Administration Of Vinorelbine Research Articles

PO84 VISUALIZING TREATMENT AND OUTCOMES IN METASTATIC BREAST CANCER

Background: Treatment of MBC is becoming more complex as more drugs are approved for this indication. A high proportion of these drugs are intravenous, and sequential use can have a detrimental effect on venous access, causing distress to the patient as well as preventing treatment. In the UK vinorelbine is licensed for the treatment of MBC and NSCLC as a single agent or in combination. Vinorelbine is a vesicant and when given intravenously can cause venous irritation, which in some cases can lead to thrombophlebitis. Administration site reactions are very common, occurring in more than 10% of patients (grade 3/4: 3.7%). We compared the incidence of venous toxicity with IV vinorelbine in patients with MBC and those with NSCLC, who generally receive vinorelbine as their first chemotherapy. Method: Case notes of all patients receiving IV vinorelbine during a 3 year period (2008 to 2011) at UHNS were reviewed retrospectively for incidence of thrombophlebitis. Results: We identified 39 patients; 11 received vinorelbine IV as a single agent for MBC whilst 28 received it with platinum as adjuvant chemotherapy for NSCLC. Median age was 55 and 67 years for MBC and NSCLC patients respectively. Patients with MBC had previously received at least 2 lines of chemotherapy (maximum of 5 previous lines), including combination regimens and nearly all had been administered IV, whereas all patients with NSCLC were chemo-naive. Almost half of the patients with MBC had prior history of venous access problems. Four required central line insertions for vinorelbine treatment. A total of 57 cycles (mean 5.1) were delivered for MBC and 93 cycles (mean 3.3) were delivered for NSCLC. Moderate to severe thrombophlebitis was recorded in 8 of the 11 patients with MBC (80%), compared to only 1 (3%) with NSCLC. A further two patients with MBC experienced mild thrombophlebitis and problems also occurred in a further four patients despite them having a central line inserted. Other side effects occurred at similar rates in both groups, apart from haematological toxicity which was slightly more pronounced in patients with NSCLC and probably related to combination treatment. Conclusions: Venous complications were frequent with intravenous administration of vinorelbine. A significantly higher incidence of thrombophlebitis was seen in patients with MBC. This was probably due vein damage from multiple lines of previous chemotherapy. We recommend consideration of oral administration of vinorelbine to reduce the need for central line insertion and to improve the patient experience and compliance.

Abstract A173: The new marine derived tubulin binding agent PM060184 shows potent antitumor activity in vivo against multidrug resistant, Pgp expressing tumors.

Abstract PM060184 is new marine derived tubulin-binding agent originally isolated from the sponge Lithoplocamia lithistoides. The compound is currently under evaluation in Phase I clinical studies in patients with advanced cancer diseases. PM060184 showed potent antitumor activity in vitro and also in vivo against a panel of different tumor xenografted models. As the overexpression of P-gp pumps is generally related to resistance to tubulin binding agents, we have analyzed whether the expression of this efflux pump could also confer resistance to PM060184. In vitro, PM060184 showed potent antiproliferative activity against tumor cells over-expressing the P-gp multidrug efflux pump (LoVo/Dox, A2780/Dox and IGROV-1/ET), with IC50s values in the low nanomolar range. In vivo, the activity of PM060184 was evaluated in mice xenografted with LoVo (wild-type) or LoVo/DX (P-gp overexpressing) subcutaneous tumors. Tumor bearing (ca. 150-200 mm3) animals were randomly allocated into the following groups (N = 10/group): i) PM060184 (16 mg/kg); ii) paclitaxel (25 mg/kg); iii) vinorelbine (16 mg/kg); and, iv) placebo. Treatments were intravenously administered once per week for 3 consecutive weeks (q7dx3). Tumor dimensions were recorded 3 times per week starting from the first day of treatment (Day 0). Tumor volume was calculated using the equation (a·b2)/2, where a and b were the longest and shortest diameters, respectively. The antitumor effect obtained following paclitaxel, vinorelbine or PM060184 administration was calculated by using T/C (%), which was defined as the percentage of the change in tumor volume for each treated (T) and placebo (C) group during the surviving period for placebo-treated animals. In mice bearing LoVo xenografted tumors paclitaxel and vinorelbine treatments induced lowest T/C values of 23.3 % (Day 26) and 18.3% (Day 23), respectively. Also, PM060184 was highly active in this model, with a lowest T/C calculated as 8.1 % (Day 26). In LoVo/DX xenografted mice, paclitaxel and vinorelbine treatments resulted in no antitumor effect. However, LoVo/DX tumors were highly susceptible to PM060184 treatment (lowest T/C = 6.7%, on Day 28) demonstrating that a strong antitumor PM060184-related effect regardless of the P-gp status in this model. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A173. Citation Format: Pablo M. Aviles, Maria José Guillen, Mandy Palomares, Praxedes Nuñez, Marta Martinez-Diez, Juan Fernando Martínez-Leal, Luis Francisco García-Fernández, Carlos M. Galmarini. The new marine derived tubulin binding agent PM060184 shows potent antitumor activity in vivo against multidrug resistant, Pgp expressing tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A173.

