A phase III study evaluating the safety and efficacy of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting over repeated cycles of chemotherapy.

BACKGROUND: Safe, effective and convenient antiemetic regimens that preserve benefit over repeated cycles are needed for optimal supportive care during cancer treatment. NEPA, an oral fixed-dose combination of netupitant, a highly selective NK1 receptor antagonist (RA), and palonosetron (PALO), a distinct 5-HT3 RA, was shown to be superior to PALO in preventing chemotherapy-induced nausea and vomiting after a single cycle of highly (HEC) or moderately (MEC) emetogenic chemotherapy in recent trials. This study was designed primarily to assess the safety but also to evaluate the efficacy of NEPA over multiple cycles of HEC and MEC. PATIENTS AND METHODS: This multinational, double-blind, randomized phase III study (NCT01376297) in 413 chemotherapy-naïve patients evaluated a single oral dose of NEPA (NETU 300 mg + PALO 0.50 mg) given on day 1 with oral dexamethasone (DEX). An oral 3-day aprepitant (APR) regimen + PALO + DEX was included as a control (3:1 NEPA:APR randomization). In HEC, DEX was administered on days 1-4 and in MEC on day 1. Safety was assessed primarily by adverse events (AEs), including cardiac AEs; efficacy by complete response (CR: no emesis, no rescue). RESULTS: Patients completed 1961 total chemotherapy cycles (76% MEC, 24% HEC) with 75% completing ≥4 cycles. The incidence/type of AEs was comparable for both groups. Most frequent NEPA-related AEs included constipation (3.6%) and headache (1.0%); there was no indication of increasing AEs over multiple cycles. The majority of AEs were mild/moderate and there were no cardiac safety concerns based on AEs and electrocardiograms. The overall (0-120 h) CR rates in cycle 1 were 81% and 76% for NEPA and APR + PALO, respectively, and antiemetic efficacy was maintained over repeated cycles. CONCLUSIONS: NEPA, a convenient single oral dose antiemetic targeting dual pathways, was safe, well tolerated and highly effective over multiple cycles of HEC/MEC.

Dose-finding study of capecitabine in combination with weekly paclitaxel for patients with anthracycline-pretreated metastatic breast cancer.

PURPOSE: Capecitabine and paclitaxel show high efficacy, non-overlapping toxicity profiles and preclinical synergism, providing the rationale for their combination in metastatic breast cancer (MBC). This dose-escalation study aimed at determining the maximum tolerated dose (MTD) of capecitabine plus paclitaxel in anthracycline-pretreated MBC patients. PATIENTS AND METHODS: Patients with MBC received fl at-dose of oral capecitabine (1,000 mg/m(2) twice daily, days 1-14) plus weekly paclitaxel 60, 75, or 90 mg/m(2), i.v., days 1, 8 and 15, every 3 weeks. RESULTS: All 11 patients enrolled onto study were evaluable for toxicity and response. Two patients receiving paclitaxel 75 mg/m(2) experienced grade 3 nail toxicity, with grade 3 hand-foot syndrome (HFS) in one patient and grade 2 dermatitis in the other. Although not life-threatening, these were considered unacceptable and the preceding dose level was selected. Eight of 11 patients achieved objective responses. CONCLUSION: The recommended regimen is capecitabine 1,000 mg/m(2) twice daily, days 1-14, plus paclitaxel 60 mg/m(2)/week. Escalation of the paclitaxel dose above 60 mg/m(2)/week is not feasible due to severe skin toxicity.

Supportive care in patients with metastatic prostate cancer.

Supportive care is the comprehensive medical, nursing, psychosocial and spiritual help that the patients need besides specific anticancer treatment. Its spectrum encompasses the control of cancer-related physical symptoms and psychological, emotional, social and spiritual problems arising from cancer, as well as prevention or treatment of toxic effects induced by anticancer treatments. The scope of supportive care in metastatic prostate cancer is very wide and heterogeneous. The goals of this paper are to: a) provide an overview of supportive care as an integral part of comprehensive care of patients with metastatic prostate cancer; b) present the major supportive care problems: the control of pain, fatigue and complications of long-term hormonal treatment; and c) discuss spinal cord compression as an oncologic emergency in metastatic prostate cancer.

