Pharmacodynamic and pharmacokinetic study of pegylated liposomal doxorubicin combination (CCOP) chemotherapy in patients with peripheral T-cell lymphomas.

AIM: To investigate the pharmacodynamic and pharmacokinetic parameters of pegylated liposomal doxorubicin (PLD) combined with cyclophosphamide, vincristine, and prednisolone in patients with peripheral T-cell lymphomas (PTCL). METHODS: Seven chemonaive patients and four patients with relapsed peripheral T-cell lymphomas were treated with a CCOP regimen consisting of an intravenous administration of cyclophosphamide (750 mg/m(2)), vincristine (1.4 mg/m(2)), and PLD (30 mg/m(2)) on d 1, as well as an oral administration of prednisolone (60 mg/m(2)) on d 1-5. This regimen was repeated every 3 weeks for six cycles, and the clinical response and toxicity of the regimen were monitored. In addition, the plasma concentration of PLD at different time points was determined before and after treatment. The pharmacokinetics (PKs) software was used to estimate the pharmacokinetic parameters of PLD. RESULTS: The 11 PTCL patients received 35 treatment cycles. Three of them achieved complete response (CR), two partial response (PR), four stable disease (SD), and two progressive disease (PD). The overall response rate (ORR) was 45.5%, and the CR rate was 27.3%. In the 7 chemonaive patients, three achieved CR, two PR, one SD, and one PD. The ORR was 71.4%, and CR rate was 42.9%. The median follow-up time was 15 months, but 6 out of 11 patients were dead at the time of data analysis. The 1-year overall survival rate was 45.5%, and the median progression-free survival (PFS) rate was 6.5 [95% confidence interval (95% CI) 3.17-19.02] with a survival rate of 11.5 months (95% CI 6.65-16.36). The main toxicity was myelosuppression. Oral mucositis and hand-foot syndrome seldom occurred. The PLD plasma concentration from nine patients ranged from 1.7036 to 9.2207 mg·L(-1) after administration of the CCOP regimen (0-168 h). The pharmacokinetic parameters AUC(0-∞), CL, t(1/2), and V(d) were 910.76 mg/L·h, 0.043 L·h(-1)·m(-2), 68.40 h, and 3.56 L/m(2), respectively. CONCLUSION: The CCOP regimen was effective and well tolerated in patients with peripheral T-cell lymphomas. The results of the pharmacokinetic parameters showed that PLD had long retention time in blood circulation.

Phase II trial of gemcitabine plus cisplatin in patients with advanced non-small cell lung cancer.

AIM: To investigate the pharmacodynamics and pharmacokinetics of gemcitabine (dFdC) administered on d 1 and 5 plus cisplatin administered on d 1 in chemonaive patients with stage IIIB or IV non-small cell lung cancer (NSCLC). METHODS: In each combination cycle, gemcitabine was administered at a dose of 1250 mg/m(2) as a 30 min intravenous (iv) infusion on d 1 and 5 followed by cisplatin at a dose of 75 mg/m(2) as a 3 h iv infusion on d 1 every 3 weeks. There was an interval of 1 h between the two infusions. Clinical response and toxicity of the regimen were observed. Furthermore, the plasma concentrations of gemcitabine (dFdC) and its metabolite (dFdU) at different time points were detected during the first cycle of infusion. Pharmacokinetic software (PKS) was used to estimate the pharmacokinetic parameters of gemcitabine and its metabolite dFdU. RESULTS: A total of 28 patients was enrolled in the study. The median age was 54 years (range 27-75 years), and most patients were in good clinical condition. Twenty-seven patients received two or more treatment cycles. The overall clinical response rate was 33.3%. The median overall survival time was 13 months. The estimated median time to tumor progression (TTP) was 6.2 months, and the 1-year survival rate was 55.6%. Toxicities were tolerated. The main toxicity was myelosuppression; 35.7% of patients had grade 3/4 hematologic toxicities and 28.6% had grade 3/4 non-hematologic toxicities, which were commonly gastrointestinal responses. The pharmacokinetic parameters of dFdC and dFdU were not different between pre- and post-administration of gemcitabine on d 1 and 5. dFdU was minimal (0.729+/-0.637 microg/mL) before gemcitabine was infused on d 5, and gemcitabine was not present. CONCLUSION: The regimen is active and well tolerated in chemonaive patients with advanced NSCLC. After gemcitabine was administered on d 1 and 5, the pharmacokinetic parameters of dFdC and dFdU showed no difference from those before the infusion, and dFdU was minimal before gemcitabine was administered on d 5.

