Gemcitabine plus celecoxib (GECO) in advanced pancreatic cancer: a phase II trial

Introduction: Single agent gemcitabine (GEM) is the standard treatment of pancreatic adenocarcinoma. Celecoxib is a selective cyclooxygenase-2 (COX-2) inhibitor. Recent studies in human pancreatic tumor cell lines suggest an involvement of COX-2 in tumor-dependent angiogenesis and provide the rational for inhibition of the COX pathway as an effective therapeutic approach. The aim of this study is to evaluate the toxicity and activity of gemcitabine plus celecoxib. Patients and methods: Forty-two consecutive patients with histologically or cytologically confirmed pancreatic adenocarcinoma entered the trial. Twenty-six patients (pts) were metastatic, 16 pts had locally advanced disease. The schedule consisted of GEM 1,000 mg/m² (as a 30 min iv infusion) on days 1, 8 every 3 weeks and celecoxib 400 mg bid. Results: Four pts (9%) achieved a partial response and 26 (62%) had stable disease, gaining a total disease control in 30 pts (71% [95% CI, 58–84%]). Overall clinical benefit response was experienced by 23 pts (54.7% [95%CI, 38.6–70.1%]). Neither grade 4 neutropenia nor grade 3–4 thrombocytopenia was observed. Grade 3 neutropenia was detected in 19% of pts. Grade 3 non-hematological toxicity was as follows: hepatic toxicity 7%, nausea 2.3%. Three pts (7%) and 5 pts (12%) had respectively a minimum creatinine increase and edema. Median survival was 9.1 months (95% CI, 7.5–10.6 months). Conclusion: GEM in combination with celecoxib showed low toxicity, good clinical benefit rate and good disease control. Further clinical investigation is warranted.     

A phase II study of capecitabine plus gemcitabine in patients with locally advanced or metastatic pancreatic cancer

PURPOSE: This open-label, multicenter phase II study was conducted to investigate the efficacy and safety of capecitabine plus gemcitabine combination chemotherapy as first-line treatment in patients with locally advanced or metastatic pancreatic cancer. PATIENTS AND METHODS: We enrolled 63 patients who received capecitabine 830 mg/m(2) orally twice daily on days 1-21 plus gemcitabine 1000 mg/m(2) as a 30-min infusion on days 1, 8 and 15 every 4 weeks for up to six cycles. RESULTS: A total of 14 patients had partial responses giving an overall response rate of 22% (95% confidence interval [CI] 13-34%) in the intent-to-treat population. The median time to progression and overall survival were 3.9 months (95% CI 3.5-5.7) and 7.5 months (95% CI 5.0-10.0), respectively, and 1-year survival rate was 27.1% in the intent-to-treat population. Capecitabine plus gemcitabine was well tolerated. Grade 3 hematological adverse events were neutropenia (21%) and thrombocytopenia (2%); the only grade 4 hematological events were anemia (2%) and neutropenia (6%). Non-hematological adverse events were mainly gastrointestinal events and hand-foot syndrome, which affected 16% of patients. Grade 3/4 non-hematological events were infrequent. CONCLUSION: The combination of capecitabine plus gemcitabine appears to be active and well tolerated as first-line treatment in patients with advanced/metastatic pancreatic cancer.     

A phase I study of radiation therapy and twice-weekly gemcitabine and cisplatin in patients with locally advanced pancreatic cancer

