroidal aromatase inhibitors (AIs) are increasingly used as adjuvant and first-line advanced therapy for postmenopausal, hormone receptor-positive (HR+) breast cancer. Because many patients subsequently experience progression or relapse, it is important to identify agents with efficacy after AI failure. MATERIALS AND METHODS Evaluation of Faslodex versus Exemestane Clinical Trial (EFECT) is a randomized, double-blind, placebo controlled, multicenter phase III trial of fulvestrant versus exemestane in postmenopausal women with HR+ advanced breast cancer (ABC) progressing or recurring after nonsteroidal AI. The primary end point was time to progression (TTP). A fulvestrant loading-dose (LD) regimen was used: 500 mg intramuscularly on day 0, 250 mg on days 14, 28, and 250 mg every 28 days thereafter. Exemestane 25 mg orally was administered once daily. RESULTS A total of 693 women were randomly assigned to fulvestrant (n = 351) or exemestane (n = 342). Approximately 60% of patients had received at least two prior endocrine therapies. Median TTP was 3.7 months in both groups (hazard ratio = 0.963; 95% CI, 0.819 to 1.133; P = .6531). The overall response rate (7.4% v 6.7%; P = .736) and clinical benefit rate (32.2% v 31.5%; P = .853) were similar between fulvestrant and exemestane respectively. Median duration of clinical benefit was 9.3 and 8.3 months, respectively. Both treatments were well tolerated, with no significant differences in the incidence of adverse events or quality of life. Pharmacokinetic data confirm that steady-state was reached within 1 month with the LD schedule of fulvestrant. CONCLUSION Fulvestrant LD and exemestane are equally active and well-tolerated in a meaningful proportion of postmenopausal women with ABC who have experienced progression or recurrence during treatment with a nonsteroidal AI.

Advanced breast cancer: a phase II trial with gemcitabine.

PURPOSE In this phase II study, the efficacy and tolerability of gemcitabine were studied in 44 patients with locally advanced or metastatic breast cancer. PATIENTS AND METHODS Of 40 patients assessable for response, 14 were chemotherapy-naive, seven had received adjuvant chemotherapy, and 19 had received one prior chemotherapy regimen for metastatic disease. Gemcitabine was administered as a 30-minute intravenous infusion once a week for 3 weeks followed by a 1-week rest every 4 weeks. The mean number of completed cycles administered was 2.7 and the mean dosage delivered was 725 mg/m2 per injection. Eighty-one percent of doses were delivered as scheduled. RESULTS There were three complete responses and seven partial responses, for an overall response rate of 25.0% (95% confidence interval [CI], 12.7% to 41.2%). Four patients were not assessable for efficacy (one had insufficient therapy, two had no bidimensionally measurable disease, and one had neither). All responses were independently validated by an external oncology review board. Responses were observed early in treatment, with a median time to response of 1.9 months. The median survival duration for all 40 assessable patients was 11.5 months. Hematologic toxicity was generally mild, with World Health Organization (WHO) grade 3 and 4 leukopenia occurring in 6.8% and 2.3% of patients and neutropenia in 23.3% and 7.0%, of patients, respectively. The only other grade 4 toxicities were infection and nausea and vomiting in one patient each. One patient was withdrawn due to shortness of breath, possibly drug-related. Flu-like symptoms, which were mild, transient, and treatable with acetominophen, were reported in 6.8% of patients. Only one patient developed alopecia of severity greater than WHO grade 2. CONCLUSION In view of the single-agent activity seen in advanced breast cancer, modest toxicity profile, and novel mechanism of action, gemcitabine deserves evaluation in breast cancer and is an ideal candidate for combination therapy.

Patient-Tailored Antiemetic Treatment With 5-Hydroxytryptamine Type 3 Receptor Antagonists According to Cytochrome P-450 2D6 Genotypes

PURPOSE The use of serotonin 5-hydroxytryptamine type 3 receptor antagonists has substantially reduced, but not eliminated, nausea and vomiting in cancer chemotherapy. This study sought to investigate whether efficacy of antiemetic treatment with ondansetron and tropisetron depends on cytochrome P-450 2D6 (CYP2D6) genotype, hypothesizing that the rapid and particularly the ultrarapid metabolizers of these drugs are at risk of being undertreated. PATIENTS AND METHODS Included in the study were 270 cancer patients receiving their first day of chemotherapy. Nausea and vomiting were documented using standardized interviews. The intensity of nausea was measured with visual analog scales before and twice during the chemotherapy. The relationship between the CYP2D6 genotypes and the tropisetron serum concentrations 3 and 6 hours after drug administration was analyzed in a subgroup of 42 patients. CYP2D6 genotyping was carried out by polymerase chain reaction-restriction fragment length polymorphism analysis. RESULTS Genetically defined poor metabolizers had higher serum concentrations of tropisetron than all other patients (P <.03). Approximately 30% of all patients receiving chemotherapy experienced nausea and vomiting. Genetically defined ultrarapid meta-bolizers of CYP2D6 substrates had higher frequency of vomiting within the first 4 hours (P <.001) and within the period 5 to 24 hours (P <.03) after treatment than all the other patients; the tendency for nausea was similar. This difference was more pronounced in patients treated with tropisetron than in those treated with ondansetron. CONCLUSION Antiemetic treatment with tropisetron or ondansetron could be improved by adjustment for the CYP2D6 genotype; approximately 50 subjects would have to be genotyped to protect one patient from severe emesis.

