Hai Liao

Gefitinib alone or with concomitant whole brain radiotherapy for patients with brain metastasis from non-small-cell lung cancer: A retrospective study

BACKGROUND Gefitinib, a tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR), is used both as a single drug and concurrently with whole brain radiotherapy (WBRT) the standard treatment for brain metastases (BM), and is reported to be effective in a few small studies of patients with BM from non-small-cell lung cancer (NSCLC). However, no study has compared the two treatment modalities. This retrospective analysis was conducted to compare the efficacy of gefitinib alone with gefitinib plus concomitant WBRT in treatment of BM from NSCLC. METHODS We retrospectively reviewed 90 patients with BM from NSCLC who received gefitinib alone (250 mg/day, gefitinib group) or with concomitant WBRT (40 Gy/20 f/4 w, gefitinib-WBRT group) between September 2005 and September 2009 at Sun Yat-Sen University Cancer Center. Forty-five patients were in each group. RESULTS The objective response rate of BM was significantly higher in gefitinib-WBRT group (64.4%) compared with gefitinib group (26.7%, P<0.001). The disease control rate of BM was 71.1% in gefitinib- WBRT group and 42.2% in gefitinib group (P=0.006). The median time to progression of BM was 10.6 months in gefitinib-WBRT group and 6.57 months in gefitinib group (P<0.001). The median overall survival (OS) of gefitinib-WBRT and gefitinib alone group was 23.40 months and 14.83 months, respectively (HR, 0.432, P=0.002). CONCLUSION Gefitinib plus concomitant WBRT had higher response rate of BM and significant improvement in OS compared with gefitinib alone in treatment of BM from NSCLC.

Phase I and biodistribution study of recombinant adenovirus vector-mediated herpes simplex virus thymidine kinase gene and ganciclovir administration in patients with head and neck cancer and other malignant tumors

In this study, we investigated the safety and efficacy in cancer patients of a single intra-tumor injection of recombinant adenovirus vector-mediated herpes simplex virus thymidine kinase gene (AdV/TK) followed by systemic administration of ganciclovir (GCV). In 18 patients with malignant tumors refractory to standard treatment, AdV/TK was injected on day 1 with dose escalation from 2.5 × 1011 to 1 × 1012 virus particles (VP), and GCV (5 mg kg−1) was delivered intravenously every 12 h from days 2 to 15. The most common treatment-related toxicities were transient fever (10/18) and local injection site reaction (10/18), and most adverse events were WHO grade I/II. Anti-adenovirus antibody levels increased continuously during treatment, but anti-HSV antibody levels remained stable. One patient had a PR at the injection site but PD was found in the primary site (lung cancer), one patient with fibrosarcoma of the neck had an MR, five patients had SD, and 10 patients had PD. In conclusion, AdV/TK followed by GCV can be administered safely to Chinese cancer patients, and achieved a local response with few environmental effects. Because the response was localized, single regional tumor relapse, especially after radiation, may be an indication for this suicide gene therapy.

Pharmacokinetics and tolerability of vandetanib in Chinese patients with solid, malignant tumors: an open-label, phase I, rising multiple-dose study.

BACKGROUND Vandetanib (ZD6474) is an orally available inhibitor of 3 signaling pathways important in tumor progression: vascular endothelial growth factor receptor, epidermal growth factor receptor, and rearranged during transfection tyrosine kinase activity. Current development of vandetanib is focused on the treatment of non-small-cell lung cancer and other tumor types, including thyroid cancer. This study was conducted as a requirement for regulatory submission for vandetanib in China. OBJECTIVE To determine the pharmacokinetics of vandetanib in Chinese patients with advanced, solid, malignant tumors and to compare these with data obtained in Japanese and Western populations. METHODS Phase I consisted of a nonrandomized, open-label, single-center study conducted in Guangzhou, China. Adult patients (12 per treatment) who had tumors refractory to standard treatments or for whom no appropriate therapies existed received oral vandetanib (100 mg every other day, 100 mg once daily, or 300 mg once daily) until disease progression or discontinuation in the study. The initial cohort was dosed at 100 mg every other day. Once at least 3 patients had received this dose of vandetanib for 28 days without experiencing dose-limiting toxicity, a second cohort at 100 mg once daily was started. Following the same criteria, the third cohort received 300 mg once daily. Pharmacokinetics, tolerability, and tumor response were assessed. The pharmacokinetics of vandetanib in Chinese, Western, and Japanese patients were compared through a combined population pharmacokinetic model. Tolerability was assessed by recording adverse events and monitoring physical examination, body weight, performance status, vital signs, urinalysis, biochemistry, hematology, and 12-lead electrocardiogram. RESULTS Thirty-six patients were enrolled (age range 21-82 years, 56% male, body mass index range 17.6-33.0 kg/m(2)). Thirty-three of 36 patients (92%) were World Health Organization performance status 0-1. Vandetanib pharmacokinetics were linear over the dose range studied with AUC(ss) for the 300 mg once daily group (38611 ng/h/mL) being 3.6-fold higher than that for the 100 mg once daily group (10826 ng/h/mL). Absorption was relatively slow following a single 100- or 300-mg dose, with T(max) ranging from 2 to 10 hours. Interpatient variability in C(max SS) and AUC(SS) was relatively high, with the coefficient of variation ranging from 29.1% to 40.6%. Vandetanib plasma clearance was slow (7.8-9.2 L/h) and was independent of dose. The most common drug-related adverse events were rash (42%) and diarrhea (39%). No QT(C) prolongation was observed. Hypertension was reported as an adverse event in 3 patients. There were no clinically relevant changes in hematology, urinalysis, or World Health Organization performance status. Elevation of alanine aminotransferase was reported as an adverse event in 1 patient. One patient with medullary thyroid cancer showed a partial tumor response. Population pharmacokinetic analysis suggests that vandetanib pharmacokinetics appear to be comparable in Chinese, Western, and Japanese patients. CONCLUSIONS The pharmacokinetic properties of vandetanib in these Chinese patients were characterized by low plasma clearance of approximately 8 L/h, a long half-life of approximately 8 to 10 days, and an accumulation of approximately 8-fold to 15-fold on multiple dosing. In these Chinese patients, the pharmacokinetic profile of vandetanib appeared to be comparable with that observed in Japanese and Western populations. Oral doses up to 300 mg once daily appeared to be well tolerated.