[Efficacy of salvage chemotherapy in the advanced non-small cell lung cancer patients who failed the treatment of chemotherapy and EGFR-TKI].

OBJECTIVE: Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) such as gefitinib and erlotinib are used as standard 2(nd)/3(rd) line therapy in previously treated advanced non-small cell lung cancer (NSCLC). However, the optimal treatment for patients who experienced disease progression after chemotherapy and EGFR-TKI is unclear. The aim of this study was to explore the efficacy and safety of a salvage chemotherapy in advanced NSCLC patients who failed the previous treatment of platinum-based chemotherapy and EGFR-TKI. METHODS: Clinicopathological data of 55 cases of advanced NSCLC patients who failure of first-line platinum-based chemotherapy and subsequent treatment with TKI were collected and analyzed. The patients were of PS = 0-2, and with normal vital organ function. Patients received salvage chemotherapy until disease progression or unacceptable toxicity or the patient refused to continue receiving treatment. A chart review assessed the key outcomes including the objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS). RESULTS: Fifty-five patients were enrolled in this study from march 2007 to october 2009. The median age of patients was 55 years (range: 34 - 72), 60.0% were males, PS 0-1 patients were 65.5%, stage IV patients were 100%; 34.5% had a TKI treatment duration ≥ 6 months. Twenty-four patients received pemetrexed as salvage chemotherapy, 21 received docetaxal and 10 had other chemotherapy. All patients were evaluable for efficacy. Among them, 7 (12.7%) patients achieved PR, 21 (38.2%) patients SD, and 27 (49.1%) patients PD, with ORR of 12.7% and DCR of 50.9%. The median follow-up duration was 5.5 months, and the median PFS was 2.0 months. The ORR and PFS were not significantly related with gender, PS and chemotherapy regimens (all P > 0.05), but patients with EGFR-TKI treatment ≥ 6 months achieved a significantly better ORR and DCR than those < 6 months (ORR: 21.1% vs. 8.3%, P = 0.012; DCR: 73.3% vs. 38.9%, P = 0.017), mPFS was significant longer in the patients received ≥ 6 months of EGFR-TKI (4.5 vs. 2.0 months, P = 0.008). The toxicity was acceptable and there were no treatment-related deaths. CONCLUSION: Advanced NSCLC patients failed with the previous treatment of first-line platinum-based chemotherapy and EGFR-TKI may benefit from salvage chemotherapy, especially in patients who received ≥ 6 months of EGFR-TKI. The toxicity of the salvage chemotherapy is acceptable.

[Efficacy of GDP regimen (gemcitabine, dexamethasone, and cisplatin) on relapsed or refractory aggressive non-Hodgkin's Lymphoma: a report of 24 cases].