PURPOSE: In vitro studies suggest that low-dose gemcitabine sensitizes cells to radiation therapy and that this effect persists for 48 h after drug exposure. Cisplatin is a radiation sensitizer and is also synergistic with gemcitabine in some in vitro tumor systems. Gemcitabine's radiosensitizing properties can theoretically be exploited by twice-weekly administration. This study assessed toxicity in patients with pancreatic cancer treated with radiation therapy, gemcitabine, and cisplatin. METHODS AND MATERIALS: Patients with locally advanced pancreatic or gastric cancer were eligible. Gemcitabine and cisplatin were given twice weekly for 3 weeks during radiation therapy (50.4 Gy in 28 fractions). The starting dose of gemcitabine was 5 mg/m(2) i.v. The starting dose for cisplatin was 5 mg/m(2). Chemotherapy doses escalated every 3 to 6 patients according to a standard Phase I study design. RESULTS: Twenty-four evaluable patients, all with pancreatic cancer, were treated on this protocol. Grade 3 neutropenia occurred in 2 patients, Grade 3 thrombocytopenia occurred in 2, and Grade 4 lymphopenia occurred in 1. There was no clear relationship between chemotherapy dose and hematologic toxicity. The most common Grade 3-4 nonhematologic toxic responses were vomiting (7 patients) and nausea (7 patients). Dose-limiting toxicity consisting of Grade 4 nausea and vomiting occurred in 2 of 3 patients at dose Level 6 (gemcitabine 45 mg/m(2) i.v. and cisplatin 10 mg/m(2) i.v.). Six patients were treated at dose Level 5 (gemcitabine 30 mg/m(2) i.v. and cisplatin 10 mg/m(2) i.v.) without dose-limiting toxicity. CONCLUSION: Gemcitabine 30 mg/m(2) i.v. twice weekly and cisplatin 10 mg/m(2) i.v. twice weekly may be given concurrently with radiation therapy (50.4 Gy in 28 fractions) with acceptable toxicity.     

奥沙利铂联合吉西他滨治疗晚期胰腺癌的临床观察

目的:观察奥沙利铂联合吉西他滨治疗晚期胰腺癌的疗效及不良反应。方法:经影像学诊断的晚期胰腺癌18例,使用奥沙利铂85mg/m2,静脉滴注2小时,第1、8天;吉西他滨835mg/m2,静脉滴注30分钟,第1、8天,21天为1周期,至少用2周期后评价疗效。结果:18例均可评价,获得CR1例,PR3例,总有效率22·2%(4/18)。主要不良反应为骨髓抑制、外周神经毒性及恶心呕吐,无化疗相关死亡。结论:奥沙利铂联合吉西他滨治疗晚期胰腺癌患者疗效较好,不良反应可以耐受,值得深入研究。     

Concurrent gemcitabine and radiotherapy with and without neoadjuvant gemcitabine for locally advanced unresectable or resected pancreatic cancer: a phase I-II study

PURPOSE: To determine the safety, efficacy, and tolerability of biweekly gemcitabine with concurrent radiotherapy (RT) for resected and locally advanced (LA) pancreatic cancer. METHODS AND MATERIALS: Eligible patients had either LA or resected pancreatic cancer. Between March 1999 and July 2001, 63 patients (31 with LA and 32 with resected disease) were treated. Of the 63 patients, 28 were enrolled in a Phase I study of increasing radiation doses (35 Gy [n = 7], 43.75 Gy [n = 11], and 52.5 Gy [n = 10] given within 4, 5, or 6 weeks, respectively, in 1.75-Gy fractions) concurrently with 40 mg/m(2) gemcitabine biweekly. Subsequently, 35 were enrolled in a Phase II study with the addition of induction gemcitabine 1000 mg/m(2) within 7 or 8 weeks to concurrent biweekly gemcitabine (40 mg/m(2)) and 52.5 Gy RT within 6 weeks. RESULTS: In the LA population, the best response observed was a complete response in 1, partial response in 3, stable disease in 10, and progressive disease in 17. In the phase II trial, gemcitabine plus RT was not delivered to 8 patients because of progression with induction gemcitabine alone (n = 5) or by patient request (n = 3). On intent-to-treat analysis, the median survival in the LA patients was 13.9 months and the 2-year survival rate was 16.1%. In the resected population, the median progression-free survival was 8.3 months, the median survival was 18.4 months, and the 2- and 5-year survival rate was 36% and 19.4%, respectively. The treatment was well tolerated; the median gemcitabine dose intensity was 96% of the planned dose in the neoadjuvant and concurrent portions of the Phase II study. No treatment-related deaths occurred. CONCLUSION: Biweekly gemcitabine (40 mg/m(2)) concurrently with RT (52.5 Gy in 30 fractions of 1.75 Gy) with or without induction gemcitabine is safe and tolerable and shows efficacy in patients with LA and resected pancreatic cancer.     