Treatment of advanced recurrent NSCLC with daily oral vinorelbine: A phase I trial.

e19108 Background: Metronomic regimens, in which small, frequent doses of chemotherapy are administered, have been suggested to lower toxicities while maintaining, or even improving, efficacy. The high frequency of administration aims to expose the tumor continuously to the drug, thereby preventing the recovery of malignant cells between cycles. Previous studies have shown that the administration of oral vinorelbine thrice weekly is feasible and well tolerated. We present a phase I dose finding study in which a regimen of daily oral vinorelbine was evaluated in pretreated patients with advanced NSCLC. Methods: Pretreated patients with advanced NSCLC were treated with vinorelbine (Navelbine oral) at fixed daily doses of 20 mg, 30 mg, 40 mg or 50 mg for 21 days of each four-week cycle. The primary end point was the identification of the maximum tolerated dose, which was reached when two out of six patients experienced dose limiting toxicity (DLT) in cycle 1 or 2. Results: 27 patients with advanced NSCLC (78% stage IV, median age 65 y) were enrolled. Most (93%) had received previous systemic therapy (mean: 2.6 lines). Daily administration of oral vinorelbine was well tolerated up to 30 mg/d without any DLT. At 40 mg one of three patients experienced DLT in cycle 1 and another patient in cycle 2. Three out of six patients had DLT at the dose level of 50 mg. Therefore, the recommended dose was established at 30 mg/d in cycle 1, with escalation to 40 mg/d in cycle 2 if no DLT had occurred. Eleven patients (2 out of 7 treated with the recommended dose) experienced treatment-related toxicities of grade 3 or higher. The adverse events were primarily hematological (febrile neutropenia: 14.8%, leukopenia: 29.6%, lymphopenia: 18.5%, neutropenia: 18.5%). One patient died as a result of colitis. The frequency of non-hematological toxicities of grade 3 or higher was low with only single cases reported for nausea, fatigue, neutropenic sepsis, pneumonia, increased gamma-glutamyltransferase and anorexia. Conclusions: Daily administration of oral vinorelbine in pretreated patients is feasible and safe. An initial dose of 30mg/d is well tolerated and can be increased to 40mg/d in cycle 2. Further studies are warranted to evaluate the efficacy and safety of this novel approach. Clinical trial information: EudraCT number 2006-001573-25.

Breast cancer manifested by hematologic disorders.

Breast cancer is the most common type of cancer in women. However, it is very rarely manifested as hematologic disorders. A 35-year-old woman was admitted because of disseminated intravascular coagulation. Examinations revealed the presence of breast cancer in her left breast; therefore, paclitaxel was administered weekly. Although disseminated intravascular coagulation was controlled, pulmonary dysfunction due to lymphangitis carcinomatosa suddenly occurred 10 weeks after treatment. Pulmonary dysfunction was effectively treated with epirubicin and cyclophosphamide. Twenty-three weeks after treatment, the patient developed liver dysfunction accompanied with jaundice due to progressive metastatic lesions in the liver; liver dysfunction improved after the administration of vinorelbine. Subsequently, because of the recurrence of pulmonary dysfunction, rechallenge with epirubicin and cyclophosphamide was performed and was effective; however, this therapy was discontinued because of its adverse effects. She expired of liver failure 33 weeks after the occurrence of disseminated intravascular coagulation. Metastatic tumors in the bone marrow, lung, and liver showed different sensitivities to different anti-cancer agents. We report a case of breast cancer manifested by hematologic disorders which was treated by a sequential chemotherapy.

Vinorelbine and capecitabine in anthracycline- and/or taxane-pretreated metastatic breast cancer: sequential or combinational?