Selective COX-2 inhibitor celecoxib combined with EGFR-TKI ZD1839 on non-small cell lung cancer cell lines: in vitro toxicity and mechanism study

Constitutive expression of cyclooxygenase-2 (COX-2) and epidermal growth factor receptor (EGFR) occurs frequently in non-small cell lung cancer (NSCLC). Anticancer research targeting EGFR has got an extensive attention especially in NSCLC and COX-2 inhibitor also shown a certain anticancer activity in recent years. Simultaneously targeting COX-2 and EGFR may be a promising therapeutic way. We carried out the in vitro study using selective COX-2 inhibitor celecoxib combined with EGFR-tyrosine kinase inhibitor (EGFR-TKI) ZD1839 on NSCLC cell lines to investigate the anti proliferation effect and the cell molecular mechanism. MTT growth assay showed the synergistic therapeutic effect of certain concentration of celecoxib combined with ZD1839 and synergistic apoptosis effect was detected by Hoechest33258 fluorescence staining and flow cytometric analysis. In western blot analysis, ZD1839 single agent inhibited the activation of EGFR and downstream cell signal transduction AKT and extrocellular signal-regulated kinase (ERK) pathways, the transcription activity of nuclear factor-kappa B (NF-κB), and the expression of COX-2. Celecoxib single agent could also inhibit AKT and ERK pathway in NSCLC, even the EGFR expression under high concentration treatment. Celecoxib combined with ZD1839 led to stronger inhibition of related cell signal transduction pathways in NSCLC.

Changes of bone resorption marker (NTX) in chemotherapy plus zoledronic acid versus chemotherapy alone for nasopharyngeal cancer patients with bone metastases

BACKGROUND Zoledronic acid (ZOL) is the only bisphosphonate with demonstrated efficacy for the prevention of skeletal-related events (SRE) in patients with bone metastases of diverse malignant tumours. A recent large, retrospective analysis reported that a reduction in N-telopeptide of type I collagen (NTX) provided a continuum of reduced SRE risk and survival benefit in patients with bone metastases. The present prospective, open-label, randomised, phase II trial sought to evaluate NTX changes after ZOL administration in nasopharyngeal cancer (NPC) patients with bone metastases (BM). METHODS Newly diagnosed NPC patients (n = 60) with bone metastasis were randomised to the test group (n = 30), who received chemotherapy with cisplatin plus 5-fluorouracil (5-FU) (q3wks) and intravenous ZOL (4 mg, q4 wks) for 3 months, or a control group (n = 30), who received cisplatin plus 5-FU alone. Urinary NTX was measured by ELISA at baseline and 1, 2 and 3months after administration of ZOL. RESULTS The median baseline NTX level was no different in both the test and control patients (75.4 and 94.6 nM bone collagen equivalent units/mM creatinine, respectively; p = 0.370). NTX decreased by 61.5% within 1month in the test group, but only by 6.6% in the control group (p < 0.01). After 3 months, the test group reached a maximum reduction (-85.9%) as compared to the other time points and to the control group (-51.5%) (p = 0.001). More patients in the test group achieved normal NTX than that in the control group (p=0.042). CONCLUSIONS ZOL administered with chemotherapy immediately and consistently reduced NTX levels for NPC patients with bone metastasis. Larger prospective randomised trial to confirm the efficacy of ZOL in NPC patients with bone metastases is pending.