A phase II trial of gemcitabine plus capecitabine for patients with advanced pancreatic adenocarcinoma

Purpose While gemcitabine (GEM) is widely accepted for the treatment of advanced pancreatic cancer, capecitabine (CAP) has shown single agent activity and promising efficacy in combination with GEM. This phase II study was conducted to evaluate the efficacy and toxicity of GEM combined with dose escalated 14-day CAP as first-line chemotherapy for advanced pancreatic cancer. In addition, we also analyzed the correlation between CA19-9 response and clinical outcomes. Methods Patients had advanced pancreatic adenocarcinoma, no prior systemic chemotherapy other than that given concurrently with radiation therapy, at lease one measurable disease, and adequate organ functions. The patients were treated with GEM 1,000 mg/m² IV on days 1, 8 and CAP 1,000 mg/m² twice a day PO on days 1–14, in 21-day cycles. Results The objective RR among 45 patients was 40.0% (95% CI; 25.1–54.9), including 1CR (2.2%). The median TTP and OS were 5.4 months (95% CI; 1.8–9.0) and 10.4 months (95% CI; 6.2–14.5), respectively. Patients with ≥25% decline of serum CA19-9 had significantly better outcomes in terms of TTP and OS than those who did not (P < 0.03). The most frequent, grade 3–4, non-hematologic toxicity was hand–foot syndrome (6.7%). Conclusions The combination of GEM with dose escalated 14-day CAP is well tolerated and offers encouraging activity in the treatment of advanced pancreatic cancer. In addition, CA19-9 response correlates well with clinical outcomes in this population.     

Frondoside A enhances the antiproliferative effects of gemcitabine in pancreatic cancer

Pancreatic cancer has a very poor prognosis. While gemcitabine is the mainstay of therapy and improves quality of life, it has little impact on survival. More effective treatments are desperately needed for this disease. Frondoside A is a triterpenoid glycoside isolated from the Atlantic sea cucumber, Cucumaria frondosa. Frondoside A potently inhibits pancreatic cancer cell growth and induces apoptosis in vitro and in vivo. The aim of the present study was to investigate whether frondoside A could enhance the anti-cancer effects of gemcitabine.Effects of frondoside A and gemcitabine alone and in combination on proliferation were investigated in two human pancreatic cancer cell lines, AsPC-1 and S2013. To investigate possible synergistic effects, combinations of low concentrations of the two drugs were used for a 72 h treatment period in vitro. Growth inhibition was significantly greater with the drug combinations than their additive effects.Combinations of frondoside A and gemcitabine were tested in vivo using the athymic mouse model. Xenografts of AsPC-1 and S2013 cells were allowed to form tumours prior to treatment with the drugs alone or in combination for 30 days. Tumours grew rapidly in placebo-treated animals. Tumour growth was significantly reduced in all treatment groups. At the lowest dose tested, gemcitabine (4 mg/kg/dose), combined with frondoside A (100 μg/kg/day) was significantly more effective than with either drug alone.To conclude: The present data suggest that combinations of frondoside A and gemcitabine may provide clinical benefit for patients with pancreatic cancer.     

