吉西他滨治疗14例晚期胰腺癌

目的：研究吉西他滨（gemcitabine)治疗晚期胰腺癌的疗效。方法：14例进行展期胰腺癌患者,用吉西他滨第1周800mg/m^2,第2周1000mg/m^2,第3周1200mg/m^2,每周1次,每次以0．9％生理盐水100ml溶解后静脉滴注,30分钟滴完,连续3周,随后休息1周为一疗程。以后每4周重复一次,共6个疗程。结果：疼痛缓解有效率为64％（9／14）,处长了中位生存期,平均为8．7个月。临床受益反应为43％。吉西他滨治疗晚期胰腺癌能显著改善晚期胰腺癌患者的临床症状,减轻疼痛。生活质量有明显提高。结论：吉西他滨可作为晚期胰腺癌综合治疗时首选的化疗药物。     

BAYPAN study: a double-blind phase III randomized trial comparing gemcitabine plus sorafenib and gemcitabine plus placebo in patients with advanced pancreatic cancer

BackgroundSorafenib is an oral anticancer agent targeting Ras-dependent signaling and angiogenic pathways. A phase I trial demonstrated that the combination of gemcitabine and sorafenib was well tolerated and had activity in advanced pancreatic cancer (APC) patients. The BAYPAN study was a multicentric, placebo-controlled, double-blind, randomized phase III trial comparing gemcitabine/sorafenib and gemcitabine/placebo in the treatment of APC.Patients and methodsThe patient eligibility criteria were locally advanced or metastatic pancreatic adenocarcinoma, no prior therapy for advanced disease and a performance status of zero to two. The primary end point was progression-free survival (PFS). The patients received gemcitabine 1000 mg/m² i.v., weekly seven times followed by 1 rest week, then weekly three times every 4 weeks plus sorafenib 200 mg or placebo, two tablets p.o., twice daily continuously.ResultsBetween December 2006 and September 2009, 104 patients were enrolled on the study (52 pts in each arm) and 102 patients were treated. The median and the 6-month PFS were 5.7 months and 48% for gemcitabine/placebo and 3.8 months and 33% for gemcitabine/sorafenib (P = 0.902, stratified log-rank test), respectively. The median overall survivals were 9.2 and 8 months, respectively (P = 0.231, log-rank test). The overall response rates were similar (19 and 23%, respectively).ConclusionThe addition of sorafenib to gemcitabine does not improve PFS in APC patients.     

白蛋白紫杉醇二线治疗晚期胰腺癌的临床观察

目的:探讨白蛋白紫杉醇二线治疗一线含吉西他滨方案化疗失败的晚期胰腺癌患者的疗效和安全性。方法:6例一线含吉西他滨方案化疗失败的晚期胰腺癌患者,给予白蛋白紫杉醇100mg/m2 静脉滴注,d1、d8、d15,28天为1周期。治疗至疾病进展或出现不可耐受的不良反应。根据实体瘤疗效反应评价标准(RECIST)评价疗效,常规毒性判定标准(NCI-CTC 3.0)评价不良反应。结果:6例患者中位治疗时间为2周期（1~8周期）,无CR病例,PR 1例,SD 3例,PD 2例。总有效率为16.7%,疾病控制率为66.7%,中位无疾病进展时间（PFS）为5.3个月,中位总生存时间（OS）为7个月,有2例患者仍存活,随访至今,生存时间分别为54个月和58个月。不良反应主要为骨髓抑制和神经毒性,多为Ⅰ-Ⅱ级,其中1例患者出现Ⅲ级白细胞下降,4例Ⅱ级下降;2例出现Ⅱ级肌肉酸痛,无Ⅳ级不良反应。结论:对于一线含吉西他滨方案化疗失败的晚期胰腺癌患者,白蛋白紫杉醇单药方案化疗可取得一定疗效,患者耐受性好,值得扩大样本量进一步研究。     

Biweekly high-dose gemcitabine alone or in combination with capecitabine in patients with metastatic pancreatic adenocarcinoma: a randomized phase II trial.