Serum levels of the angiogenic cytokines basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) in multiple myeloma

Abstract: Angiogenesis is a crucial process in growth and progression of cancer and there is growing evidence that neovascularisation is important in hematological malignancies. Since an increased angiogenic potential has been identified in multiple myeloma, we simultaneously measured circulating serum levels of the cytokines bFGF, VEGF, HGF and IL‐6 by ELISA in 67 patients with multiple myeloma or monoclonal gammopathies of undetermined significance (MGUS) and in 20 controls. Median values of bFGF were 4.7 pg/ml in healthy volunteers, 6.2 in MGUS, 6.3 in myeloma stage I, 13.4 in stage II and 21.7 in stage III. Myeloma patients had significantly higher bFGF serum levels than controls (p<0.001). Pretreatment bFGF levels differed significantly in the Salmon and Durie stages I–III (p=0.02) and were significantly elevated in stage II–III compared to stage I myeloma (p=0.02). In patients responding to chemotherapy according to the CLMTF criteria, a significant decrease in serum bFGF, VEGF and HGF levels occurred (median pretreatment values for bFGF 23.9 pg/ml, post‐treatment 6.5 pg/ml; p<0.001, for VEGF 223 pg/ml versus 105 pg/ml; p=0.02 and for HGF 1429 pg/ml versus 1077 pg/ml; p=0.02, respectively). In 11 patients who did not achieve a remission, there was no significant decrease in bFGF, VEGF and HGF levels. These data show that myeloma in stages II and III is associated with an increase in serum bFGF concentrations and give the first report that effective chemo‐therapy is accompanied by a significant decrease in the angiogenic factors bFGF, VEGF and HGF, while no decrease of these factors could be found in nonresponders.

Biomarkers of depression in cancer patients

Inflammation and perturbation of the hypothalamic‐pituitary‐adrenal (HPA) axis function appears to play a putative role in the etiology of depression. Patients with metastatic cancer demonstrate elevated prevalence rates for depression. The objective of the current study was to illustrate the efficacy of interleukin‐6 (IL‐6) and HPA axis function as adjuncts to support the diagnosis of depression in cancer patients.

PHASE II TRIAL OF GEMCITABINE AS PROLONGED INFUSION IN METASTATIC BREAST CANCER

Gemcitabine is an active agent in the treatment of metastatic breast cancer. The phosphorylation of gemcitabine into the active gemcitabine triphosphate (dFdCTP) is catalyzed by deoxycytidine kinase. This enzyme is saturated at plasma concentrations achieved after an infusion over 30 min. Therefore

Histone deacetylase inhibitors reduce VEGF production and induce growth suppression and apoptosis in human mantle cell lymphoma.

Abstract:  Objectives: Mantle cell lymphoma (MCL) is an incurable disease with an aggressive course and novel treatment strategies are urgently needed. The purpose of this study was to evaluate the effects of histone deacetylase (HDAC) inhibitors, a new group of antiproliferative agents, on human MCL cells. Methods: Three MCL cell lines (JeKo‐1, Hbl‐2 and Granta‐519) were exposed to different concentrations of the HDAC inhibitors sodium butyrate (NaB) and suberoylanilide hydroxamic acid (SAHA) for 8–72 h. Their effects on cell viability, apoptosis induction and cell cycle proliferation were studied. Moreover, the influence of SAHA on the expression of cyclin D1, the cell cycle regulators p21 and p27 and the production of vascular endothelial growth factor (VEGF) were analyzed. Results: The HDAC inhibitors induced accumulation of acetylated histones in MCL cells. MTT assays and Annexin‐V staining showed that they potently inhibited viability in a dose‐dependent manner and induced apoptosis in all cell lines tested. Cell cycle analysis indicated that their exposure to SAHA or NaB decreased the proportion of cells in S phase and increased the proportion of cells in the G0/G1 and/or G2/M phases. Incubation with the two HDAC inhibitors resulted in downregulation of cyclin D1. SAHA lead to an upregulation of p21 in all cell lines and an upregulation of p27 in JeKo‐1 and Granta‐519 cells, while expression of p27 in Hbl‐2 was not altered. In addition, SAHA inhibited the production of the angiogenic cytokine VEGF. Treatment with NaB increased the expression of p21 in JeKo‐1 and Hbl‐2 cells, while in Granta 519 cells no effect was noted. The expression of p27 remained constant in all three cell lines after exposure to NaB. Conclusion: Based on these findings, we provide evidence that HDAC inhibitors have antiproliferative effects in MCL and may represent a promising therapeutic approach.