吉西他滨单药化疗与联合化疗治疗进展期胰腺癌的疗效观察

目的观察比较吉西他滨单药与联合化疗治疗进展期胰腺癌的疗效。方法回顾性分析了大连医科大学附属一院2002年至2009年收治的45例进展期胰腺癌患者的临床资料,吉西他滨单药组17例,剂量为1000mg/m2,d1、8,三周为一周期;吉西他滨联合治疗组28例,联合化疗方案包括吉西他滨1000mg/m2,d1、8,分别联合：（1）氟尿嘧啶425～600mg/m2,静滴或持续静脉泵入,d1～5;（2）顺铂60～75mg/m2,分3～4d静脉滴入;（3）奥沙利铂85～130mg/m2,d1,静脉滴入;（4）卡培他滨1000mg/m2,每天两次口服,d1～14。21d为一周期。采用Kaplan-Meier生存曲线分析患者的生存期,并比较两组间的临床受益率、中位疾病进展时间、中位生存时间及不良反应。结果吉西他滨联合组及单药组的临床收益率均得到提高,但两组间比较临床受益率、疾病控制率、中位生存时间均无统计学意义。结论吉西他滨联合化疗方案与吉西他滨单药治疗进展期胰腺癌相比,疗效、临床受益率、中位生存期均相似。     

吉西他滨联合顺铂与单药吉西他滨治疗晚期胰腺癌的疗效比较

目的比较吉西他滨联合顺铂与单药吉西他滨治疗晚期胰腺癌的疗效。方法将53例局部晚期或转移性胰腺癌患者随机分两组,27例采用吉西他滨联合顺铂化疗(联合组),26例单纯应用吉西他滨化疗(单药组),对其疗效及毒副反应进行观察。结果可评估病例51例。联合组和单药组有效率分别为15.4%和12.0%(χ2=0.0031,P=0.9555),临床获益率(CR PR SD)分别为76.9%和44.0%(χ2=5.7955,P=0.0161);6个月生存率分别为73.1%和48.0%(χ2=3.3623,P=0.0667);CA199降低率分别为55.6%和47.6%(χ2=0.2444,P=0.6211);Ⅲ～Ⅳ度血液学毒性发生率分别为14.8%和11.5%(χ2=0.0029,P=0.9573)。结论吉西他滨联合顺铂与单药吉西他滨治疗晚期胰腺癌安全有效,前者在临床获益方面优于后者,在延长生存期方面也显示出一定的优势,但该差异未达到有显著性;在严重血液学毒性反应和降低CA199方面,二者差异无显著性。     

白蛋白结合型紫杉醇联合吉西他滨一线治疗晚期胰腺癌的疗效观察

目的 探讨白蛋白结合型紫杉醇联合吉西他滨一线治疗晚期胰腺癌的疗效和安全性。方法 本院2012年3月至2015年1月收治的27例经病理确诊为晚期转移性胰腺癌患者,接受白蛋白结合型紫杉醇联合吉西他滨一线治疗,具体方案：白蛋白结合型紫杉醇125 mg／m²静滴,d₁、d₈;吉西他滨1000 mg／m²静滴,d₁、d₈,每21天为1个周期。2个周期后按照RECIST 1.1版标准评价客观疗效,采用国立癌症研究所毒性判定标准（NCI CTC）3.0评价化疗毒性反应,同时随访其生存情况并比较不同临床病理特征的中位无进展生存期（PFS）和总生存期（OS）。结果 所有患者均可评价疗效,无CR病例,PR 2例,SD 19例,有效率（RR）和疾病控制率（DCR）分别为 7.4％和77.8％。全组患者的中位PFS和OS分别为5.0个月（95%CI：4.0～6.7个月）和8.0个月（95%CI：7.5～13.8个月）。亚组分析显示化疗周期数与患者的PFS和OS有关。主要不良反应为恶心呕吐（48.1％）、疲劳（55.5％）、发热（7.4％）、皮疹（3.7％）及周围神经异常（11.1％）;严重不良反应主要为骨髓抑制,其中3～4级血液学毒性包括白细胞减少、血小板减少和血红蛋白减少。结论白蛋白结合型紫杉醇联合吉西他滨治疗国人晚期胰腺癌疗效确切,不良反应可以耐受。     

A phase II study of erlotinib in gemcitabine refractory advanced pancreatic cancer