The difference between combinational and pre-planned sequential therapies using regimens that include non-anthracycline and taxane in the first-line setting remains unclear. The purpose of this study is to explore the interaction between vinorelbine (N) and capecitabine (X) in breast cancer cells and to compare the simultaneous or sequential administration of the two drugs in patients with metastatic breast cancer (MBC) as first-line treatment. First, we explored the effects of vinorelbine on thymidine phosphorylase (TP) and thymidylate synthase (TS) expression in breast cancer cells. Next, we designed a prospective randomized phase II trial of MBC patients comparing the combinational and pre-planned sequential administration of vinorelbine and capecitabine in the first-line metastatic setting. The primary end point was progression-free survival (PFS). The correlation between clinical characteristics and class III β-tubulin expression and patient survival was also explored. Vinorelbine upregulates TP and downregulates TS in breast cancer cells, thereby further sensitizing tumor cells to capecitabine, which indicated the proper order for sequential therapy should be N → X. Sixty patients were eligible for the phase II trial. No significant difference was observed between the combinational arm and the sequential arm in terms of progression-free survival (PFS), overall response rate (ORR), and overall survival (OS). Only in the subgroup of patients with liver metastases were median PFS and OS significantly prolonged in the combinational arm (8.5 vs. 6.4 months, P = 0.041 and 23.8 vs. 13.9 months, P = 0.028, respectively). No association between class III β-tubulin expression and patient outcome was identified. Grade 3/4 adverse events were more common in the combinational arm. Both the NX regimen and pre-planned sequential N → X regimen are acceptable as first-line treatments with comparable efficacies for MBC patients previously treated with anthracyclines and/or taxanes. Sequential monotherapies are recommended as the preferred approach to first-line chemotherapy for most MBC patients in the absence of an imminent visceral crisis and the need for rapid symptom and/or disease control.

Prospective study into the necessity of hemogram on day 8 in oral vinorelbine and cisplatin regimen.

e18011 Background: One of the standard treatments for metastatic non-small-cell lung cancer patients is the combination of cisplatin plus vinorelbine. This regimen is associated with a high rate of severe neutropenia, and a hemogram is therefore routinely performed on day 8 before the administration of vinorelbine. However, no prospective study has ever examined the rate of neutropenia detected in this hemogram or the rate of discontinuation of chemotherapy as a result. Since one of the objectives in the treatment of advanced lung cancer is to maintain quality of life, we performed this prospective study of cisplatin plus vinorelbine to address the question of whether this hemogram on day 8 could be avoided, thus eliminating unnecessary venipunctures without endangering patient safety. Methods: We included 58 chemotherapy-naïve advanced NSCLC patients from 10 centers. They received intravenous doses of cisplatin on day 1 plus oral vinorelbine on days 1 and 8, every 3 weeks, for a maximum of six cycles. Median age was 61 years; 87% were males; ECOG 1: 66%. Results: Of 189 cycles analyzed, vinorelbine was administered on day 8 in 661 (97.8%), and the dose was reduced or canceled in 15 (2.2%; IC 95%: 0.5 - 5.45) due to hematological toxicity. Conclusions: The hemogram on day 8 could potentially be avoided in patients ECOG 0-1 while still maintaining an acceptable safety margin.

Phase I and II Trials of Vinorelbine With Carboplatin for Patients 75 Years of Age or Older With Previously Untreated Non–Small-Cell Lung Cancer

BackgroundThe safety and efficacy of platinum-based combination chemotherapy for elderly patients with advanced non–small-cell lung cancer (NSCLC) remains unclear. We conducted phase I and phase II trials of a combination of vinorelbine and carboplatin for patients ≥75 years of age and with advanced NSCLC. Patients and MethodsPreviously untreated patients (≥75 years of age) with stage IIIB or IV NSCLC were enrolled. Based on a 4-week cycle, vinorelbine was given on days 1 and 8, and carboplatin was given on day 1. Dose-limiting toxicity was defined as grade 4 hematologic toxicity that lasted 4 days or more, febrile neutropenia; grade 3 or worse nonhematologic toxicities; or the omission of vinorelbine administration on day 8 in the first cycle. ResultsThirteen patients were enrolled in phase I. dose-limiting toxicity was grade 4 neutropenia that lasted 4 days or more, observed in 2 of 4 patients at level 4. Phase II study used the dose of level 3 (20 mg/m2 vinorelbine, area under the curve of 4 mg/mL/min carboplatin). Forty-two patients were enrolled. The response rate was 14.6% of 41 assessable patients (95% CI, 3.8-25.4). The median time to progression was 98 days (95% CI, 61-135 days), and the median survival time was 366 days (95% CI, 321-411 days). All toxicities were mild and manageable. ConclusionUse of 20 mg/m2 vinorelbine on days 1 and 8, followed by carboplatin area under the curve of 4 mg/mL/min on day 1 every 4 weeks warrants a phase III study for elderly patients with advanced NSCLC.