BACKGROUND: Gemcitabine is an active antitumor agent in the treatment of advanced pancreatic cancer, and has shown potential synergistic activity with the oral fluoropyrimidine capecitabine in previous phase I/II trials. Based on this background and in order to define the therapeutic potential and tolerance of this combination more precisely, the present randomized multicenter phase II trial was initiated. PATIENTS AND METHODS: We prospectively randomized 83 patients to treatment with biweekly gemcitabine 2,200 mg/m(2) given as a 30 min intravenous infusion on day 1, or the same treatment plus oral capecitabine 2,500 mg/m(2) given from days 1 to 7. In both arms, chemotherapy was administered for a duration of 6 months unless there was prior evidence of progressive disease. The efficacy of the two treatment arms was evaluated according to standard criteria, i.e. objective response, progression-free survival (PFS) and overall survival (OS), as well as by analysis of clinical benefit response. RESULTS: The overall objective response rate among the 42 patients treated with gemcitabine alone was 14% compared with 7/41 (17%) among those treated with the combination arm. Similar to response rates, there was no apparent difference between the two groups in terms of median PFS (4.0 versus 5.1 months) and median OS (8.2 versus 9.5 months) in the gemcitabine and combination arm, respectively. Of 61 patients with tumor-related symptoms, who were considered evaluable for clinical benefit response, 10/30 (33%) and 15/31 (48.4%) experienced significant palliation in the gemcitabine and combination arm, respectively. Chemotherapy was well tolerated in both arms with only four versus six patients experiencing WHO grade 3 symptoms. Apart from the occurrence of hand-foot syndrome in 10 patients, no major increase in incidence and/or degree of adverse reactions was noted in the combination arm. CONCLUSIONS: Results of this trial suggest a fairly good therapeutic index for the combination of biweekly high-dose gemcitabine and capecitabine for the treatment of advanced pancreatic cancer. Despite a somewhat superior clinical benefit response rate, no advantage over single-agent gemcitabine, however, was noted in terms of objective efficacy parameters.     

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。     

Phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer.

PURPOSE: Vascular endothelial growth factor (VEGF) plays a key role in the biology and prognosis of pancreatic cancer. Inhibitors of VEGF suppress the growth of pancreatic cancer in preclinical models. The objectives of this phase II study were to assess the response rate and overall survival of pancreatic cancer patients who received gemcitabine with the recombinant humanized anti-VEGF monoclonal antibody bevacizumab. PATIENTS AND METHODS: Patients with previously untreated advanced pancreatic cancer received gemcitabine 1,000 mg/m(2) intravenously over 30 minutes on days 1, 8, and 15 every 28 days. Bevacizumab, 10 mg/kg, was administered after gemcitabine on days 1 and 15. Tumor measurements were assessed every two cycles. Plasma VEGF levels were obtained pretreatment. RESULTS: Fifty-two patients were enrolled at seven centers between November 2001 and March 2004. All patients had metastatic disease, and 83% had liver metastases. Eleven patients (21%) had confirmed partial responses, and 24 (46%) had stable disease. The 6-month survival rate was 77%. Median survival was 8.8 months; median progression-free survival was 5.4 months. Pretreatment plasma VEGF levels did not correlate with outcome. Grade 3 and 4 toxicities included hypertension in 19% of the patients, thrombosis in 13%, visceral perforation in 8%, and bleeding in 2%. CONCLUSION: The combination of bevacizumab plus gemcitabine is active in advanced pancreatic cancer patients. Additional study is warranted. A randomized phase III trial of gemcitabine plus bevacizumab versus gemcitabine plus placebo is ongoing in the Cancer and Leukemia Group B.     

Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor, in combination with gemcitabine for advanced pancreatic cancer: a multicenter phase II Trial.