BackgroundErlotinib induced skin toxicity has been associated with clinical benefit in several tumour types. This phase II study evaluated the efficacy of erlotinib, dose escalated to rash, in patients with advanced pancreatic cancer previously treated with gemcitabine.MethodsErlotinib was given at an initial dose of 150 mg/day, and the dose was escalated by 50 mg every 2 weeks (to a maximum of 300 mg/day) until >grade 1 rash or other dose limiting toxicities occurred. Erlotinib pharmacokinetics were performed, and baseline tumour tissue was collected for mutational analysis and epidermal growth factor receptor (EGFR) expression. The primary end-point was the disease control rate (objective response and stable disease >8 weeks).ResultsFifty-one patients were accrued, and 49 received treatment. Dose-escalation to 200–300 mg of erlotinib was possible in 9/49 (18%) patients. The most common ⩾grade 3 adverse events included fatigue (6%), rash (4%) and diarrhoea (4%). Thirty-seven patients were evaluable for response, and the best response was stable disease in 12 patients (32% (95% confidence interval (CI) 17–47%)). Disease control was observed in nine patients (24% (95% CI: 10–38%)). Median survival was 3.8 months, and 6 month overall survival rate was 32% (95% CI 19–47%). Mutational analysis and EGFR expression were performed on 29 patients, with 93% having KRAS mutations, none having EGFR mutations, and 86% expressing EGFR. Neither KRAS mutational status nor EGFR expression was associated with survival.ConclusionsErlotinib dose escalated to rash was well tolerated but not associated with significant efficacy in non-selected patients with advanced pancreatic cancer.     

吉西他滨联合奥沙利铂治疗晚期胰腺癌患者的疗效

背景与目的:吉西他滨是目前治疗晚期胰腺癌的最有效的药物之一,初步的研究显示,与奥沙利铂联合(GEMOX)的疗效优于吉西他滨单药,但国内使用GEMOX方案治疗胰腺癌的研究报道并不多.本研究目的是观察GEMOX方案治疗晚期胰腺癌患者的有效率、生存期和毒副反应,为临床治疗提供指导.方法:本研究为单中心、回顾性临床分析.选择32例未接受过化疗的初治Ⅲ～Ⅳ期胰腺癌患者,所有患者均至少接受2个周期的GEMOX方案(吉西他滨1000 mg/m2,静脉滴入,d1、d8;奥沙利铂85～130 mg/m2,静脉滴入,d1;每21 d重复)化疗.结果:28例患者可评价疗效,8例部分缓解(partial remission,PR),8例病情稳定(stable disease,SD),12例病情进展(progressive disease,PD),4例不能评估(not assessable,NA),总有效率为25.0%,临床获益率46.9%(15例),中位无进展生存期(progression-free survival,PFS)为4.7个月,中位生存期8.6个月,1年生存率为32.6%.骨髓抑制的总发生率为70.9%,其中Ⅲ、Ⅳ度的发生率为32.3%(白细胞下降的发生率为19.4%,血红蛋白下降的发生率为12.9%,血小板下降的发生率为22.6%).恶心、呕吐和腹泻的发生率为56.2%,其中Ⅲ度呕吐2例.肝功能异常的总发生率为25.0%,全部为Ⅰ、Ⅱ度.外周神经毒性发生率为43.8%,全部为Ⅰ度.无化疗相关的死亡.结论:GEMOX方案是治疗晚期胰腺癌的有效方案,总体临床耐受性良好,其主要的不良反应为骨髓抑制.     