Unexpected High Levels of Vorinostat when Combined with Vinorelbine in Patients with Advanced Cancer

This study was a multi-centre, dose-escalation trial in patients with advanced cancers. Primary objective was to determine maximum tolerated dose (MTD) of vorinostat, a competitive inhibitor of histone deacetylase (HDAC), in combination with vinorelbine. Secondary aims were to determine (1) corresponding pharmacokinetics, (2) safety of this regimen, and (3) impact of UGT1A1 and 2B17 polymorphisms on vorinostat pharmacokinetics. Starting dose of once daily oral vorinostat was 200 mg for 7 days every 21 days in combination with a 20-min intraveinous weekly infusion of vinorelbine 25 mg/m2, starting 4 hours after the first vorinostat dose. During cycle 1, blood samples were collected at day 1 for vorinostat and at days 1 and 8 for vinorelbine for pharmacokinetic evaluation. Seven patients were included. Most of adverse events observed were mild (grades 0-2) and reversible after treatment discontinuation (hemotological toxicity, asthenia, diarrhea, dyspnea, fever, hyperglycemia and nausea). Two patients had a dose limiting toxicity at the first dose level that consisted of grade 3 hyperglycemia and vinorelbine administration was delayed. The first dose-level was considered as the MDT and therefore dose escalation was stopped. Mean vorinostat plasma AUC was higher than reported previously at a similar dose when used as single agent or in combination with other cytotoxics. There was no obvious vinorelbine-vorinostat interaction nor any correlation with UGT1A1 or 2B17 polymorphisms. MDT of the combination was 200 mg oral vorinostat for 7 days in combination with 25 mg/m2 weekly vinorelbine. Severity of hyperglycemia was most likely related to unexpected high vorinostat exposures.

Oral metronomic administration of cyclophosphamide and vinorelbine in previously treated patients with metastatic breast cancer: Phase II trial.

e11017 Background: Patients with metastatic breast cancer who previously was treated with anthracyclin and taxane therapy have low clinical benefit rate with subsequent chemotherapy. Metronomic chemotherapy is an anticancer strategy which uses conventional cytotoxic drugs administered at very low dose in close interval. Oral metronomic administration of cyclophosphamide has been administrated in metastatic breast cancer at dose of 50 mg orally daily. We designed a phase II study to evaluate the safety and activity of adding vinorelbine at 60 mg per square meter to metronomic cyclophosphamide in women with measurable metastatic breast cancer. Methods: Patients received vinorelbine at dose of 60 mg per square weekly by mouth for three weeks every 28 days and oral cyclophosphamide at dose of 50 mg orally daily. The primary study end point response rate (RR) and the safety of this regimen. Results: 20 patients were enrolled at median follow up of one year. The median age was 54 years old (36-72), Histologic type was ductal (80%), lobular (15%) and mixed (5%). Sites of metastasis were nonvisceral (35%) and visceral (65%). Patients with hormone receptor positive were 65% and with Her2/neu positive (15%). 75% of patients received more than four cycles of this regimen and with a medium of 175 days (28-322). 20 patients (100%) had prior chemotherapy for MBC. Global response rate was 60%, 5 patients (20%) with partial response and eight patients (40%) with stable disease Toxicities were minimal except for grade 3 vomiting and fatigue in 1 patient (5%). Grade 3/4 hematologic toxicity was neutropenia in 1 patient (5%) and grade 2 in 5 patients (25%). In five patients had dose reduction by 10-20% in subsequent doses and one patient withdrawn from the study because of chemotherapy related toxicity. Conclusions: Oral metronomic administration of cyclophosphamide and vinorelbine is a regimen with acceptable toxicity and efficacy with similar response to other chemotherapy in metastatic breast cancer.

Cisplatin (CDDP) plus oral vinorelbine (NVBO) as first-line treatment for advanced non-small cell lung cancer (NSCLC): Prospective analysis to improve the patient’s convenience on day 8 NVBO administration.

