Sequential Administration Of Docetaxel Research Articles

Interactions between anti-EGFR therapies and cytotoxic chemotherapy in oesophageal squamous cell carcinoma: why clinical trials might have failed and how they could succeed

PurposeOesophageal squamous cell carcinoma (ESCC) has a poor prognosis. Advanced tumours are treated with fluoropyrimidine/platinum chemotherapy followed by irinotecan or taxane monotherapy, but resistance is common and new treatments are needed. Approximately 20% of ESCCs carry copy number gain (CNG) of the epidermal growth factor receptor (EGFR) gene. Previous trials show that while anti-EGFR monotherapy benefits biomarker-selected patients with EGFR CNG and/or high EGFR expression, combining anti-EGFR therapies with platinum fluoropyrimidine chemotherapies is not effective, and uncertainty remains regarding the optimal cytotoxic chemotherapy partner for anti-EGFR therapies in ESCC.MethodsThe effects of EGFR CNG on fluoropyrimidine/platinum chemotherapy sensitivity in a cohort of gastroesophageal cancer patients (n = 302) was evaluated. Drug combination studies using the EGFR inhibitor gefitinib with cytotoxic chemotherapies, docetaxel, cisplatin, oxaliplatin and irinotecan, on cell proliferation and cell death of EGFR CNG ESCC cell lines were assessed.ResultsEGFR CNG in gastroesophageal cancer patients was associated with improved overall survival following fluoropyrimidine/platinum chemotherapy. However, co-administration of gefitinib and oxaliplatin or cisplatin was frequently antagonistic in cell-based assays in EGFR CNG ESCC, whereas the combination of gefitinib with docetaxel or irinotecan was more efficacious. Co-administration of gefitinib/docetaxel and sequential administration of docetaxel before gefitinib showed synergy, but docetaxel given after gefitinib was antagonistic.ConclusionGefitinib/platinum co-administration demonstrated antagonism suggesting a possible explanation for the lack of benefit from addition of anti-EGFR therapies to fluoropyrimidine/platinum chemotherapy in trials. Gefitinib/docetaxel co-administration demonstrated synergy suggesting taxanes could be the most effective cytotoxic partner for anti-EGFR therapies in EGFR CNG-positive ESCC, but careful consideration of drug scheduling is required.

Sequence-dependent antiproliferative effects of gefitinib and docetaxel on non-small cell lung cancer (NSCLC) cells and the possible mechanism.

PurposeRecent clinical trials showed that the sequential combination of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and chemotherapy could prolong the PFS and/or OS of advanced non-small cell lung cancer (NSCLC) patients with EGFR mutation. The aim of present study was to assess the optimal combination sequence and to explore its possible mechanism.MethodsPC-9 cells and A549 cells, the lung adenocarcinoma cells with mutant and wide-type EGFR respectively, were treated with docetaxel/gefitinib alone or in different combination schedules. The EGFR and K-ras gene status was determined by qPCR-HRM technique. Cell proliferation was detected by MTT assay. The expression and phosphorylation of EGFR, ERK, Akt and IGF-1R were detected by western blot. Cell cycle distribution was observed by flow cytometry.ResultsOnly sequential administration of docetaxel followed by gefitinib (D→G) induced significant synergistic effect in both cell lines (Combination Index<0.9). The reverse sequence (G→D) resulted in an antagonistic interaction in both cell lines (CI>1.1), whereas the concurrent administration (D+G) showed additive (0.9<CI<1.1)-synergistic effect in PC-9 cells and antagonistic-additive effect in A549 cells. Mechanism studies showed that docetaxel-induced phosphorylation of EGFR and ERK was repressed by subsequently used gefitinib, but not by concurrent exposure of gefitinib. The gefitinib-repressed phosphorylation of EGFR and ERK was reversed neither by concurrent nor by subsequent administration of docetaxel. D+G reinforced their inhibition on the phosphorylation of IGF-1R in PC-9 cells.ConclusionsThe cytotoxic drugs followed by EGFR-TKIs may be the optimal combination for antiproliferative effects in EGFR-mutant NSCLC cells, and the phosphorylation of EGFR and ERK might contribute to this effect.