Phase I clinical trial of the novel platin complex dicycloplatin: Clinical and pharmacokinetic results

UNLABELLED TRANSLATIONAL RELEVANCE: Dicycloplatin (DCP) is a novel super molecule composed of carboplatin (CBP) and 1,1-cyclobutane dicarboxylate (CBDCA) joined by a strong hydrogen bond. The solubility and stability of platinum complexes have a direct bearing on their activity, toxicity and pharmacokinetics. Preclinical studies have shown that DCP overcomes the problem of CBP instability in aqueous solution and maintains anticancer effects. Clinical evaluation in a Phase I dose-escalation study in patients with tumors showed that DCP was tolerated at doses ranging from 100 to 550 mg/m(2) and had potential efficacy in Chinese cancer patients. DCP showed favourable bioavailability and stability in vivo, and the recommended Phase II dosage for DCP-containing chemotherapy is 450 mg/m(2). DCP is currently being investigated as a monotherapy in several cancer types, such as prostatic carcinoma, and in combination with paclitaxel in a Phase II non-lung cancer study. PURPOSE Dicycloplatin (DCP) is a novel supramolecule composed of carboplatin (CBP) and 1,1-cyclobutane dicarboxylate (CBDCA) joined by a strong hydrogen bond. DCP is stable in aqueous solution unlike CBP alone. The purpose of this study was to assess the maximally tolerated dose, safety, and pharmacokinetics of DCP in Chinese cancer patients. EXPERIMENTAL DESIGN 29 patients were included in this study. DCP was administered by intravenous infusion over 1 hour once every 21 days. The dose of DCP was escalated from 50 mg/m(2) to 650 mg/m(2) using a modified Fibonacci scheme. Pharmacokinetic analysis was performed in 26 patients to determine the total and ultrafiltered platinum concentrations in plasma. RESULTS 29 and 20 patients were evaluated for toxicities and response, respectively. The primary adverse effects were nausea/vomiting (58.6%), thrombocytopenia (24.1%), neutropenia (17.2%), anemia (20.7%), fatigue (10.3%), anorexia (10.3%), liver enzyme elevation (10.3%) and alopecia (3.5%). There was no significant toxicity with doses up to 350 mg/m(2). At higher doses, a variety of dose-limiting toxicities (DLTs) were observed, including Grade 3/4 anemia, Grade 3/4 thrombocytopenia, and Grade 3/4 emesis under antiemetic treatment. The maximum tolerated dose of DCP was 550 mg/m(2). Two partial responses occurred in patients with non-cell lung cancer who had received cisplatin- or carboplatin-based chemotherapy. Plasma decay of total and free platinum concentrations was best fitted by using a twocompartment analysis. The terminal plasma half-life of total platinum after DCP administration ranged from 41.86 to 77.20 hours without significant dose dependency. However, the terminal plasma half-life of free platinum concentrations ranged from 42.34 to 61.07 hours. CONCLUSIONS DCP displayed a favorable safety profile at doses between 50 mg/m(2) and 550 mg/m(2), and first efficacy signals were observed. DLTs were thrombocytopenia, anemia and emesis. The recommended starting dose for a subsequent Phase II study is 450 mg/m(2) once every 3 weeks.

Phase II study of gemcitabine plus S-1 chemotherapy in recurrent and metastatic nasopharyngeal carcinoma patients after failure of platinum-based chemotherapy

Purpose: No standard salvage regimen has been established for patients with recurrent and metastatic nasopharyngeal carcinoma (NPC) and disease progression after prior platinum-based chemotherapy. This phase II study was designed to evaluate the efficacy and safety of gemcitabine plus S-1 (GS) chemotherapy as a remedial regimen in this setting. Methods: In this multicenter phase II study, 49 patients with recurrent and metastatic NPC who failed previous platinum-based chemotherapy received gemcitabine (1.0 g/m2 on days 1 and 8) plus oral S-1 chemotherapy (twice daily from day 1 to 14). Each cycle was repeated every 3 weeks for two cycles at least. The dose of S-1 was determined according to the body surface area (BSA): 40 mg twice a day for BSA <1.25 m2; 50 mg twice a day for 1.25 m2 ⩽ BSA <1.5 m2; and 60 mg twice a day for BSA ⩾1.5 m2. Results: Treatment was generally well-tolerated. A total of seven patients (14.3%) had grade 3 toxicities and the main toxicity was myelosuppression, whereas the nonhematology adverse events were minimal. There were 3 complete responses (6.4%), 17 partial responses (36.2%), and the overall response rate was 42.6% (95% confidence interval: 27.3–61.2). Median time to progression was 5.8 months and median survival was 14.8 months. The 1- and 2-year survival rates were 64% and 30%, respectively. Conclusions: Gemcitabine plus S-1 offers a satisfactory clinical activity and an acceptable safety profile for recurrent and metastatic NPC patients after failure of platinum-based chemotherapy.