BACKGROUND & OBJECTIVE: The prognosis of relapsed or refractory aggressive non-Hodgkin's lymphoma (NHL) after front-line therapy remains poor. The development of more effective and less toxic salvage regimens remains a major challenge. Gemcitabine is effective in treating lymphoma and, when combined with cisplatin, is effective for some solid tumors. This study was to evaluate the efficacy of GDP regimen (gemcitabine, dexamethasone, and cisplatin) on relapsed or refractory aggressive NHL, and observe the adverse events. METHODS: Patients with relapsed or refractory aggressive NHL, measurable disease, and had received previously at least one chemotherapy regimen were enrolled and treated with GDP regimen (gemcitabine 1000 mg/m2 on Days 1 and 8, dexamethasone 20-40 mg on Days 1-3, and cisplatin 25 mg/m2 on Days 1-3) every 3 weeks. The efficacy and adverse events were evaluated according to the WHO criteria. RESULTS: Twenty-four patients had received a total of 76 chemotherapy cycles, and were assessable for efficacy and adverse events. Five (20.8%) patients had complete response, 9 had partial response, 8 had stable disease, and 2 had progressive disease. The overall response rate (RR) was 58.3% for assessable patients; it was 57.1% for B-cell NHL patients and 60.0% for T-cell NHL patients (P=0.889). The median follow-up was 1.2 years. The 1-year overall survival rate was 41.7%; it was 42.9% in B-cell NHL patients and 40.0% in T-cell NHL patients (P=0.986). The occurrence rate was 37.5% for grade III/IV leucopenia, 25.0% for thrombocytopenia, and 16.7% for anemia in all patients. Non-hematologic toxicities were mild. There was no treatment-related death. Two patients proceeded to stem cell transplantation after salvage chemotherapy and obtained sufficient stem cells. CONCLUSION: GDP regimen is an effective and relatively nontoxic salvage chemotherapy regimen for relapsed or refractory aggressive NHL.

[MINE regimen for patients with relapsed or chemo-resistant invasive non-Hodgkin's lymphoma].

BACKGROUND & OBJECTIVE: Treatment of relapsed or refractory non-Hodgkin's lymphoma (NHL) remains problematic with no standard salvage chemotherapy regimen. This study was to evaluate the efficacy of MINE (mitoxantrone, mesna/ifosfamide and etoposide) regimen on relapsed or refractory NHL, and observe its toxicity. METHODS: Records of 38 patients with relapsed or refractory invasive NHL, treated with MINE regimen from Jan. 2001 to Jun. 2003, were reviewed. All patients had received at least 1 type of chemotherapy regimen (median, 2 types; range, 1-4 types) with a median of 6 chemotherapy cycles (range, 2-12 cycles). The patients received a median of 4 cycles (range, 2-6 cycles) of MINE regimen. RESULTS: The treatment outcome and adverse events of all patients were assessable. The overall response rate was 47.4%, with a complete response (CR) rate of 15.8%. The response rates were 57.7% in the 26 patients with B-cell lymphoma and 25.0% in the 12 patients with T-cell lymphoma. The 1- and 2-year survival rates were 34.2% and 7.9%, respectively. The major adverse event was myelosuppression: the prevalence of grade III-IV neutropenia was 39.5%, and that of grade III-IV thrombocytopenia was 13.1%. One patient suffered grade III liver toxicity. CONCLUSIONS: MINE regimen was effective for patients with relapsed or refractory invasive NHL, and its toxicity is well tolerated, but the response term is relatively short. Further clinical study on the application of MINE regimen is warranted.

[Detection of soluble Apo-1/Fas in plasma, pleural and ascites fluid of malignant tumor patients and its clinical significance].

OBJECTIVE: To study the changes of soluble Apo-1/Fas levels in plasma, pleural and ascites fluid of malignant tumor patients and to evaluate their clinical significance. METHODS: The soluble Apo-1/Fas levels were measured by enzyme-linked immunosorbent assay (ELISA) in the plasma of 157 malignant tumor patients and 25 normal controls as well as in the pleural and ascite fluids of 129 patients with various diseases. RESULT: The plasma soluble Apo-1/Fas levels in acute and chronic leukemia and multiple myeloma were significantly higher than those in normal controls (P <0.05). The plasma soluble Apo-1/Fas levels in chronic myeloid leukemia and chronic lymphocytic leukemia were significantly higher than those in acute myeloid leukemia and acute lymphocytic leukemia, respectively (P <0.05). After chemotherapy, the plasma soluble Apo-1/Fas levels in complete remission group were distinctly decreased(P <0.05),whereas the levels in no remission and recurrence groups remained high. Compared with normal controls, the plasma soluble Apo-1/Fas levels in solid tumors were significantly increased (P <0.01), and the levels in metastasis cancers were significantly higher than those in non-metastasis cancer (P <0.0 1). Simultaneously the levels in remission cancer patients after operation and radiotherapy were distinctly lower than those before treatment(P <0.01), but were significantly increased in recurrence cancer patients (P <0.01). The soluble Apo-1/Fas levels in pleural and ascites fluid of malignant tumors were significantly higher than those in tuberculous effusions and transudates. CONCLUSION: The soluble Apo-1/Fas levels in plasma, pleural and ascites fluid of malignant tumor patients are markedly increased, which might be associated with the progress of cancers. The changes of soluble Apo-1/Fas levels may be useful for understanding the pathologic process of cancers and to differential diagnosis of various pleural and ascites fluids.