e18060 Background: Severe neutropenia observed during chemotherapy (CT) is a clinical finding leading to treatment modification and, sometimes, life-threatening events. The results of a previous study with 180 p treated with IV vinorelbine plus CDDP as first-line treatment for advanced NSCLC could lead to consider not performing a blood count prior to day 8 vinorelbine administration for patients aged 70 years (y) or less who presented a good haematological tolerability profile during previous cycles (cy) in order to improve treatment convenience. The aim of this study is to prospectively validate these results with the combination of NVBO plus CDDP. Methods: Between October 2007 and March 2009, 56 chemo-naïve p with histologically confirmed stage IIIB/IV NSCLC were included. Treatment consisted of CDDP 75 mg/m2 day 1 plus NVBO 80 mg/m2 days 1 and 8, with a prior test of myelosensitivity at 60 mg/m2 for the first cycle, every 21 days. Patient’s characteristics were: Median age, 61 years (range 32-75); males, 85.7%; smokers, 35.7%; all PS 0-1; adenocarcinoma, 37.5% / squamous, 35.7%; stage IIIB, 17.9% / IV, 75%. Results: Patients received a total of 251 cycles. For the purpose of this report 181 were analyzed (cycle 1 from each p was excluded). NVBO administration on day 8 was cancelled in 4 cycles due to haematological events (2.2% [95% CI: 0.6%, 5.56%]). The reported events were: 3 grade 2-4 neutropenia and 1 grade-2 thrombocytopenia. Among 54 p evaluable for response, 1 p achieved complete response and 21 p partial response (overall response rate, 40.7% [95% CI: 27.6-55]). Toxicity was mild with neutropenia WHO grade 3-4 observed in 2.8% cy (12.5% p), leukopenia grade 3-4 in 1.6% cy (7.2% p); 2 cases of febrile neutropenia were reported. Grade-3 fatigue was observed in 9 cy (8 p), grade-3 nausea in 4 cy (4 p) and grade 3-4 vomiting in 5 cy (5 p). Conclusions: The findings of this study could lead to consider not performing a blood count prior to day 8 NVBO administration for patients aged 70 y or less who presented a good haematological tolerability profile during previous cycles in first-line treatment for advanced NSCLC.

A multicenter phase I trial of metronomic oral vinorelbine plus cisplatin in patients with NSCLC

The purpose of the present study was to determine the maximum-tolerated doses (MTDs) and the dose-limiting toxicities of a metronomic administration of oral vinorelbine and cisplatin in patients with advanced/metastatic NSCLC. Twenty-six patients with advanced/metastatic NSCLC were enrolled. Escalating doses of vinorelbine (40-70 mg p.o./trice per week) and cisplatin (70-85 mg/m(2) intravenous infusion) were administered on day 1 every 3 weeks. ΜΤDs were reached at 60 mg thrice/week p.o. for vinorelbine and 85 mg/m(2) for cisplatin. Grade 4 neutropenia, febrile neutropenia and grade 4 diarrhea were the dose-limiting events during the first cycle of chemotherapy. The most common grade III-IV hematologic toxicity was neutropenia occurring in seven (27%) patients, while non-hematological toxicities were relatively infrequent and mostly of grade I or II. Objective responses were observed in 20.8% of patients with measurable disease. The regimen of metronomic administration and cisplatin is feasible and active in patients with NSCLC.

Low-Dose Metronomic Oral Administration of Vinorelbine in the First-line Treatment of Elderly Patients With Metastatic Breast Cancer

Background The concept of metronomic chronic administration of low-dose chemotherapy has become relevant for the treatment of cancer in the last several years. This study sought to determine the safety and activity of oral vinorelbine (VNB), using a metronomic schedule of administration, in elderly patients with metastatic breast cancer (MBC). Patients and Methods From October 2004 to March 2007, 34 patients with MBC (median age, 74 years; range, 70–84 years) were treated with oral VNB at 70 mg/m 2, fractionated on days 1, 3, and 5, for 3 weeks on and 1 week off, every 4 weeks, for a maximum of 12 cycles. The objective response rate was the primary endpoint. Results All 34 patients received at least 3 cycles of therapy and were evaluable. Two achieved complete responses (6%), and 11 achieved partial responses (32%). Median progression-free survival and median overall survival entailed 7.7 months (95% confidence interval, 6.9-9.05 months) and 15.9 months (95% CI, 13.1-15.91 months), respectively, for all patients. Conclusion The fractionated administration of oral VNB is well tolerated and presents promising activity in elderly patients with metastatic cancer, warranting further investigation in combination with other chemotherapy agents.

Vinorelbine for non-small cell lung cancer

Importance of the field: Vinorelbine is a ‘third-generation’ vinca alkaloid approved for the treatment of NSCLC. The introduction of ‘third-generation’ drugs (vinorelbine, gemcitabine, taxanes) in platinum combination improved survival of patients with advanced NSCLC, with substantially similar results among the different drugs. Treatment toxicities are considerable in this setting.Areas covered in this review: This narrative review reports a synthesis of evidence available from published clinical trials, systematic reviews and meta-analyses on the activity and safety of vinorelbine, used as single agent or in combination chemotherapy in patients with NSCLC, from 1990 to 2009.What the reader will gain: When vinorelbine was administered in a weekly schedule without interruptions, the most common toxicity was neutropenia that often precluded administration of the drug, therefore, reducing the dose intensity. A schedule providing administration of vinorelbine on days 1 and 8 every 3 weeks seemed to improve the tolerability of the drug. Tolerability of the drug did not result lower in the elderly subset. None of the other ‘third-generation’ drugs were clearly better tolerated than vinorelbine. Moreover, in the adjuvant setting, vinorelbine is the only third-generation drug that demonstrated, in combination with cisplatin, a consistent improvement in survival on a long-term basis.Take home message: Vinorelbine is an active and generally manageable therapeutic option for the treatment of both early and advanced NSCLC.

