Clinical outcomes of oral metronomic vinorelbine in advanced non-small cell lung cancer: correlations with pharmacokinetics and MDR1 polymorphisms.

PURPOSE: This study investigated correlations of the clinical outcomes of oral metronomic vinorelbine (VNR) with VNR pharmacokinetics and MDR1 polymorphisms. METHODS: Eighty-two patients with metastatic non-small cell lung cancer (NSCLC) unfit for standard chemotherapy were treated with VNR at the oral doses of 20-30 mg every other day or 50 mg three times a week. They had a performance status (PS) ≤ 3, were > 70-year-old and drug-naïve or cisplatin-pretreated. MDR1 2677G > T and 3435C > T polymorphisms were analysed and blood concentrations of VNR and desacetyl-VNR (dVNR: active metabolite) assayed. Overall survival (OS), treatment duration and drug-related toxicity were the main endpoints. RESULTS: Median OS and treatment duration were 27 weeks (range 1.3-183) and 15 weeks (range 1.3-144), respectively. OS was directly correlated with the duration of VNR treatment and number of therapy lines after VNR treatment (multiple linear regression: adjusted r2 = 0.71; p < 0.00001). Neither MDR1 genotypes nor VNR/dVNR concentrations predicted OS. VNR blood levels were positively correlated with platelet counts (r2 = 0.12; p = 0.0036). Patients who had long-term benefit (treated for ≥ 6 month without toxicity) showed lower VNR concentrations than those who had not. Twelve patients stopped therapy due to grade 3-4 toxicity. Toxicity was associated with blood concentrations of VNR ≥ 1.57 ng/mL and dVNR ≥ 3.04 ng/mL, but not with MDR1 polymorphisms. CONCLUSIONS: Neither pharmacokinetic nor pharmacogenetic monitoring seem useful to predict OS. On the other hand, high VNR and dVNR blood levels were associated with severe toxicity.

Oral Metronomic Vinorelbine (OMV) in elderly or pretreated patients with advanced non small cell lung cancer: outcome and pharmacokinetics in the real world.

Background Oral metronomic therapy (OMV) is particularly suitable for palliative care, and schedules adapted for unfit patients are advisable. This study investigated the effects of oral vinorelbine given every other day without interruption and its pharmacokinetic profile in patients with advanced lung cancer. Materials and Methods Ninety-two patients received OMV at doses of 20, 30 or 50 mg. Toxic events, clinical benefit and overall survival were analysed. Blood pharmacokinetics were evaluated in 82 patients. Results Median treatment duration and overall survival were 15 (range 1.3-144) and 32.3 weeks, respectively; fourty-eight (60%) patients experienced clinical benefit. Outcomes were unrelated to previous therapies, age, histology or comorbidities. Toxicity was associated with higher blood concentrations of the drug. Pharmacokinetics were stable for up to two years, and were not influenced by treatment line or age. Conclusions OMV produced non-negligible survival in patients and also showed stable long-term blood concentrations. The schedule of 20-30 mg every other day without interruption gave good tolerability and clinical benefit.

Age affects pegylated liposomal doxorubicin elimination and tolerability in patients over 70 years old.

PURPOSE: Pegylated liposomal doxorubicin (PLD) is often used in elderly people, due to its improved tolerability. However, clinical and pharmacological data in the subset of patients over 70 are scanty. METHODS: PLD safety was evaluated in 35 patients (aged ≥70 years) who were treated with PLD as a single agent for 165 cycles. Doxorubicin plasma levels, leukocyte DNA breaks and monocyte count variations were measured as markers of drug exposure, DNA repair capability and reticuloendothelial system activation, respectively. A correlation between these markers and age was sought. RESULTS: Treatment was generally well tolerated. Skin erythrodysesthesia was the most frequent side effect, and no severe (G4) toxicity occurred. PLD plasma half-life generally correlated with age (P < 0.001) and was particularly prolonged in octogenarians (P = 0.005). Doxorubicin clearance significantly declined up to 70 % at cycle 7. DNA breaks increased over the first two cycles (P = 0.007) and were inversely correlated with age (P = 0.007) and directly with clearance (P = 0.006). Pre-treatment monocyte counts increased over cycles (P < 0.001) and were associated with an increase in clearance at cycle 3 (P = 0.015). The hand-foot-skin syndrome was significantly more severe in patients of advanced age or longer PLD half-life. CONCLUSIONS: This study showed (1) increased systemic drug exposure over subsequent cycles; (2) association of age with increased drug exposure, reduced DNA repair capability and worse skin toxicity; (3) a relation between monocyte count and drug clearance.

Bi-weekly liposomal doxorubicin for advanced breast cancer in elderly women (≥ 70 years).