替吉奥与吉西他滨同步放化疗治疗局部晚期胰腺癌的临床研究

目的探讨替吉奥联合吉西他滨同步放化疗治疗局部晚期胰腺癌的疗效和安全性。方法选择26例不可手术切除的局部晚期胰腺癌患者,随机分为替吉奥联合吉西他滨同步放化疗组(观察组,13例)和5氟尿嘧啶(5-FU)联合吉西他滨同步放化疗组(对照组,13例)。观察组给予替吉奥40mg/m2,bid,第1～18天;同时给予吉西他滨1000mg/m2第1天、第5天、第29天,应用6 MV直线加速器,接受总放疗剂量54 Gy、27次。对照组给予5-Fu 750mg/m2,第1～4天、第25～28天;吉西他滨的用法及放疗方法均同观察组。结果观察组总有效率为38.5%,1年生存率为53.8%,与对照组比较有生存优势。观察组不良反应较轻,患者耐受性更好,生活质量明显改善。结论替吉奥联合吉西他滨同步放疗治疗局部晚期胰腺癌患者临床疗效好,不良反应明显轻,患者耐受性良好。     

A prospective randomized study of gemcitabine with doxifluridine versus paclitaxel with doxifluridine in concurrent chemoradiotherapy for locally advanced pancreatic cancer

PURPOSE: The objective of this study was to compare the efficacy and toxicity of gemcitabine-based concurrent chemoradiotherapy (CCRT) with paclitaxel-based CCRT in patients with locally advanced pancreatic cancer. METHODS AND MATERIALS: A total of 48 patients who had received no prior therapy were enrolled. The patients were treated with 4500 cGy radiation in 25 fractions over 5 weeks concomitant with gemcitabine 1000 mg/m(2)/week/intravenously (IV) and doxifluridine 600 mg/m(2)/day/by mouth (PO), or paclitaxel 50 mg/m(2)/week/IV and doxifluridine 600 mg/m(2)/day/PO. After a 4-week rest, the responses were evaluated and maintenance therapies (operation or chemotherapy) (gemcitabine 1000 mg/m(2)/week/IV and doxifluridine 600 mg/m(2)/day/PO) were conducted. RESULTS: The median survival was 12 months in the gemcitabine group vs. 14 months in the paclitaxel group. The response rate was 13.6% vs. 25%, and the median time to progression was 12 months vs. 12.5 months, respectively. The positive rate of the clinical benefit response was 59.1% vs. 41.7%, respectively. Toxicities were acceptable in both groups. CONCLUSION: In this trial, we demonstrated that the gemcitabine-based CCRT and the paclitaxel-based CCRT in combination of doxifluridine are clearly acceptable treatment strategy, and appear more effective than the 5 fluorouracil-based CCRT for locally advanced pancreatic cancer with comparable tolerability. Furthermore, the paclitaxel-based CCRT showed similar efficacy and toxicities to the gemcitabine-based treatment when it was combined with 5-fluorouracil.     

A phase I pharmacokinetic study of hypoxic abdominal stop-flow perfusion with gemcitabine in patients with advanced pancreatic cancer and refractory malignant ascites