[Detection of thrombomodulin in both plasma and tissue extracts of cancer patients and its clinical significance].

OBJECTIVE: To study the changes of thrombomodulin(TM) in both plasma and tissue extracts of cancer patients for evaluating its clinical significance. METHODS: Plasma TM levels were measured by enzyme-linked immunosorbent assay(ELISA) in plasma of 188 cancer patients and in 24 cancer tissue extracts including their adjacent normal tissue. RESULTS: The plasma TM levels both in cancer patients and in metastasis patients were significantly higher than that in controls [(33.47+/-14.25) microg/L/ (41.68 +/-16.96) micro/L, compared with (20.40+/-7.22) microg/L, P<0.01]. The plasma TM levels in cancer patients after operation decreased obviously [(18.45+/-9.96) microg/L, compared with (28.29+/-11.74) microg/L,P<0.01]. Whereas, the plasma TM levels in patients with recurrence and metastasis after operation increased obviously [(34.50+/-12.57 micro/L]. The plasma TM levels in metastasis of lung cancers, gastric cancers and pancreatic cancers were significantly higher than that in non-metastasis (P<0.05 approximate, equals 0.01) respectively, but no significant differences were found between controls and non-metastasis cancers including gastric cancers, pancreatic cancers, nasopharyngeal cancers, large intestine cancers and laryngeal cancers (P>0.05). The TM levels in cancer tissue extracts were significantly lower than that in their adjacent normal tissue extracts [(647.71+/-317.51)) microg/L,compared with (1455.63+/-772.22) microg/L,P<0.01]. On the contrary, the plasma TM levels in these cancers were higher than that in controls. CONCLUSION: The rise of plasma TM levels in cancer patients is associated with metastasis and diffusion of cancers. The TM levels can be used as an sensitive index for judging progression and metastasis of cancers.

[Detection and clinical significance of plasma urokinase-type plasminogen activator and its soluble receptor in patients with multiple myeloma].

OBJECTIVE: To study the plasma levels of urokinase-type plasminogen activator(u-PA) and its soluble receptor(suPAR )in patients with multiple myeloma(MM) and to evaluate their clinical significance. METHODS: Plasma u-PA and suPAR levels in 34 MM cases were measured with enzyme- linked immunosorbent assay (ELISA). The changes of plasma u-PA and suPAR levels in 6 MM cases were observed in succession before and after chemotherapy. RESULT: The plasma u-PA and suPAR levels of MM patients were significantly higher than those of controls. The plasma u-PA and suPAR levels in the progress period was significantly higher than those in the stable period of MM patients as well as in controls (P<0.01), whereas there were no significant difference between the stable period of MM patients and controls (P>0.05). Among 6 cases,the plasma u-PA and suPAR levels after chemotherapy were significantly lower than those before chemotherapy (P<0.05). MM patients with tumor cells >20% in bone marrow smear had higher levels of plasma u-PA and suPAR than those with tumor cells <19% (P<0.05 P<0.01). The plasma u-PA and suPAR levels were positively correlated with the levels of serum globulin and the percentage of tumor cells in bone marrow,but negatively correlated with the levels of serum albumin. CONCLUSION: Plasma u-PA and suPAR levels can serve as an index for clinical staging and assessing the therapeutic effect in MM patients.