BACKGROUND: We conducted a multicenter prospective trial to assess tolerability and activity of pegylated liposomal doxorubicin (PLD) in women ≥ 70 years with locally-advanced or metastatic breast cancer. PATIENTS AND METHODS: All patients underwent Multidimensional Geriatric Assessment (MGA). Frail patients were excluded. Normal cardiac function was required for inclusion. A bi-weekly schedule of PLD at 20mg/mq was adopted. RESULTS: Thirty-two patients were enrolled with a median age of 78 years, 78.1% with visceral involvement, and 37.6% previously treated with chemotherapy for advanced disease. A mean of 7.8 cycles were delivered (range 1 to 20), with a median cumulative dose intensity of 8.9 mg/m(2)/week. Grade 3-4 toxicities were anemia (6.3%), palmar-plantar erythrodysesthesia (6.3%), mucositis (6.3%), infection (3.1%), and pulmonary embolism (3.1%). No cardiac events were registered. Causes of treatment interruption were maximal response (15.6%), progression (40.6%), refusal/loss to follow-up (28.1%), toxicities (9.4%), or other (6.3%). Response was obtained in 33.3% of 27 evaluable patients; median time to progression (TTP) was 10.3 months. MGA status (vulnerable vs. fit) did not have an impact on response, progression, and toxicity. CONCLUSIONS: Bi-weekly PLD is well tolerated in both fit and vulnerable patients, with an apparently fairly good response rate and TTP (possibly biased by subsequent endocrine therapy and loss to follow-up). Close observation of patients is recommended in order to avoid early refusal/loss to follow-up.

Equilibrative nucleoside transporter 1 genotype, cytidine deaminase activity and age predict gemcitabine plasma clearance in patients with solid tumours.

AIM: Gemcitabine (GEM) enters normal and tumour cells via concentrative (CNT) and equilibrative nucleoside transporters (ENT) and is subsequently deaminated to the inactive difluorodeoxyurine (dFdU) by cytidine deaminase (CDA). The aim of our study was to ascertain whether the nucleoside transporter genotype and the CDA activity phenotype can predict total GEM plasma clearance. METHODS: Forty-seven patients received GEM 1000-1250mgm(-2) i.v. over 30min. Plasma concentrations of GEM and dFdU were measured and individual pharmacokinetic profiles were determined. CDA activity was measured ex vivo in plasma samples. The two most common hENT1 and hCNT1 polymorphisms were determined from genomic DNA. RESULTS: Multivariate analysis revealed that GEM plasma clearance (CL) was positively correlated with the end of infusion dFdU : GEM ratio (P < 0.0001), which is a marker of in vivo CDA activity. The ENT1 genotype characterized by high transport capacity (G/G) and age were inversely correlated with CL (P= 0.027 and 0.048, respectively). A strong correlation was found between end of infusion GEM concentration and area under the concentration-time curve from time 0 to infinity (AUC(0,∞)) (r(2) = 0.77). CONCLUSIONS: Our results confirm the role of CDA and age on the interindividual variability of GEM CL and show the contribution of the hENT1 genotype for the first time.

Retinoic acid inhibits the proliferative response induced by CD40 activation and interleukin-4 in mantle cell lymphoma.

Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin's lymphoma with poor response to therapy and unfavorable prognosis. Here, we show that retinoic acid (RA) isomers significantly inhibit the proliferation of both primary MCL cultures (n = 7) and established cell lines (Granta 519 and SP-53) as shown by [(3)H]thymidine uptake and carboxyfluorescein diacetate succinimidyl ester labeling coupled with cyclin D1 staining. RA induces cell accumulation in G(0)-G(1) together with a marked up-regulation of p27(Kip1) by inhibiting ubiquitination and proteasome-dependent degradation of the protein. The p21(Cip1) inhibitor was also up-regulated by RA in Granta 519 cells, whereas the expression of cyclin D1 is unaffected. Most of RA-induced p27(Kip1) was bound to cyclin D1/cyclin-dependent kinase 4 complexes, probably contributing to the decreased cyclin-dependent kinase 4 kinase activity and pRb hypophosphorylation observed in RA-treated cells. Experiments with receptor-selective ligands indicate that RA receptor alpha cooperates with retinoid X receptors in mediating RA-dependent MCL cell growth inhibition. Notably, RA isomers, and particularly 9-cis-RA, also inhibited the growth-promoting effect induced in primary MCL cells by CD40 activation alone or in combination with interleukin-4. Immunohistochemical analysis showed that significant numbers of CD40L-expressing lymphoid cells are present in lymph node biopsies of MCL patients. These results therefore further strengthen the possibility that triggering of CD40 by infiltrating CD40L+ cells may continuously promote the growth of MCL cells in vivo. On these grounds, our findings that RA inhibits basal MCL proliferation as well as MCL growth-promoting effects exerted by microenvironmental factors make these compounds highly attractive in terms of potential clinical efficacy in this setting.