Purpose  As no curative treatment for advanced pancreatic and biliary cancer with malignant ascites exists, new modalities possibly improving the response to available chemotherapies must be explored. This phase I study assesses the feasibility, tolerability and pharmacokinetics of a regional treatment of gemcitabine administered in escalating doses by the stop-flow approach to patients with advanced abdominal malignancies (adenocarcinoma of the pancreas, n = 8, and cholangiocarcinoma of the liver, n = 1). Experimental design  Gemcitabine at 500, 750 and 1,125 mg/m² was administered to three patients at each dose level by loco-regional chemotherapy, using hypoxic abdominal stop-flow perfusion. This was achieved by an aorto-caval occlusion by balloon catheters connected to an extracorporeal circuit. Gemcitabine and its main metabolite 2′,2′-difluorodeoxyuridine (dFdU) concentrations were measured by high performance liquid chromatography with UV detection in the extracorporeal circuit during the 20 min of stop-flow perfusion, and in peripheral plasma for 420 min. Blood gases were monitored during the stop-flow perfusion and hypoxia was considered stringent if two of the following endpoints were met: pH ≤ 7.2, pO₂ nadir ratio ≤0.70 or pCO₂ peak ratio ≥1.35. The tolerability of this procedure was also assessed. Results  Stringent hypoxia was achieved in four patients. Very high levels of gemcitabine were rapidly reached in the extracorporeal circuit during the 20 min of stop-flow perfusion, with C _max levels in the abdominal circuit of 246 (±37%), 2,039 (±77%) and 4,780 (±7.3%) μg/ml for the three dose levels 500, 750 and 1,125 mg/m², respectively. These C _max were between 13 (±51%) and 290 (±12%) times higher than those measured in the peripheral plasma. Similarly, the abdominal exposure to gemcitabine, calculated as AUC_t0–20, was between 5.5 (±43%) and 200 (±66%)-fold higher than the systemic exposure. Loco-regional exposure to gemcitabine was statistically higher in presence of stringent hypoxia (P < 0.01 for C _max and AUC_t0–20, both normalised to the gemcitabine dose). Toxicities were acceptable considering the complexity of the procedure and were mostly hepatic; it was not possible to differentiate the respective contributions of systemic and regional exposures. A significant correlation (P < 0.05) was found between systemic C _max of gemcitabine and the nadir of both leucocytes and neutrophils. Conclusions  Regional exposure to gemcitabine—the current standard drug for advanced adenocarcinoma of the pancreas—can be markedly enhanced using an optimised hypoxic stop-flow perfusion technique, with acceptable toxicities up to a dose of 1,125 mg/m². However, the activity of gemcitabine under hypoxic conditions is not as firmly established as that of other drugs such as mitomycin C, melphalan or tirapazamine. Further studies of this investigational modality, but with bioreductive drugs, are therefore warranted first to evaluate the tolerance in a phase I study and later on to assess whether it does improve the response to chemotherapy.     

Intraperitoneal gemcitabine pharmacokinetics: a pilot and pharmacokinetic study in patients with advanced adenocarcinoma of the pancreas

BACKGROUND: The pyrimidine analogue gemcitabine (2', 2'-difluorodeoxycitidine, dFdC) is active against pancreatic cancer, and its high clearance (CL(tb)) and low incidence of local toxicity make it an excellent candidate for evaluation as intraperitoneal (IP) therapy. We designed a dosing schema that used multiple sequential exchanges of a peritoneal dialysate containing dFdC in an effort to produce prolonged IP dFdC exposure. METHODS: As part of a study involving multi-modality therapy for advanced pancreatic adenocarcinoma, patients were treated with four 6-h IP dwells of dFdC (50 mg/m(2) in 2 l) over a 24-h period. A second 24-h cycle of IP dFdC therapy was repeated 1 week later. Each exchange of dialysate contained 50 mg/m(2) dFdC in 2 l of commercial 1.5% dextrose dialysis solution. Plasma and peritoneal fluid were analyzed by HPLC to determine concentrations of dFdC and its inactive metabolite 2', 2' difluorodeoxyuridine (dFdU). Clinical data were recorded to note drug toxicity and response. RESULTS: Nine patients underwent IP dFdC therapy, and eight were able to receive two cycles. There were no recorded significant toxicities. Low plasma dFdC concentrations (<1 mug/ml) were present transiently in seven of nine patients, and dFdC was not detectable in the plasma of the other two. Plasma dFdU concentrations were low but increased gradually until 12 h and then declined little if any. IP dFdC concentrations declined rapidly, and dFdC was seldom measurable prior to administration of the next scheduled 6-h dwell. dFdU concentrations in peritoneal fluid were very low (<0.5 mug/ml) throughout treatment. The mean area under the concentration versus time curve (AUC) for dFdC in peritoneal fluid was 182 mug/ml x h, which was approximately 70x the AUC of dFdC reported in the ascites of a patient undergoing systemic dFdC therapy. CONCLUSIONS: IP dFdC was well tolerated, and no significant toxicities were noted. The rapid decrease in peritoneal dFdC concentrations and low concentrations of IP dFdU imply almost total absorption of IP-administered dFdC. Little, if any, dFdC could be detected in plasma, but the steady-state plasma dFdU concentrations also imply absorption and inactivation of virtually all IP-administered dFdC. These findings are consistent with the known high CL(tb) and low incidence of local toxicity of dFdC and argue for its further evaluation as a drug for IP therapy.     