PURPOSE: To determine the response rate, time to disease progression, survival duration and rate, and toxicity with the combination of cetuximab and gemcitabine in patients with epidermal growth factor receptor (EGFR)-expressing advanced pancreatic cancer. PATIENTS AND METHODS: Patients with measurable locally advanced or metastatic pancreatic cancer who had never received chemotherapy for their advanced disease and had immunohistochemical evidence of EGFR expression were eligible for the multicenter phase II trial. Patients were treated with cetuximab at an initial dose of 400 mg/m(2), followed by 250 mg/m(2) weekly for 7 weeks. Gemcitabine was administered at 1,000 mg/m(2) for 7 weeks, followed by 1 week of rest. In subsequent cycles, cetuximab was administered weekly, and gemcitabine was administered weekly for 3 weeks every 4 weeks. RESULTS: Sixty-one patients were screened for EGFR expression, 58 patients (95%) had at least 1+ staining, and 41 were enrolled onto the trial. Five patients (12.2%) achieved a partial response, and 26 (63.4%) had stable disease. The median time to disease progression was 3.8 months, and the median overall survival duration was 7.1 months. One-year progression-free survival and overall survival rates were 12% and 31.7%, respectively. The most frequently reported grade 3 or 4 adverse events were neutropenia (39.0%), asthenia (22.0%), abdominal pain (22.0%), and thrombocytopenia (17.1%). CONCLUSION: Cetuximab in combination with gemcitabine showed promising activity against advanced pancreatic cancer. Further clinical investigation is warranted.     

Phase I trial of gemcitabine and candesartan combination therapy in normotensive patients with advanced pancreatic cancer: GECA1

Our retrospective study showed inhibition of the renin-angiotensin system was associated with better outcomes in patients with advanced pancreatic cancer receiving gemcitabine. The primary objective of this phase I study was to determine the recommended dose of candesartan in combination with gemcitabine in normotensive patients with advanced pancreatic cancer. Candesartan was given orally at an escalating dose (4, 8, 16, and 32 mg) q.d. daily, and gemcitabine was given 1000 mg/m(2) 30 min i.v. on days 1, 8, and 15, repeated every 4 weeks. Dose-limiting toxicity (DLT) was defined as grade 4 hematological toxicities, grade 2 hypotension, abnormal creatinine or potassium, and grade 3 or 4 other non-hematological toxicities. A standard "3+3" phase I dose-escalation design was used. A total of 14 patients (candesartan 4 mg, three patients; 8 mg, three patients; 16 mg, six patients; 32 mg, two patients) were enrolled. One of six patients at 16 mg showed DLT of grade 4 neutropenia and two of two patients at 32 mg showed DLT of grade 2 hypotension. Response rate and disease control rate were 0% and 79%, respectively. Progression-free survival and overall survival were 7.6 and 22.9 months, respectively. Candesartan 16 mg is the recommended dose in combination with gemcitabine in the treatment of advanced pancreatic cancer. (UMIN CTR: UMIN000002152).     

A phase I study of combination chemotherapy with gemcitabine and oral S-1 for advanced pancreatic cancer

OBJECTIVE: The aim of this study was to determine the maximum-tolerated dose and dose-limiting toxicity (DLT) of combination therapy with gemcitabine and S-1 in patients with advanced pancreatic cancer. METHODS: Chemotherapy-naive patients with histologically or cytologically proven unresectable or metastatic pancreatic cancer were enrolled. The patients received gemcitabine intravenously over 30 min on days 1 and 8 and S-1 orally twice daily from days 1 to 14. Cycles were repeated every 21 days until disease progression. Patients were scheduled to receive gemcitabine (mg/m(2)/week) and S-1 (mg/m(2)/day) at four dose levels: 800/60 (level 1), 1,000/60 (level 2), 1,000/70 (level 3) and 1,000/80 (level 4). RESULTS: Eighteen patients were enrolled in this study. The maximum-tolerated dose was not reached even at the highest dose level (level 4) because only 2 of the 6 patients at this level experienced DLT. The DLTs were neutropenia and rash. Six (33%) of the 18 patients achieved a partial response and median overall survival time was 7.6 months. CONCLUSIONS: Combination chemotherapy with gemcitabine and S-1 was well tolerated and showed good antitumor activity in the treatment of pancreatic cancer. We recommend a gemcitabine dose of 1,000 mg/m(2)/week and an S-1 dose of 80 mg/m(2)/day in further studies with this schedule.     