Intravenous versus oral vinorelbine plus capecitabine as second-line treatment in advanced breast cancer patients. A retrospective comparison of two consecutive phase II studies

Vinorelbine (i.v.) plus capecitabine (oral) combination therapy is active in anthracycline/taxane pretreated patients with metastatic breast cancer. Availability of oral vinorelbine provides this combination in an all-oral formulation. Two consecutive phase II trials differing only in vinorelbine administration routes evaluated their respective activities and tolerabilities in this population. In the i.v. group ( n = 38) disease control was 61% (37% PR, 24% SD), median TTP 6.8 months and median survival 11.3 months. In the oral group ( n = 38) disease control was 77% (5.4% CR, 34% PR, 38% SD), median TTP 7 months and median survival 10 months. G3–G4 neutropenia was more common in the oral group ( p < 0.05); G2–G3 anaemia [5] and G3 thrombocytopenia [1] were observed only in the oral group. Although the comparison between the two regimens was not randomized, the results observed in these two consecutive phase II studies may suggest that oral and iv vinorelbine, in combination with capecitabine, can achieve similar responses in patients with metastatic breast cancer refractory to anthra–taxane combinations.

Dose-Ranging Study of Metronomic Oral Vinorelbine in Patients with Advanced Refractory Cancer

To determine the safe dose range and pharmacokinetics of metronomic oral vinorelbine and obtain preliminary data on biomarkers and efficacy in patients with advanced cancer. Successive cohorts of patients received escalated doses of oral vinorelbine given thrice a week until disease progression, unacceptable toxicity (UT), or consent withdrawal. UT was any grade 4 toxicity, or grade 2 or 3 toxicity that would result to longer than 2-week break during the first 2 months of treatment. Blood samples were collected for pharmacokinetics and quantification of angiogenesis regulatory proteins. Sixty-two patients (median age, 60 years) enrolled at six dose levels from 20 to 70 mg and received treatment for median 12.25 weeks (range, 2-216+). Unacceptable toxicity occurred in two of six patients treated at 60 mg (leucopenia grade 4 and epistaxis grade 2) and in one at 70 mg (leucopenia grade 2). The upper metronomic dose was 50 mg. Objective antitumor response documented in eight cases and 32% of patients experienced disease stability for minimum 6 months. Three responders (renal cancer, medullary thyroid carcinoma, and Kaposi sarcoma) received nonstop treatment for over 3 years without overt toxicity. Low pretreatment levels of circulating interleukin-8, vascular endothelial growth factor, and basic fibroblast growth factor were found predictors of efficacy. Steady-state concentrations of vinorelbine and its active metabolite ranged from 0.5 to 1.5 ng/mL. Metronomic administration of oral vinorelbine is feasible at doses up to 50 mg thrice a week and can yield sustainable antitumor activity without overt toxicity, probably through antiangiogenic mechanism. Further clinical investigation is warranted.

Cisplatin plus vinorelbine as first-line treatment for advanced non-small-cell lung cancer: Is a hemogram on day 8 essential?

One of the standard treatments for metastatic non-small-cell lung cancer patients is the combination of cisplatin plus vinorelbine. This regimen is associated with a high rate of severe neutropenia, and a hemogram is therefore routinely performed on day 8 before the administration of vinorelbine. However, no study has ever examined the rate of neutropenia detected in this hemogram or the rate of discontinuation of chemotherapy as a result. Since one of the objectives in the treatment of advanced lung cancer is to maintain quality of life, we have retrospectively analyzed a Spanish Lung Cancer Group study of cisplatin plus vinorelbine to address the question of whether this hemogram on day 8 could be avoided, thus eliminating unnecessary venipunctures without endangering patient safety. Between April 2004 and January 2006, 180 chemotherapy-naïve, advanced NSCLC patients were included from 35 centers. They received intravenous doses of cisplatin 75 mg/m 2 on day 1 plus vinorelbine 25 mg/m 2 on days 1 and 8, every 3 weeks, for a maximum of six cycles. Median age was 62.5 years; 87.2% were males; 80.6% were smokers; 48.2% were adenocarcinomas and 36% were squamous cell carcinomas; 17.2% were stage IIIB and 82.8% stage IV. Of 750 cycles analyzed, vinorelbine was administered on day 8 in 661 (88.1%), and the dose was reduced or canceled in 15 (2%) due to hematological toxicity. Among patients aged < 70 with no dose modification in previous cycles, the likelihood of observing hematological toxicity at day 8 was only 0.8% (95% CI, 0.1–3%). We speculate that the hemogram on day 8 could potentially be avoided in this subgroup of patients while still maintaining an acceptable safety margin. Prospective clinical studies to further examine this hypothesis are warranted.