Gabapentin for relief of neuropathic pain related to anticancer treatment: a preliminary study.

The aim of our study was to explore a potential analgesic effect of gabapentin in patients with neuropathic pain caused by anticancer treatment. A total of 23 outpatients without active disease and with chronic, treatment-related pain were included in this single-center, open-label, exploratory, non-controlled study. The primary end-points were pain intensity and pain relief following a 4-week treatment period. A total of 15 patients (65%) completed the study, 5 (22%) discontinued the study due to treatment failure and 3 (13%) due to toxicity. More than 50% reduction in pain intensity was obtained in 11 of 23 patients (48%, 95% CI 30-66%). Pain relief increased from 8.33% (+/- 13.64) to 66.58% (+/- 18.35) (p <0.01). Somnolence, mental clouding, and headache were the most frequently reported adverse events. We concluded that gabapentin should be accepted for further investigation in this important setting of supportive care.

High efficacy of a single oral dose of ondansetron 8 mg versus a metoclopramide regimen in the prevention of acute emesis induced by fluorouracil, doxorubicin and cyclophosphamide (FAC) chemotherapy for breast cancer.

The aim of our single-center, prospective, randomized, open study was to evaluate the antiemetic efficacy and tolerability of a regimen based on a single oral dose of ondansetron 8 mg in comparison with a metoclopramide-based regimen, for prevention of acute FAC (fluorouracil, doxorubicin and cyclophosphamide) chemotherapy-induced emesis. A total of 149 chemotherapy-naive, female outpatients, under 50 years of age and with no history of alcohol consumption, scheduled to receive their first cycle of FAC chemotherapy, were included. The patients received either oral ondansetron (8 mg) or metoclopramide (1.5 mg/kg, i.v.), both combined with dexamethasone (16 mg, i.v.) and alprazolam (0.5 mg t.i.d. orally). No antiemetic prophylaxis was given for delayed emesis. Complete control of acute vomiting was obtained in 69/74 (93%) of patients receiving ondansetron, and in 49/75 (65%) of those receiving metoclopramide (p=0.00003). Complete control of acute nausea was obtained in 58% of patients receiving ondansetron and in 36% of those receiving metoclopramide (p=0.007). Complete prevention of delayed vomiting/nausea was achieved in 73%/20% and 60%/16% of patients, respectively. Sedation was more frequent in the metoclopramide arm (p=0.04). As far as we know this is the first study that supports the efficacy of a regimen based on a single oral dose of ondansetron 8 mg in the prevention of acute FAC chemotherapy-induced emesis. The ondansetron regimen was highly effective in female patients and was superior to the metoclopramide based regimen.

Patient statement of satisfaction with antiemetic treatment is related to quality of life.

The aim of our study was to explore the possible relationship between patient satisfaction with antiemetic treatment and quality of life (QoL). The study sample consisted of 136 chemotherapy-naive patients with breast cancer, with Karnofsky index 90% to 100%, scheduled to receive their first cycle of, mainly adjuvant, 5-fluorouracil/doxorubicin/cyclophosphamide chemotherapy. Two antiemetic regimens were used for the prevention of acute emesis. No antiemetic prophylaxis was given for delayed emesis. QoL was assessed using the Rotterdam Symptom Checklist (RSCL). The RSCL was completed before chemotherapy (day 1) and on day 5. Statement of satisfaction was given on day 5. The change in RSCL scores between day 5 and day 1 was calculated and compared in three subgroups of patients: those very satisfied (n = 55), satisfied (n = 65), and unsatisfied with antiemetic treatment (n = 16). Patient statement of satisfaction was related to psychological distress (p = 0.002), physical symptom distress (p = 0.002), and activity level (p = 0.002). It was also related to the control of nausea (p < 0.01) and vomiting (p < 0.0001). We suggest that patient statement of satisfaction with antiemetic treatment could be an outcome measure for response assessment in antiemetic trials.

[Evaluation of quality of life in oncology]. / Procena kvaliteta zivota u onkologiji.