吉西他滨和西妥昔单抗联合放疗治疗局部晚期胰头癌的疗效分析

目的:评估吉西他滨和西妥昔单抗联合放疗靶向治疗局部晚期胰头癌的疗效。方法:收集2008年11月到2012年1月145例经组织学确诊的胰腺导管腺癌患者参与本项研究。所有患者接受三维适形放射治疗,常规分割1.8 Gy/（f·d）,5次/周,总照射剂量50.4 Gy。放疗开始的同一天给予每周300 mg/m2吉西他滨,第1天400 mg/m2西妥昔单抗,后续每周250 mg/m2西妥昔单抗。结果:全部患者完成放化疗,59例（40.7%）CR,49例（33.8%）PR,35例（24.1%）SD,2例（1.4%）PD,总有效率为74.5%。2年无转移生存率为27%（中位13.6个月,95%CI:2.8~27.1）。1年和2年总生存率分别为68.3%和27.8%,中位总生存期为14.9个月（95%CI:10.3~20.7）;1年和2年无进展生存率分别为41.5%和19.8%,中位无进展生存期10.2个月（95%CI:9.2~18.0）。治疗后血液系统出现Ⅲ-Ⅳ级毒副反应（44.8%白细胞减少症、4.8%血小板减少、21.4% γ-GT升高和0.7%碱性磷酸酶升高）。Ⅲ-Ⅳ级非血液毒性较少出现。结论:吉西他滨和西妥昔单抗联合放疗治疗局部晚期胰头癌具有一定疗效,能显著改善患者的临床症状,且毒副反应均能耐受。     

Gemcitabine combined with docetaxel for the treatment of unresectable pancreatic carcinoma

Purpose. To assess the efficacy and toxicity of combination therapy with gemcitabine and docetaxel in patients with unresectable pancreatic carcinoma. Patients and Methods. Thirty-four patients with unresectable stage III, IVA, and IVB pancreatic carcinoma were eligible for this study. The first 18 patients received gemcitabine 800 mg/m² intravenously (IV) on days 1, 8, and 15 and docetaxel 75 mg/m² IV on day 1, repeated every 28 days. Due to a high incidence of myelosuppression in this first group, the treatment schedule was modified in the remaining patients to gemcitabine 1,000 mg/m² IV and docetaxel 40 mg/m² IV on days 1 and 8 of a 21-day schedule. The primary study endpoints were objective response rate and duration of survival. Results. Ten of 33 evaluable patients achieved a partial response, for an overall response rate of 30.3% (95% CI, 16.21%-48.87%). Partial responses noted in the pancreas and a variety of metastatic sites were maintained for 4 to 12 months (median 6 months). Twelve additional patients (36%) experienced stable disease. The median time to progression was 6 months, and median survival was 10.5 months. The toxicity profile of the modified gemcitabine/docetaxel schedule was more favorable than that associated with the initial regimen, particularly with respect to hematologic toxicity. Conclusion. The response and survival data reported here for combination therapy with gemcitabine and docetaxel are encouraging given the poor prognosis associated with unresectable pancreatic cancer. These data suggest that gemcitabine plus docetaxel may be more effective than either agent alone in the treatment of pancreatic cancer and warrants further study.     