晚期胰腺癌全身化疗的疗效观察

背景与目的:晚期胰腺癌是恶性程度很高的肿瘤,全身化疗是其主要的治疗方法。本研究拟观察、比较三种不同化疗方案对晚期胰腺癌的客观疗效及其临床受益反应。方法:对我科2000年2月～2001年4月期间收治的经病理检查证实的74例晚期胰腺癌患者的临床资料进行回顾性分析,其中26例采用5-氟尿嘧啶、醛氢叶酸、顺铂方案治疗(A组);23例采用吉西他滨单药治疗(B组);25例采用吉西他滨联合5-氟尿嘧啶、醛氢叶酸方案治疗(C组)。采用Kaplan-Meier法分析患者生存期,Cox比例风险回归模型分析影响预后的因素。结果:A、B、C三组客观缓解率分别为7.7%、17.4%与24.0%,三组间无显著性差异(P=0.261,χ2检验);临床受益反应率分别为19.2%、47.8%与60.0%,B、C组优于A组,差异具有显著性(P<0.05,χ2检验)。A、B、C三组中位生存期分别为6.50个月(95%CI=5.00,7.99)、8.03个月(95%CI=6.72,9.35)、8.79个月(95%CI=7.31,10.26),B、C组长于A组,差异有显著性(Breslow=8.85,P=0.0119)。三组间血液学毒性和非血液学毒性发生率差异无显著性。结论:吉西他滨与5-氟尿嘧啶、醛氢叶酸联合作为一线方案治疗晚期胰腺癌有一定的客观缓解率,可改善患者的生活质量,患者耐受良好,值得进一步研究。     

Phase I trial of gefitinib with concurrent radiotherapy and fixed 2-h gemcitabine infusion, in locally advanced pancreatic cancer

PURPOSE: Pancreatic cancers are resistant to radiotherapy (RT) and current chemotherapy agents. Epidermal growth factor receptor is overexpressed in pancreatic cancer, and in vitro studies have shown that epidermal growth factor receptor inhibitors can overcome radio- and chemoresistance. The aim of the study was to determine whether the addition of gefitinib to RT and gemcitabine for patients with locally advanced pancreatic carcinoma (LAPC) was feasible and safe. METHODS AND MATERIALS: Eighteen patients with pathologically proven LAPC, based on major vascular invasion based on helical computed tomography (CT) and endoscopic ultrasound, were entered into the study. The targeted irradiated volume included the tumor and 2-cm margin. Prophylactic irradiation of regional nodes was not allowed. Patients with >500 cm(3) of planning tumor volume were excluded. An initial cohort of 6 patients was treated with RT (45 Gy/25 fractions/5 weeks) plus concomitant gefitinib (250 mg/day). Successive cohorts of patients received 100, 150, and 200 mg/m(2)/day of gemcitabine in a 2-h infusion over Weeks 1, 2, 3, 4, and 5 with gefitinib (250 mg/day) and RT. Gefitinib was continued after RT until progression. A pharmacodynamic study of angiogenic markers was also performed to evaluate a possible antiangiogenic effect. RESULTS: There were no dose-limiting toxicities. Common toxicities were mild neutropenia, asthenia, diarrhea, cutaneous rash and nausea/vomiting. The median (95% confidence interval [CI]) progression-free survival was 3.7 (95% CI = 1.9-5.5) months, and the median overall survival was 7.5 (95% CI = 5.2-9.9) months. No significant reduction of vascular endothelial growth factor and interleukin-8 was observed after treatment. CONCLUSION: Our results support that the combination of gefitinib, RT, and gemcitabine has an acceptable toxicity but with modest activity in LAPC.