Phase II trial of docetaxel combined with nedaplatin for patients with recurrent and metastatic nasopharyngeal carcinoma

Purpose This Phase II trial was designed to evaluate the efficacy and safety of docetaxel combined with nedaplatin as first-line treatment for patients with recurrent or metastatic nasopharyngeal carcinoma. Methods In this multicenter Phase II trial, the patients were treated with intravenous docetaxel (75 mg/m2, day 1) and nedaplatin (80 mg/m2, day 1), each cycle repeated every 3 weeks for two cycles at least. Results From January 2010 to November 2013, a total of 78 patients were recruited in this trial. Among them, 73 patients were assessable for response. The treatment was well tolerated. The main hematological adverse event was neutropenia. A total of 12 patients (15.4%) had grade 3 or grade 4 neutropenia. Grade 3 anemia was observed in six patients (7.7%) and no grade 3/4 thrombocytopenia was observed. No Grade 3/4 non-hematological toxicity was observed. There were five complete response (6.8%), 43 partial responses (58.9%), and the overall response rate was 65.8% (95% confidence interval [CI], 48.7%–81.2%). With a median follow-up period of 18.6 months, the median time to progression was 7.9 months (95% CI, 4.2–10.8 months), median overall survival was 15.7 months (95% CI, 11.6–18.5 months). Conclusion Docetaxel combined with nedaplatin offers a satisfactory clinical activity and an acceptable safety profile as first-line chemotherapy for patients with recurrent and metastatic nasopharyngeal carcinoma.

Multi-institutional prospective study of nedaplatin plus S-1 chemotherapy in recurrent and metastatic nasopharyngeal carcinoma patients after failure of platinum-containing regimens

Background: In this multi-institutional prospective study, we aimed to assess the safety and efficacy of nedaplatin plus S-1 (NS) chemotherapy for patients with recurrent and metastatic nasopharyngeal carcinoma (NPC) when platinum-containing regimens failed. Methods: A total of 52 recurrent and metastatic NPC patients who previously received, but failed with platinum-containing chemotherapy, had oral S-1 chemotherapy (twice daily from the first day to the fourteenth day) and nedaplatin (80 mg/ m2, day 1) every 3 weeks. The body surface area (BSA) decided the dose of S-1: 40 mg twice a day when BSA < 1.25 m2; 50 mg twice daily when 1.25 m2 ⩽ BSA < 1.5 m2; and 60 mg twice daily when BSA ⩾ 1.5 m2. Results: Treatment was well tolerated. The main hematological adverse event was neutropenia. Five patients (9.6%) had grade 3 neutropenia. Three patients were found with grade 3 anemia (5.8%). One patient was found with grade 3 thrombocytopenia (1.9%). No patient was found with grade 3 or 4 nonhematological toxicity. The rates of complete response, partial response and overall response were 3.8%, 38.5% and 42.3%, respectively. Median time to progression was 6.2 months and median survival was 14.6 months. The rates of 1-year survival and 2-year survival were 63% and 27%, respectively. Conclusions: NS chemotherapy provides a satisfactory and safe clinical activity for patients with recurrent and metastatic NPC after platinum-containing chemotherapy failed.

Determination of Photocyanine in Human Serum by HPLC and Application to Pharmacokinetic Study

Photocyanine, a novel amphoteric phthalocyanine drug, showed favorable anticancer activity in vivo. Pharmacokinetic study in cancer patients is an important component in dose administration choice. In this study, a rapid, sensitive analytical method based on high-performance liquid chromatography with ultraviolet detection was developed and validated for the determination of four isomers of photocyanine (FD1-4) in cancer patients. Sample preparation involved liquid-liquid extraction with a combination of ultrasound and N,N-dimethyl formamide. Calibration curves (1/x(2)) offered satisfactory linearity for the four isomers of photocyanine. The lower limit of quantification (LLOQ) for FD1-3 isomers was 30 ng/mL, and LLOQ for FD-4 was 5 ng/mL. Inter- and intra-day accuracies for four isomers ranged from 96.6 to 105.5%, and 95.0 to 103.6%, respectively. Inter- and intra-day precision ranged from 4.8 to 8.9%, and 3.6 to 12.2%, respectively. Stability studies showed that photocyanine was stable. This method was successfully used to quantify photocyanine in a pharmacokinetic study in which a single-dose of photocyanine (0.1 mg/kg) was intravenously administered to patients with cancer. On the basis of the discovery that photocyanine has a half-life of 57.5 h in vivo, we suggest that avoiding light for a longer period is essential for patients undergoing photocyanine therapy.