Combined radiochemotherapy of locally advanced unresectable pancreatic adenocarcinoma with mitomycin C plus 24-hour continuous infusional gemcitabine

BACKGROUND: In locally advanced pancreatic cancer, the combination of chemotherapy with radiotherapy is gaining increasing importance; although, in view of the reported long-term results of several contemporary trials, further improvements are certainly warranted. The aim of the present study was to evaluate the effectiveness and safety of a combined-treatment modality consisting of systemic chemotherapy with 24-h continuous infusional gemcitabine and mitomycin C, plus external beam radiotherapy in patients with localized unresectable adenocarcinoma of the pancreas. METHODS AND MATERIALS: Systemic chemotherapy consisted of mitomycin C 8 mg/m2 given as i.v. bolus injection on day 1 and gemcitabine administered as a 24-h continous infusion once weekly for 3 of 4 weeks. The starting dose of gemcitabine was 100 mg/m2 and dose levels were escalated in consecutive cohorts of 3-6 patients to 130 and 160 mg/m2, utilizing an escalating-dose Phase I trial design. Radiation therapy using megavolt irradiation (total dose, 45 Gy, 1.8 Gy/day) of 6 MV photons or greater with a 3- or 4-field technique was delivered concurrently for 5-6 weeks. RESULTS: Between January 1997 and August 1998, a total of 15 patients were enrolled in this trial, all of whom were assessable for toxicity, response, and survival. The dose-limiting toxicities at the 160 mg/m2 gemcitabine level were myelosuppression, specifically neutropenia +/- thrombocytopenia, and gastrointestinal symptoms, including stomatitis, vomiting, and diarrhea. Only 1 partial response was observed (7%), and disease was stabilized in 10 additional patients (67%). The median time to progression was 5.5 months (range, 2-12 months). Whereas all patients developed distant metastases, locoregional failure occurred in only 3. The median survival time was 8.3 months (range, 2.5 to 22.0+ months), and the 1-year survival rate was 13.3%. CONCLUSION: The MTD of gemcitabine when given as prolonged infusion in combination with mitomycin C and radiation therapy was 130 mg/m2/week. Therapeutic results suggest that combined chemoradiation with this regimen is feasible and effective for local control of pancreatic cancer, but essentially ineffective in counteracting metastatic tumor growth.     

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.     

白蛋白结合型紫杉醇联合吉西他滨动脉灌注治疗进展期胰腺癌的安全性和有效性回顾性研究

背景与目的：白蛋白结合型紫杉醇联合吉西他滨（nab-paclitaxel combined with gemcitabine,AG）方案静脉化疗是进展期胰腺癌有效治疗方案之一,动脉灌注化疗（transcatheter arterial chemotherapy,TAC）具有增强疗效并降低不良反应的优势,观察AG方案经TAC治疗进展期胰腺癌患者的有效性和安全性。方法：回顾性分析2016年1月—2019年6月复旦大学附属肿瘤医院收治的63例接受治疗的进展期胰腺癌患者,患者均经病理学检查确诊为胰腺导管腺癌,其中Ⅲ期15例,Ⅳ期48例,所有患者接受经动脉灌注化疗和（或）栓塞治疗,动脉灌注化疗用药方案为盐酸吉西他滨1 000 mg/m ² 联合白蛋白结合型紫杉醇125 mg/m ² ,灌注时间≥10 min,伴有肝转移者同时行供血动脉栓塞。结果：63例患者中,术中行数字减影血管造影（digital subtraction angiography,DSA）可见胰腺肿瘤和肝转移灶动脉供血比例分别为66.67%和35.29%;接受治疗1次4例,2次6例,3次6例,4次及以上47例,治疗次数最多为9次,间隔时间为21～45 d。1年生存率为36.51%,中位生存期（median overall survival,mOS）为9.2个月,6个月无进展生存（progression-free survival,PFS）率为44.44%,中位PFS（median PFS,mPFS）为4.7个月。多因素分析显示KPS≥80、Ⅲ期与较长的生存期相关,接受多次动脉灌注化疗和（或）栓塞是良好的生存预后相关因素。发生治疗相关的Ⅲ度及以上血液学不良反应包括中性粒细胞减少（3.17%）和血小板下降（4.76%）,非血液学不良反应包括乏力（6.35%）、恶心呕吐（9.52%）、腹泻（4.76%）和转氨酶升高（4.76%）;17.46%和22.22%的患者出现发热及肝区疼痛栓塞综合征,所有不良反应经治疗后均好转,无治疗相关性死亡病例。结论：白蛋白结合型紫杉醇联合吉西他滨经动脉灌注治疗进展期胰腺癌具有较好的安全性,不良反应与静脉给药相比有所减少,可有效地控制病情,使患者生存获益。     