Cisplatin (CDDP) plus oral vinorelbine (NVBO) as first-line treatment for advanced non-small cell lung cancer (NSCLC): Prospective analysis to improve the patient's convenience on day 8 NVBO administration

e19096 Background: Severe neutropenia observed during chemotherapy (CT) is a clinical finding leading to treatment modification and, sometimes, life-threatening events. The results of a previous study with 180 p treated with IV vinorelbine plus CDDP as first-line treatment for advanced NSCLC could lead to consider not performing a blood count prior to day 8 vinorelbine administration for patients aged 70 years (y) or less who presented a good haematological tolerability profile during previous cycles (cy) in order to improve treatment convenience. The aim of this study is to prospectively validate these results with the combination of NVBO plus CDDP. Methods: Between October 2007 and September 2008, 31 chemo-naïve p with histologically confirmed stage IIIB/IV NSCLC were included. Treatment consisted of CDDP 75 mg/m2 day 1 plus NVBO 80 mg/m2 days 1 and 8, with a prior test of myelosensitivity at 60 mg/m2 for the first cycle, every 21 days. Patient's characteristics were: Median age, 62 years (range 32–73); males, 93.5%; smokers, 38.7%; all PS 0–1; adenocarcinoma, 33.3% / squamous, 36.7%; stage IIIB, 14.8% / IV, 85.2%. Results: We analyzed 129 cy. NVBO administration on day 8 was cancelled in 3 cycles due to haematological events (2.3% [95% CI: 0.4%-6.6%]. The reported events were: 1 grade-2 neutropenia, 1 grade-4 neutropenia and 1 grade- 2 thrombocytopenia. Among 22 p evaluable for response, 10 p achieved partial response (overall response rate, 45.5% [95% CI: 24.4- 67.8]). Toxicity was mild with neutropenia WHO grade 3–4 observed in 2.1% cy (9.7% p), leukopenia grade 3 in 1.4% cy (6.5% p); 1 case of febrile neutropenia was reported. Grade-3 fatigue was observed in 6 cy (6 p), grade-3 nausea in 2 cy (2 p) and grade-3 vomiting in 2 cy (2 p). Conclusions: The findings of this study could lead to consider not performing a blood count prior to day 8 NVBO administration for patients aged 70 y or less who presented a good haematological tolerability profile during previous cycles in first-line treatment for advanced NSCLC. [Table: see text]

Vinorelbine plus capecitabine in salvage therapy of breast cancer. Comparison of intravenous vs oral administration of vinorelbine

1114 Background: Capecitabine (C) and vinorelbine (V) have shown activity in advanced breast cancer (ABC). Two subsequent phase II trial were conducted in order to evaluate the response rate (RR) and time to progression (TTP) of CV combination in patients (pts) with ABC progressing after first line anthracycline plus/minus taxane based chemotherapy. Due to the supposed equiactivity of iv and oral (po)formulation of V, the only difference of the two trials was the route of administration of V. Methods: Seventy-six pts affected by ABC were included (38 in each study, respectively) and treated with the combination of C 2,000 mg/m2 (from 1st to 14th day) plus V 25 mg/m2/iv or 60 mg/m2 /po (days 1st+8th) q3w. With regard to previous treatments for metastatic disease, 12 patients (15.8%) had received anthracyclines, 6 patients (7.9%) taxanes, and 58 patients (76.3%) both drugs, respectively. The pts characteristics were well balanced between the two pts groups. Results: In the iv V group, of 38 evaluable pts, 14 (36.9%) achieved PR, 9 (23.6%) SD, and 15 (39.5%) PD, (overall disease control: 60.5%). With a median follow-up of 24 months (range 6–40+), the median TTP was 6.8 months (range 1–20.5+) and median survival was 11.3 months (range 6–40+). In the po V group, out of 38 pts, we observed 2 (5.3%) CR, 13 (34%) PR, 14 (36.9%) SD, and 9 (23.6%) PD (overall disease control: 76,3%). The median TTP was 7 months (range 2–18 months), and the median survival was 10 months (range 2–26+). A total of 462 courses were given with a mean of 6 cycles per patient (range 1–20). Grade 3–4 neutropenia was observed in 4 pts (9.4%) in the iv group vs 8 pts (21.6%) in the po group, respectively (p<.05). Moreover, G2-G3 anemia in 5 pts (13.5%) and G3 thrombocytopenia in 1 pt (2.7%) were observed only in the po group. Grade 2–3 hand foot syndrome and G2 diarrhoea were observed in 2 pts (5.4%) and in 3 pts (8%) in each group, respectively. Conclusions: The combination of CV, with V administered either iv or po, had comparable activity with overall disease control of 60.5 vs 76.3%, respectively. Toxicity was also similar, although po V induced significant more neutropenia. In conclusion, the full oral combination of CV represents a good treatment alternative for pts with pretrated ABC. No significant financial relationships to disclose.