Clinical benefits of sequential administration of docetaxel and intermittent erlotinib as a second-line therapy for advanced non-small cell lung cancer (NSCLC): A phase II randomized study.

e18049 Background: Patients (p) with advanced NSCLC have few treatment options after progressing to 1st-line platinum doublet chemotherapy. Several preclinical and phase I studies have suggested that sequential administration of erlotinib (E) and docetaxel could avoid possible negative interactions and optimize the benefit obtained against NSCLC. This randomized phase II was designed to address the clinical benefit obtained with the use of sequential administration of docetaxel and intermittent E. Methods: 70 p with advanced NSCLC progressing to previous PDC for advanced disease were randomized (1:1): Group A (n = 34): Docetaxel 75 mg/m2 day 1 and intermittent E (day 2-16), up to 4 cycles, followed by E in monotherapy; and Group B (n = 36): E in monotherapy. Treatment was administered until unacceptable toxicity or disease progression. Primary endpoint: rate of p free of progression at 6 months; secondary endpoints: progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and safety. The study has completed enrolment. At the date of cut-off for this communication, data of 60 patients were available: 30 in Group A/30 in Group B. Results: Baseline characteristics: non-adenocarcinoma (60.3%), current/former smokers (95%), male (90%) and stage IV (87.9%). 6 months PFS: 13.5% in the sequential arm. PFS: 2.7 months (m) in Group A (95% CI 2.1 – 3.8) and 2 m in Group B (95% CI 1.7 – 2.4) p value 0.08. Median OS: 11.0 m (95% CI 4.5 – 13.4) in group A and 4.7m (95% CI 2.5 – 6.6) in Group B with a p value 0.02. DCR: 44.4% in the experimental group whereas in the E one was 30.8%. Adverse events (AEs), including skin rash and diarrhea, were all generally tolerable. Of interest, the low number of p developing neutropenia in the D + E arm. Conclusions: Although the primary objective has not been met, an encouraging benefit on survival has been shown in the exploratory analysis, with a median overall survival of 11 months for patients treated with the sequential regimen (p value 0.02). Final data will be presented during the meeting.

Extended Benefit from Sequential Administration of Docetaxel after Standard Fluorouracil, Epirubicin, and Cyclophosphamide Regimen for Node-Positive Breast Cancer: The 8-Year Follow-Up Results of the UNICANCER-PACS01 Trial

The initial report from the Programme Action Concertée Sein (PACS) PACS01 trial demonstrated a benefit at 5 years for disease-free survival (DFS) and overall survival (OS) rates with the sequential administration of docetaxel after FEC100 (fluorouracil 500 mg/m(2), epirubicin 100 mg/m(2), and cyclophosphamide 500 mg/m(2)) for patients with node-positive, operable breast cancer. We evaluate here the impact of this regimen at 8 years. Between June 1997 and March 2000, a total of 1,999 patients (age <65) with localized, resectable, non-pretreated, unilateral breast cancer were randomly assigned to receive either standard FEC100 for 6 cycles or 3 cycles of FEC100 followed by 3 cycles of 100 mg/m(2) docetaxel (FEC-D), both given every 21 days. Radiotherapy was mandatory after conservative surgery and tamoxifen was given for 5 years to hormone receptor (HR)-positive patients. Five-year DFS was the trial's main endpoint. Updated 8-year survival data are presented. With a median follow-up of 92.8 months, 639 patients experienced at least one event. A total number of 383 deaths were registered. Eight-year DFS rates were 65.8% with FEC alone and 70.2% with FEC-D. OS rates at 8 years were 78% with FEC alone and 83.2% with FEC-D. Cox regression analysis adjusted for age and number of positive nodes showed a 15% reduction in the relative risk of relapse and a 25% reduction in the relative risk of death in favor of FEC-D. Significant relative risk reductions were observed in the HR-positive, HER2-positive, and Ki67 ≥20% subpopulations. Benefits for DFS and OS rates with the sequential FEC-D regimen are fully confirmed at 8 years.