A phase 1 study of fixed dose rate gemcitabine and irinotecan in patients with advanced pancreatic and biliary cancer

BACKGROUND: The combination of a fixed dose rate (FDR) infusion of gemcitabine and irinotecan may have a synergistic effect in the treatment of patients with advanced and metastatic pancreatic and biliary cancer. The current study was conducted to determine the dose-limiting toxicity (DLT) and the maximum tolerated dose (MTD) of the combination. METHODS: There were 32 patients with metastatic pancreatic and advanced unresectable/metastatic biliary adenocarcinoma who were entered into this open-label, phase 1 dose escalation trial. Gemcitabine was administered at an FDR of 10 mg/m(2)/minute intravenously (iv). Irinotecan was administered iv over 60 minutes after gemcitabine. Both gemcitabine and irinotecan were given on Days 1 and 8 of a 21-day cycle. RESULTS: The MTD of the combination was gemcitabine at an FDR of 1200 mg/m(2) and irinotecan at a dose of 100 mg/m(2). The DLTs were neutropenia and neutropenic fever. Other DLTs included diarrhea, dehydration, and fatigue. Two patients developed deep venous thrombosis during the treatment. The efficacy of the combination was encouraging, even at the lower dose levels. Of 30 assessable patients, there was 1 complete response, 6 partial responses, and 16 patients with stable disease, with a response rate of 23%, a disease control rate of 76%, a median progression-free survival of 4.7 months, and a median overall survival of 7.0 months. The average number of treatment cycles received was 11. CONCLUSIONS: The recommended doses of the combination for future study are gemcitabine at an FDR of 1200 mg/m(2) and irinotecan at a dose of 100 mg/m(2). The efficacy of the combination is encouraging. Further assessment of the combination with or without biologic agents is suggested.     

Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer.

PURPOSE: To determine whether addition of the farnesyltransferase inhibitor tipifarnib (Zarnestra, R115777; Johnson and Johnson Pharmaceutical Research and Development, Beerse, Belgium) to standard gemcitabine therapy improves overall survival in advanced pancreatic cancer. PATIENTS AND METHODS: This randomized, double-blind, placebo-controlled study compared gemcitabine + tipifarnib versus gemcitabine + placebo in patients with advanced pancreatic adenocarcinoma previously untreated with systemic therapy. Tipifarnib was given at 200 mg bid orally continuously; gemcitabine was given at 1,000 mg/m(2) intravenously weekly x 7 for 8 weeks, then weekly x 3 every 4 weeks. The primary end point was overall survival; secondary end points included 6-month and 1-year survival rates, progression-free survival, response rate, safety, and quality of life. RESULTS: Six hundred eighty-eight patients were enrolled. Baseline characteristics were well balanced between the two treatment arms. No statistically significant differences in survival parameters were observed. The median overall survival for the experimental arm was 193 v 182 days for the control arm (P =.75); 6-month and 1-year survival rates were 53% and 27% v 49% and 24% for the control arm, respectively; median progression-free survival was 112 v 109 days for the control arm. Ten drug-related deaths were reported for the experimental arm and seven for the control arm. Neutropenia and thrombocytopenia grade > or = 3 were observed in 40% and 15% in the experimental arm versus 30% and 12% in the control arm. Incidences of nonhematologic adverse events were similar in two groups. CONCLUSION: The combination of gemcitabine and tipifarnib has an acceptable toxicity profile but does not prolong overall survival in advanced pancreatic cancer compared with single-agent gemcitabine.     