Detection of Amplifiable Messenger RNA in the Serum of Patients with Lung Cancer

Abstract: Recently, in addition to the detection of circulating tumor cells in peripheral blood of patients with solid tumors, the presence of free circulating nucleic acids in the plasma and serum has also been described. We have focused on the possibility of isolating and amplifying intact extracellular, tumor‐related mRNA from the plasma/serum of patients with lung cancer. For this purpose, we established several RT‐PCR‐based amplification systems for the detection of a panel of five different genes. The expression of these genes was either shown to be restricted to lung tissue or associated with malignancy. We examined two small groups of 18 patients with lung cancer before and during chemotherapy, respectively. The message for β‐actin (control for integrity of the RNA) was detected in all of the analyzed sera from the control group and patients with lung cancer. Analysis of CK‐19 expression was positive in the majority of tumor patients, but positive results were also shown in all of the control sera. The expression of MAGE‐2 and TTF‐1 genes was not observed in any of the patients in either the lymphocyte preparations or serum samples. Expression of the PGP 9.5 gene was observed in the cells of all 18 patients, but mRNA in the serum was only detectable in one case. The hnRNP‐B1 mRNA was detectable in 14/18 sera, and Her2/neu‐specific mRNA could be amplified from the serum of 7/18 patients. Combining the last two markers, we were able to detect all patients with a malignant lung tumor.

Proteasome: an emerging target for cancer therapy.

Proteasome inhibitors represent novel anti-cancer drugs which interact with the proteasome–ubiquitin pathway. The 26S proteasome is a multicatalytic threonine protease with three distinct catalytic activities. It is responsible for intracellular protein turnover in eukaryotic cells, including the processing and degradation of short- and some long-living proteins required for regulation of various cellular functions. Subsequently, the inhibition of the proteasomal function results in stabilization and accumulation of its substrates, which notably include cyclins, cyclin-dependent kinase inhibitors, transcriptional factors, tumor suppressor proteins and proto-oncogenes. This results in confounding signals in the cell inducing cell cycle arrest and activation of apoptotic programs. Acting on transcriptional factor NF-κB, which is upregulated in some tumors undergoing chemotherapy or irradiation and downregulated by proteasome inhibition, a significant chemosensitization and consequently synergistic effects concerning the anti-tumor activity could be achieved. Bortezomib is the first proteasome inhibitor that has entered clinical trials. In multiple myeloma, both the US Food and Drug Administration and European Medicine Evaluation Agency granted approval for the use of bortezomib (Velcade) for the treatment of multiple myeloma patients who have received at least two prior therapies and have demonstrated disease progression on the last therapy. At present, other trials examine the activity in a variety of solid tumors and hematological malignancies. This paper reviews preclinical and clinical results.

Prolonged infusion of gemcitabine in stage IV breast cancer: a phase I study.

Gemcitabine is an effective agent in the treatment of metastatic breast cancer. The phosphorylation of gemcitabine into the active gemcitabine triphosphate (dFdCTP) is catalyzed by deoxycytidine kinase. This enzyme is saturated at plasma concentrations achieved after an infusion over 30 min. Therefore accumulation of higher intracellular dFdCTP concentrations, which may result in an enhanced antineoplastic activity, cannot be achieved by higher dosage, but only by prolonged infusion time. The objectives of this phase I trial were to determine the dose-limiting toxicities (DLT) and the maximum tolerated dose (MTD) of gemcitabine given as a 6 h i.v. infusion. Patients with metastatic breast cancer were treated with gemcitabine as a 6 h infusion on days 1, 8 and 15 every 4 weeks. The starting dose was 200 mg/m2 with an interindividual escalation in 50 mg/m2 increments. Sixteen patients received 196 doses through three dose levels. All patients were assessable for toxicity, 13 assessable for response. The MTD was 250 mg/m2. DLT was observed at 300 mg/m2 consisting of a reversible elevation of transaminases WHO grade 3 in two patients and cutaneous toxicity grade 3 in one patient. Most common non-hematologic toxicities were mild to moderate and rapidly reversible elevation of liver enzymes in all patients, nausea and vomiting (four patients grade 2, five patients grade 3), and mild alopecia. Hematologic toxicity was mild with neutropenia WHO grade 3 and 4 in only one patient each, and no grade 3 thrombocytopenia. One patient achieved a complete remission and another patient a partial response, for an overall response rate of 15% (two of 13). In addition, seven patients (54%) had stable disease and four (31%) failed to respond to the treatment. We conclude gemcitabine 250 mg/m2 days 1, 8 and 15 every 4 weeks can be safely administered as 6 h infusion. Toxicity, especially myelosuppression, is surprisingly mild. Based on this result a phase II study with 250 mg/m2 administered over 6 h was initiated to determine the efficacy.