Abstract 3710: Preclinical dose scheduling studies of LOR-253, a novel anticancer drug, in combination with chemotherapeutics in lung and colon cancers

Abstract LOR-253 is an anticancer small molecule that is currently in a Phase I clinical study in patients with advanced or metastatic solid tumors. LOR-253 has a novel anticancer mechanism based on chelation of intracellular labile zinc, leading to inhibition of angiogenesis as well as G1/S cell cycle arrest due to induction of the tumor suppressor Kruppel-like factor 4 (KLF4). In preclinical studies, LOR-253 has shown potent antitumor activity against several cancers, including non-small cell lung cancer (NSCLC) and colon cancer, without significant toxicity. To support the clinical development of LOR-253 in combination with chemotherapeutics, we investigated the effect of dose scheduling of LOR-253 plus chemotherapy agents on anticancer activity in NSCLC (H226) and colon cancer (SW620) cell lines. Treatment of H226 cells in vitro with docetaxel, paclitaxel, or cisplatin for two days followed by increasing doses of LOR-253 resulted in significantly higher anti-proliferative activity than either agent alone. Assessment of drug interactions by determination of the combination index (D) (Berenbaum MC, Adv Cancer Res., 1981; 35:269-335) showed that the anticancer activities of the combination of LOR-253 with these chemotherapy agents were synergistic (D &amp;lt; 1). In studies with LOR-253 and docetaxel, synergistic anticancer activity against H226 was maintained with either concurrent or sequential treatments of each agent. Anticancer synergy was also seen in SW620 cells treated with LOR-253 in combination with oxaliplatin, CPT-11, or Fluorouracil. The effects of dose scheduling on activity of LOR-253 and docetaxel in vivo was also examined. Nude mice with H226 tumor xenografts were treated with repeat cycles of docetaxel once per week, followed two days later by treatment with LOR-253 for three consecutive days. Docetaxel was administered at an experimentally-determined ED50 dose level (defined as the effective dose at which 50% of mice showed tumor growth inhibition), while LOR-253 was given at its maximum efficacious dose in this model (10 mg/kg) or sub-optimal dose (5 mg/kg). Sequential administration of docetaxel followed by LOR-253 showed significant antitumor activity when docetaxel was given at either ED50 or sub-ED50 doses plus 10 mg/kg of LOR-253, compared to either agent alone given at the same dose, or with concurrent administration of LOR-253 and docetaxel at these dose levels. Preliminary results also show significant antitumor activity of LOR-253 plus docetaxel against H226 tumors in mice treated with repeat cycles of the reverse order of these treatments (LOR-253 for three days, followed by docetaxel 1X/week). In summary, dose scheduling studies with LOR-253 plus chemotherapy drugs demonstrate strong anticancer activities in NSCLC and colon cancer, providing support for the design of LOR-253 combination strategies for treatment of these cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3710. doi:1538-7445.AM2012-3710

9121 POSTER A Multi-center, Open, Randomized, Phase II Study to Investigate the Sequential Administration of Docetaxel and Intermittent Erlotinib Versus Erlotinib as a Second-line Therapy for Advanced Non-small Cell Lung Cancer (NSCLC)

9121 POSTER A Multi-center, Open, Randomized, Phase II Study to Investigate the Sequential Administration of Docetaxel and Intermittent Erlotinib Versus Erlotinib as a Second-line Therapy for Advanced Non-small Cell Lung Cancer (NSCLC)

Synergistic interaction between sunitinib and docetaxel is sequence dependent in human non–small lung cancer with EGFR TKIs-resistant mutation

Previous studies have demonstrated that sunitinib has the anti-tumor activity in human non-small cell lung cancer (NSCLC). This study was aimed to investigate the efficacy of single use of sunitinib and that of concurrent or sequential administration of sunitinib and docetaxel in NSCLC cell lines that are resistant to EGFR TKIs. NSCLC cell lines with EGFR T790M mutation and K-ras mutation were exposed to either sunitinib or docetaxel or both based on various sequential administrations. After exposure, the cell viability was measured by MTT assay, cell cycle distribution was analyzed by flow cytometry, and alterations in signaling pathway were determined by immunoblotting. Sunitinib exhibited dose-dependent growth inhibition in NSCLC cell lines and arrested cell cycle at G1 phase, whereas docetaxel arrested at S phase. Although single or concurrent use of sunitinib and docetaxel has some anti-proliferative effects, the sequential administrations of both drugs remarkably enhanced anti-tumor activity. When cells were exposed to docetaxel followed by sunitinib, synergism was observed. The molecular basis of this synergism is that the signaling pathways that were initially activated by docetaxel exposure were efficiently suppressed by the subsequent exposure to sunitinib. In contrast, the reverse of this sequential administration resulted in antagonism, which may be due to differential effects on cell cycle arrest. Sunitinib as a single agent exhibits anti-proliferative effects in vitro in NSCLC cell lines with EGFR T790M and K-ras mutations but the sequential administration of docetaxel followed by sunitinib is superior to sunitinib followed by docetaxel and concurrent administration.