Studies of quality of life are more and more becoming an integral part of cancer care in situations when treatment of cancer patients is burdened with significant toxicity, and results of survival of these patients are unsatisfactory. Modern concept of health-related quality of life measurement means consensus about its two basic features: multidimensionality of concept, and essentially subjective experience in a treated person. As a minimum, domains of physical, psychological and social are assessed, and the patient is considered to be the primary source of information. The most widely used instruments for quality of life assessment are questionnaires, especially developed for cancer patients, with supplemental items for particular diagnosis. These instruments must satisfy the basic psychometric properties-validity and reliability. Quality of life studies are focused mostly on phase III trials, where differences between treatment arms for tumour response and survival are expected to be small. Another approach is developed in parallel which, based upon quality of life measurement, initiates decisions for the treatment of a set of patients up to health policy level. In these "cost-utility" studies, efficacy and cost of the treatment, and improvement of patients' quality of life are independently estimated, and then integrated in medical decision making.

Single 8 mg dose of oral ondansetron failed to prevent FAC chemotherapy-induced acute nausea and vomiting.

The aim of this open, nonrandomized, monocentric study was to evaluate the efficacy of a single daily dose of 8 mg oral ondansetron in the prophylaxis of acute nausea and vomiting in chemotherapy-naive breast cancer patients receiving their first cycle of chemotherapy with 5-fluorouracil, doxorubicin and cyclophosphamide (FAC). Forty-five female patients were recruited, median age 42 years. The number of emetic episodes and the grade of nausea were recorded. 51% of patients achieved complete, and 9% major control of acute emesis. 33% of patients experienced no acute nausea, and in 18% nausea was mild. Complete protection from nausea and vomiting (complete prophylaxis) was obtained in 12/45 (27%) of patients. Treatment success (no vomiting with no more than mild nausea) was achieved in 18/45 (40%) of patients. We conclude that the efficacy of a single dose of 8 mg oral ondansetron in controlling acute nausea and vomiting induced by FAC chemotherapy is not high enough to justify its use as a sole antiemetic agent in outpatients.

Daily oral etoposide in metastatic breast cancer.

Etoposide, administered i.v. or orally, as a single agent, in 1- to 5-day courses, was found to be minimally effective in pretreated advanced breast cancer patients. Clinical data suggested an effectiveness of a chronic low-dose oral etoposide schedule, in refractory and those malignancies otherwise unresponsive to the drug. Therefore, the aim of our open-labeled, non-randomized, phase II clinical study was to investigate the efficacy and toxicity of chronic daily etoposide (50 mg/m2 daily, for 21 consecutive days, every 28 days) as a first-line chemotherapy for metastatic breast cancer. Twenty-one advanced breast cancer patients, with or without previous adjuvant CMF chemotherapy, were included. One complete (CR) and five partial remissions (PR) were obtained in 18 patients evaluable for response. Disease stabilization was obtained in 10 patients (55%), while two patients (11%) failed to respond. Grade 3-4 hematological toxicity developed in seven out of 21 patients evaluable for toxicity or in 15 out of 96 cycles. Nonhematological toxicity was moderate. Our results showed the efficacy and relative low toxicity of a chronic oral etoposide regimen in advanced breast cancer patients. Adjuvant CMF chemotherapy did not influence the therapeutic response. Previous irradiation of the breast tended to increase the etoposide hematological toxicity.

Cardioprotection with ICRF-187 (Cardioxane) in patients with advanced breast cancer having cardiac risk factors for doxorubicin cardiotoxicity, treated with the FDC regimen.

A study of cardioprotection with ICRF-187 (Cardioxane, Eurocetus) has been performed in 35 patients with metastatic breast cancer treated with the FDC regimen (5-fluorouracil 500 mg/m2 i.v., day 1; doxorubicin 50 mg/m2 i.v., day 1; cyclophosphamide 500 mg/m2 i.v., day 1). All patients had one or more cardiac risk factors for doxorubicin cardiotoxicity including 24 who had previously received left-chest-wall irradiation. Cardioxane was applied at a dosage of 1000 mg/m2 as a 15-min infusion in Ringer lactate solution 30 min before doxorubicin administration. Cardiological monitoring included left-ventricular ejection fraction (LVEF) determination by echocardiography before treatment and before each cycle following the cumulative doxorubicin dose of 200 mg/m2. Of the 35 patients, 34 were evaluable fore response, and the overall response rate was 19/34 (56%) with 3/34 complete responses and 16/34 partial responses. Statistical analysis of LVEF values in relation to increasing cumulative doxorubicin doses with Wilcoxon's test of equivalent pairs and Friedman's test has demonstrated that no cardiotoxicity was detected up to a cumulative doxorubicin dose of between 800 mg/m2 and 1000 mg/m2, except for 2 patients in whom a decrease of 20% in relation to the LVEF pretreatment level was demonstrated following a cumulative drug dose of 250 mg/m2. Thus Cardioxane provides an effective cardioprotection even in breast cancer patients with cardiac risk factors for doxorubicin cardiotoxicity treated with the FDC regimen.