Bioimpedance vector pattern in cancer patients without disease versus locally advanced or disseminated disease.

OBJECTIVE: Bioelectrical impedance vector analysis allows non-invasive evaluation of soft tissue hydration and mass through pattern analysis of vector plots as height, normalized resistance, and reactance measurements. METHODS: Whole-body impedance measurements were made with a single frequency (50 kHz) analyzer (BIA-101, Akern/RJL Systems) in 148 adult, white, male subjects 45 to 85 y old: 56 healthy control subjects, 31 cancer patients after surgical procedure (without disease), and 61 patients with locally advanced (30 patients) or disseminated (31 patients) disease with the same body mass index and age. All patients were free from antineoplastic treatment and active nutritional intervention. RESULTS: Mean vectors of cancer groups without disease and locally advance disease versus the control group were characterized by a comparable normalized resistance component with a reduced reactance component (separate 95% confidence limits, P < 0.05), indicating a comparable ionic conduction (hydration) with loss of dielectric mass (cell membranes and tissue interfaces) of soft tissues. Overlapping 95% confidence limits of their mean vectors indicated comparable electrical tissue properties in less versus more advanced disease. CONCLUSION: Monitoring vector displacement trajectory toward the reference target vector position may represent useful feedback in support therapy planning of individual patients.

Comparison of magnesium concentration in serum, erythrocytes and gastric tissue in two groups of patients affected by chronic gastritis, Helicobacter pylori negative and positive.

UNLABELLED: Magnesium seems to be an important factor both for acid gastric secretion regulation (together with Ca2+) and for Helicobacter pylori survival and virulence. It can therefore be useful to evaluate if Helicobacter pylori (HP) infection is accompanied by variations in the host Mg availability. In this study serum, erythrocytary and gastric tissue Mg concentration was measured in 36 patients affected by chronic antral gastritis. Based on the presence of Helicobacter pylori infection, the patients were subdivided in two groups: group A: Helicobacter pylori negative, n = 23; group B: Helicobacter pylori positive, n = 13. RESULTS: While no differences were found between the two groups for serum Mg (group A 0.81 +/- 0.07 mm/L, group B 0.81 +/- 0.11 mm/L), both erythrocytary Mg (EMg) and gastric tissue Mg were found significantly lower in the HP positive subjects (erythrocytary Mg: 2.14 +/- 0.55 vs. 1.81 +/- 0.34 mm/L; gastric tissue Mg: 729.2 +/- 333.8 vs. 510.6 +/- 178.8 microg/g of dried tissue for group A and B respectively, p < 0.001 for both determinations). Erythrocytary Mg reduction is a clue of the whole body reduction in Mg availability (and consequently in gastric cells as well); the erythrocytary Mg reduction detected in the present paper for Helicobacter pylori positive patients can weaken gastric cells by impairing their metabolism. The hypothesis submitted is to impair Mg utilization in Helicobacter pylori, in order to improve eradication treatment, and in the meantime to preserve Mg homeostasis in infected cells.

Phase II trial of interferon-alpha-2a plus psolaren with ultraviolet light A in patients with cutaneous T-cell lymphoma.

PURPOSE: To evaluate the efficacy and side effects of psolaren with ultraviolet light A (PUVA) and interferon-alpha-2a (IFN-alpha-2a) in patients with mycosis fungoides (MF) and Sézary syndrome (SS). PATIENTS AND METHODS: From May 1993 to January 1999, 63 symptomatic patients with all stages of MF and SS were treated in a prospective Phase II trial with systemic escalating doses of IFN-alpha-2a combined with PUVA for 1 year, followed by indefinite PUVA maintenance in complete responding patients. RESULTS: Sixty-three patients were enrolled (Stage IA, n = 6; IB, n = 37; IIA, n = 3; IIB, n = 3; III, n = 12; IVA, n = 2). Ten patients had received previous therapy. The median follow-up duration for the entire cohort is 37 months. Of 63 patients, 51 achieved a complete response (CR; 74.6%) or partial response (PR; 6%) to therapy. The median response duration is 32 months. The 5-year overall survival rate is 91% and the 5-year disease-free survival rate is 75%. No life-threatening side effects were observed. Five patients stopped IFN-alpha-2a therapy due to toxicity. Eighty-four percent of the patients received more than 75% of the planned dose (12 million units three times a week). CONCLUSIONS: This combination of IFN-alpha-2a and phototherapy is an effective and safe therapy for patients with symptomatic MF.