Concurrent and sequential administration of sunitinib malate and docetaxel in human non-small cell lung cancer cells and xenografts

Optimal scheduling of chemotherapy with molecular-targeted agents is important to maximize clinical benefit. We compared the effects of concurrent and sequential administration of docetaxel and multi-target inhibitor sunitinib malate on tumor cells and xenografts and studied several mechanisms involved in drug interaction to provide experimental data in support of their clinical use in non-small cell lung cancer (NSCLC). Human umbilical vein endothelial cells (HUVECs), NCI-H460 human non-small lung carcinomas cells, and NCI-H460 xenograft were treated with docetaxel and Sunitinib malate, using concurrent and sequential treatment schedules. Cell proliferation was detected by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)- 2H-tetrazolium (MTS) assay. Cell cycle analysis was conducted using flow cytometry. Extracellular signal-regulated kinases (ERK1/2) phosphorylation was evaluated by immunoblot analysis. Effects on xenografts were assessed by tumor growth delay. There were no significant difference in the cell proliferation and cell cycle distribution of NCI-H460 cells between concurrent treatment and the first sequential treatment. Both docetaxel and sunitinib malate had no effect on each other in inhibiting ERK1/2 phosphorylation in sequential treatments, while docetaxel eliminated inhibitory activity of sunitinib malate on ERK1/2 phosphorylation in concurrent treatment. For NCI-H460 xenografts, the first sequential treatment showed superior effect to concurrent treatment on inhibiting tumor growth. Combined treatment with sunitinib malate and docetaxel had a greater therapeutic effect than monotherapy, and the first sequential scheduling was more effective than concurrent scheduling, which partly due to the effect of docetaxel on receptor tyrosine kinase (RTK) signaling pathway.

Benefit of the Sequential Administration of Docetaxel after Standard FEC Regimen for Node-Positive Breast Cancer: Long-Term Follow-Up Results of the FNCLCC-PACS 01 Trial.

Abstract Objective: To evaluate the long-term impact on disease-free survival (DFS) and on overall survival (OS) of the sequential administration of docetaxel (D) following FEC100 among patients (pts) with node positive, operable breast cancer.Patients and Methods: Pts with localized, resectable, non pre-treated, unilateral breast cancer were randomly assigned to receive either Arm A: 6 cycles of FEC100 (5FU/epirubicin/cyclophosphamide 500/100/500 mg/m² day 1, every 3 weeks), or Arm B: 3 cycles of FEC100 followed by 3 cycles of docetaxel (D) 100 mg/m² (day 1, every 3 weeks). First chemotherapy cycle was to be started no more than 42 days after surgery. Radiotherapy was mandatory after conservative surgery and hormone therapy was given for 5 years if tumors were positive for at least one hormone receptor. Main inclusion criteria were: age &amp;lt; 65 years, at least one positive node, no metastasis and normal cardiac, hematologic and renal functions. The main end-point of this prospective, non blinded, randomized, multicentre phase III trial was the 5-year DFS. These results have been already published (Roché et. al. J Clin Oncol. 2006 24(36):5664-71). Since this first analysis, survival data have been updated.Results: Between June 1997 and March 2000, 1999 pts were recruited. Main pts characteristics were well balanced between the 2 arms: median age 50 years, conservative surgery 57%, grade III 39%, both HR negative 21%, both HR positive 60%, 1-3 involved nodes 62%. Treatment was completed for 95% and 93.4% of pts in arms A and B, respectively.As of 15 April 2009, with a median long term follow-up of 92.8 months, 639 pts have experienced at least one event: 124 loco regional relapses, 421 metastasis, 68 contra lateral breast cancer, and 26 deaths as first event. A total number of 71 second cancers and 383 deaths have been registered.8-year DFS rates were 65.8% with FEC and 70.2% with FEC-D. Cox regression analysis adjusted for age and number of positive nodes showed a 15% reduction in the relative risk of relapse with FEC-D (HR = 0.846 [95%CI 0.724 – 0.988], p=0.03).8-year OS rates were 78% with FEC and 83.2% with FEC-D. Cox regression analysis adjusted for age and number of positive nodes showed a 25% reduction in the relative risk of death with FEC-D (HR = 0.754 [95%CI 0.616 – 0.922], p=0.006).Conclusion: Initial report of 5-year benefit in DFS and OS with sequential administration of FEC followed by D are fully confirmed at 8 years. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 603.