A Randomized Multicenter Study of Optimal Circadian Time of Vinorelbine Combined with Chronomodulated 5‐Fluorouracil in Pretreated Metastatic Breast Cancer Patients: EORTC Trial 05971

Studies in animals synchronized with an alternation of 12 h of light and 12 h of darkness have showed that hematological and systemic toxicities could be reduced if vinorelbine were administered 19 or 23 hours after light onset (HALO), corresponding to 17:00 and 21:00 h in diurnally active humans. This trial aimed to define the least toxic time of vinorelbine administration in metastatic breast cancer patients. Initially, the study treatment consisted of three courses of vinorelbine of 30 mg/m2/d on D1 and D6 and chronomodulated 5‐fluorouracil of 850 mg/m2 from D2 to D5 every 21 days. Ninety metastatic breast cancer patients were randomized to receive vinorelbine at one of the eight possible dosing times. Further to the recommendations of the Independent Data Monitoring Committee, the vinorelbine dose was reduced to 25 mg/m2/d midway through the study. The primary objective of the study was detection of the least toxic time based on the incidence of grade 3–4 (G3–4) neutropenia. To show a significant result, the 90% confidence interval width of the least toxic time had to be<6 h. The least toxic time detection based on the incidence of other toxicities was also analyzed. The time of least drug toxic was estimated using a logistic regression model assuming that the logit transformation of the toxicity rate follows a sinusoidal distribution over 24 h. The bootstrap technique was used to obtain the 90% confidence interval. The least toxic time of G3–4 neutropenia was observed at 21:00 h with a non‐significant 90% CI. Secondary endpoint analyses indicated the least toxic time could differ when based on other toxicity parameters (e.g., a significant least toxic time of 17:00 h was observed for G3–4 leucopenia), in agreement with animal data. The least toxic time of 10:30 h was estimated for any G3–4 gastrointestinal toxicity. This results of this study do not allow us to recommend an optimal time for vinorelbine administration. It has highlighted, however, the inherent methodological difficulties in the conduct of such a trial in the human setting. It indicates that future optimal time‐finding trials should have tolerability and/or activity as the primary endpoint in place of a particular toxicity. The randomized optimal time‐finding design may be used to identify the best time of chemotherapy administration. (Author correspondence: bcoudert@dijon.fnclcc.fr)

Methods of preventing vinorelbine-induced phlebitis: an experimental study in rabbits.

In order to identify methods for preventing phlebitis caused by intravenous administration of vinorelbine (VNR), we established a procedure for estimating the severity of phlebitis in an animal model. Four different factors (administration rate, dilution, flushing, and infusion of fat emulsion) were evaluated for alleviation of phlebitis caused by VNR infusion. VNR was diluted with normal saline to prepare test solutions with concentrations of 0.6 mg/mL or 0.3 mg/mL for infusion into the auricular veins of rabbits. Two days after VNR infusion, the veins were subjected to histopathological examination. VNR did not cause obvious loss of venous endothelial cells, the most sensitive and common feature of phlebitis, but VNR infusion led to inflammatory cell infiltration, edema, and epidermal degeneration. Tissue damage was significantly decreased by shortening the administration time and by diluting the VNR solution for infusion from 0.6 mg/mL to 0.3 mg/mL. However, there was no effect of flushing with normal saline after VNR infusion, while treatment with fat emulsion before and after VNR infusion only had a minimal effect. Rapid infusion and dilution are effective methods of reducing phlebitis caused by the infusion of VNR, but the efficacy of flushing with normal saline or infusion of fat emulsion was not confirmed.