[Granulocyte colony-stimulating factor: biologic effects and possibilities of therapeutic use]. / Stimulantni faktor granulocitnih kolonija: bioloska dejstva i moguca terapijska upotreba.

This review is a brief overview on recent advances in biology as well as in the potential clinical application of recombinant methionil human granulocyte colony-stimulating factor (r-metHuG-CSF). Biologically active human granulocyte colony-stimulating factor is a recombinant human protein expressed in Escherichia coli. It is localized on membrane of stroma cells in molecules of extracellular matrix. R-metHuG-CSF increases the number of circulating neutrophils, and to a much lesser extent macrophages. The clinically relevant uses of r-metHuG-CSF at present lie in two general areas: neutropenia and febrile netropenia present in patients with non-myeloid malignant diseases induced by anticancer agents. R-metHuG-CSF produces dose-dependent and reversible side effects such as: musculoskeletal pain, urinary disorders, retention of fluid, pericarditis, dyspnea, hypoxia and hypotension.

[Biologic effects and possible therapeutic use of the granulocyte-macrophage colony-stimulating factor. Modern treatment of leukopenia]. / Bioloska dejstva i moguca terapijska uptreba stimulantnog faktora granulocito-makrofagnih kolonija. Savreno lecenje leukopenija.

This review is a brief overview of recent advances in biology as well as in potential clinical application of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF). Biologically active rhGM-CSF is a recombinant human protein expressed in Escherichia coli. GM-CSF is produced by nontransformed (T-lymphocytes, trophoblasts, keratinocytes, osteoblasts, tracheal epithelial cells, renal mesangial cells, endothelial cells, macrophages, fibroblasts, smooth muscle cells) and transformed (murine plasmocytoma, bladder carcinoma HIBY cell line, anaplastic carcinoma of the gall bladder, Yoshida sarcoma cell line, HC3T3-osteoblast cell line) cells. RhGM-CSF increases the number of circulating neutrophils, monocytes and eosinophils and increases chemotactic, microcidal killing and cytotoxic activity of monocytes and granulocytes. The present clinically relevant uses of rhGM-CSF two general areas: restoration of haematopoietic dysfunction by raising cell counts from suppressed to normal levels, and augmentation of host defence against infection. Thus, rhGM-CSF reduces risk of infections. In addition, rhGM-CSF may increase tumour cell destruction in some malignant diseases. RhGM-CSF produces dose-dependent toxicity consisting of myalgic fever, fluid retention and serosal effusions.

Stimulation by 17 alpha-hydroxyprogesterone of glycoprotein and glycosaminoglycan synthesis in human placenta in vitro.

The incorporation of 14C-glucosamine into glycoproteins (GP) and glycosaminoglycans (GAG), of 3H-leucine into protein, and the hexuronic acid (HA) content of polymerized GAG was determined in incubated placental tissue. In placentae of earlier gestational age (GA), incorporation of 14C-glucosamine was 2.6 times greater than other at 38-39 weeks GA. 19 of 26 placentae at 38-39 weeks GA responded by one or more parameters when incubated with 0.5-3 microM 17 alpha-OH-progesterone (17OHP). Those which did not respond were all of earlier GA; the placental content of GAG decreased in these from 31.1 +/- 1.8 nmol HA/mg protein to 16.4 +/- 1.5 nmol in placentae of GA 38-39 weeks. In the latter, 17OHP increased GAG by 42.5% to 24.4 +/- 2.5 nmol HA/mg protein in a 2-hour incubation. Progesterone, oestriol, cortisol and testosterone were without effect. It is concluded that synthesis of placental GAG decreases toward the end of gestation, but can be increased by 17OHP specifically. This indicates that 17OHP is a biologically active steroid and might have a role in maintaining placental function.