Sequential administration of docetaxel followed by epirubicin plus cyclophosphamide versus FE 75C as adjuvant chemotherapy in axillary lymph node-positive breast cancer. A subgroup analysis for patients over 65 years of age, of a randomized phase III trial of Hellenic Oncology Research Group (HORG)

Anthracyclines and taxanes are among the most effective agents in the treatment of advanced breast cancer, refractory or non-responsive to endocrine manipulation. Several recently published phase III studies have addressed the role of these compounds in combination compared with established chemotherapy regimens. This report considering a total of 4244 patients evaluates the data of those trials with respect to the efficacy and toxicity of the treatment regimens. Currently, evidence is growing that especially patients with symptomatic visceral tumour spread may benefit from the combined application of anthracyclines and taxanes. Adequately dosed polychemotherapy appears to be more successful than monotherapy, and, at present, the combination of anthracyclines (doxorubicin, epirubicin) and taxanes (docetaxel (Doc), paclitaxel (Pac)) might lead to a promising approach to improve the course of the metastatic disease.

Sequential administration of docetaxel followed by maintenance gefitinib, as salvage treatment in patients with advanced NSCLC: A multicenter phase II trial

To evaluate the activity and toxicity of the sequential administration of docetaxel followed by gefitinib in patients with advanced non-small cell lung cancer (NSCLC). Forty-one patients pre-treated with at least one prior chemotherapy regimen (platinum- or taxane-based) for advanced/metastatic NSCLC received three cycles of docetaxel 30 mg/m2, administered as a 1-h IV infusion, on days 1, 8 and 15 of each 4-week cycle followed by gefitinib 250 mg daily po. Gefitinib treatment was continued until disease progression, development of unacceptable toxicity, or withdrawal of patients consent. Two (4.9%) patients achieved a partial response and 10 (24.4%) stable disease, for a disease control rate of 29.3% (95% CI: 15.3%-43.2%) while on weekly docetaxel treatment. Additionally, progressive disease (PD) was observed in 29 (70.7%). No objective responses were observed during the gefitinib maintenance therapy; however, 17 (41.5%) patients presented stable disease maintained for more than 2 months. Median time to progression was 3.0 months (range: 1-38.3 months; 95% CI: 2.4-3.6); median overall survival 6.9 months (range: 1.2-40.2 months; 95% CI: 5.34-8.52) while the 1-year survival was 28.8%. Therapy was generally well tolerated with diarrhea and rash being the most frequent toxicities. The sequential administration of docetaxel and gefitinib was well tolerated and moderately active against advanced pre-treated NSCLC.

Survival Benefit with Capecitabine/Docetaxel Versus Docetaxel Alone: Analysis of Therapy in a Randomized Phase III Trial

In a large phase III trial of 511 patients with anthracycline-pretreated advanced/metastatic breast cancer, capecitabine/docetaxel combination therapy was shown to have significantly superior efficacy compared with single-agent docetaxel, including superior progression-free and overall survival and objective response rate. An updated survival analysis with ≥ 27 months follow-up shows that patients receiving combination therapy maintained significantly superior survival (hazard ratio [HR], 0.777 [95% CI, 0.645–0.942]; P < 0.01; median survival, 14.5 months vs. 11.5 months) compared with those receiving single-agent docetaxel. Following the failure of docetaxel monotherapy, 35% of patients did not receive additional cytotoxic chemotherapy. Among patients randomized to single-agent docetaxel, only those given poststudy single-agent capecitabine had significantly prolonged survival compared with those given any other poststudy chemotherapy (HR, 0.500; P = 0.0046; median survival, 21.0 months vs. 12.3 months, respectively). By contrast, poststudy vinorelbine-containing chemotherapy did not affect survival following progression on single-agent docetaxel compared with other poststudy chemotherapy regimens (HR, 1.014; P = 0.94; median survival, 13.5 months vs. 12.6 months, respectively). Among patients randomized to combination therapy, discontinuing docetaxel of capecitabine has a similar effect on survival (HR, 0.720; P = 0.20; median survival, 15.8 months vs. 18.3 months, respectively). Median survival was 18.3 months in patients who discontinued docetaxel and continued to receive capecitabine versus 15.8 months in patients who discontinued capecitabine and continued to receive docetaxel, with a trend toward improved survival in patients continuing to receive capecitabine. Although this is a retrospective analysis, these data suggest that the sequential administration of docetaxel followed by capecitabine is associated with prolonged survival in patients who are candidates for sequential single-agent therapy.

A Phase II Study of Sequential Docetaxel Followed by Doxorubicin/Cyclophosphamide as First-Line Chemotherapy For Metastatic Breast Cancer

This phase II study assessed the activity and toxicity profile of the sequential administration of 3 cycles of docetaxel (100 mg/m 2 every 3 weeks) followed by 3 cycles of AC (doxorubicin/cyclophosphamide; 60/600 mg/m 2 every 3 weeks) as first-line chemotherapy in 30 patients with metastatic breast cancer. The response rate was 60% after docetaxel and 73% after AC. This reflected an increase in the rate of complete response (from 7% after docetaxel to 17% after AC). The median duration of response was 10.5 months, and the median time to progression was 12.6 months. The median survival time had not been reached after a median follow-up of 23.2 months. The sequential treatment was generally well tolerated, with grade 3/4 neutropenia found in 20% and 14% of patients treated with docetaxel and AC, respectively. No cumulative myelosuppression was detected. The incidence of grade 3/4 nonhematologic toxicities was low. The sequential administration of docetaxel followed by AC showed a high antitumor activity and a good safety profile. The hematologic toxicity found is markedly lower than that found using concomitant chemotherapy with the same drugs. Our results support the design of phase III trials that directly compare a sequential schedule with a concomitant schedule of docetaxel plus AC (or with doxorubicin only), focusing on the toxicity profile.

Alternating and sequential administration of docetaxel with fluorouracil, epirubicin and cyclophosphamide have similar safety profiles for metastatic breast cancer

Alternating and sequential administration of docetaxel with fluorouracil, epirubicin and cyclophosphamide have similar safety profiles for metastatic breast cancer

A sequence-dependent combination of docetaxel and vinorelbine: pharmacokinetic interactions

We studied possible pharmacokinetic interactions between docetaxel (DTX) and vinorelbine (VNR) in patients affected by different types of cancer. Patients with metastatic breast cancer or recurrent head and neck cancer received the following schedules: Protocol A: 11 patients were i.v. infused for 1 h with DTX (80 mg/m 2) at once, followed by VNR (25 mg/m 2) as slow i.v. bolus; Protocol B: VNR (25 mg/m 2) as a slow 10 min i.v. bolus was administered to 12 patients, immediately followed by 1 h i.v. infusion of DTX (80 mg/m 2). In both schedules, VNR and DTX plasma concentrations versus time were analysed by HPLC obtaining the corresponding non-compartmental pharmacokinetic parameters. VNR appeared pharmacokinetically affected by the sequential administration of DTX, since with protocol B, C max and AUC were significantly higher and clearance lower than in protocol A. Moreover, a significant increase in the VNR plasma level was observed in correspondence with the peak plasma level of DTX. By contrast, C max, AUC and clearance of DTX did not vary in the two protocols. Also the number of neutrophils at nadir on day 8 of treatment varied significantly in the two schedules. In conclusion we observed altered pharmacokinetic parameters between protocol A (DTX/VNR) and protocol B (VNR/DTX). In particular, patients following protocol B seemed to be exposed to higher VNR plasma concentration and to higher haematological toxicity.

A phase II study of sequential administration of docetaxel and vinorelbine with gemcitabine for inoperable stage III or IV non-small cell lung cancer (NSCLC)

A phase II study of sequential administration of docetaxel and vinorelbine with gemcitabine for inoperable stage III or IV non-small cell lung cancer (NSCLC)

D.I.G. — Phase I trial of sequential administration of docetaxel (D) followed 24 hs by gemcitabine (G) and irinotecan (I) in patients with solid tumors

D.I.G. — Phase I trial of sequential administration of docetaxel (D) followed 24 hs by gemcitabine (G) and irinotecan (I) in patients with solid tumors