奈达铂联合吉西他滨治疗晚期复治肺鳞癌的临床观察

目的 观察奈达铂联合吉西他滨治疗晚期复治肺鳞癌的疗效和毒性反应。方法 26例经病理组织学或细胞学检查确诊的晚期肺鳞癌复治患者,给予奈达铂80mg／m2 d1,吉西他滨1000mg／m2 d1、d8, 21天为1周期。1～2周期后评价疗效及毒性反应,并随访患者无进展生存时间（PFS）。结果 26例患者中23例可评价疗效,无完全缓解（CR）病例,部分缓解（PR） 6例,稳定（SD） 12例,进展（PD） 5例,总有效率（RR）为261％,临床获益率（DCR）为 783％。中位PFS 为4个月。主要毒副反应为骨髓抑制、肝功能损害和胃肠道反应,骨髓抑制明显但可耐受。结论 奈达铂联合吉西他滨治疗晚期复治肺鳞癌疗效确切,毒副反应可耐受,值得进一步推广研究。     

Irinotecan plus raltitrexed vs raltitrexed alone in patients with gemcitabine-pretreated advanced pancreatic adenocarcinoma

There is no established second-line treatment for advanced pancreatic cancer after gemcitabine failure. In view of the urgent need for such therapy, and since preclinical and phase I clinical data suggest an encouraging, potentially synergistic activity between raltitrexed and irinotecan, the present randomised phase II study was initiated. A total of 38 patients with metastatic pancreatic adenocarcinoma, who progressed while receiving or within 6 months after discontinuation of palliative first-line chemotherapy with gemcitabine, were enrolled in this study. They were randomised to 3-weekly courses of raltitrexed 3 mg x m(-2) on day 1 (arm A) or irinotecan 200 mg x m(-2) on day 1 plus raltitrexed 3 mg x m(-2) on day 2 (arm B). The primary study end point was objective response, secondary end points included progression-free survival (PFS) and overall survival (OS), as well as clinical benefit response in symptomatic patients (n=28). In the combination arm, the IRC-confirmed objective response rate was 16% (three out of 19 patients had a partial remission; 95% CI, 3-40%), which was clearly superior to that in the comparator/control arm with raltitrexed alone, in which no response was obtained. Therefore, the trial was already stopped at the first stage of accrual. Also, the secondary study end points, median PFS (2.5 vs 4.0 months), OS (4.3 vs 6.5 months), and clinical benefit response (8 vs 29%) were superior in the combination arm. The objective and subjective benefits of raltitrexed+irinotecan were not negated by severe, clinically relevant treatment-related toxicities: gastrointestinal symptoms (42 vs 68%), partial alopecia (0 vs 42%), and cholinergic syndrome (0 vs 21%) were more commonly noted in arm B; however, grade 3 adverse events occurred in only three patients in both treatment groups. Our data indicate that combined raltitrexed+irinotecan seems to be an effective salvage regimen in patients with gemcitabine-pretreated pancreatic cancer. The superior response activity, PFS and OS (when compared to raltitrexed), as well as its tolerability and ease of administration suggest that future trials with this combination are warranted.     

Gemcitabine and ISIS-2503 for patients with locally advanced or metastatic pancreatic adenocarcinoma: a North Central Cancer Treatment Group phase II trial.

PURPOSE: Gemcitabine remains the standard therapy for metastatic pancreatic adenocarcinoma (ACA), but has limited activity. ISIS-2503 is an antisense compound directed against H-ras with preclinical activity against pancreatic ACA in tumor models. The combination of ISIS-2503 and gemcitabine has been evaluated in a prior phase I study. METHODS: Patients with metastatic or locally advanced pancreatic ACA not amenable to surgery or local radiation received gemcitabine 1,000 mg/m(2) intravenously over 30 minutes on days 1 and 8 and ISIS-2503 6 mg/kg/d as a continuous intravenous infusion over 14 days of an every-3-weeks cycle. Responses were monitored by radiologic imaging every 6 weeks. RESULTS: Forty-eight eligible patients were enrolled, 43 with metastatic disease. Median follow-up was 12.6 months (range, 2.2 to 16.8 months) for living patients. A median of four cycles of treatment was given (range, 1 to 18 cycles). All patients were assessable for response and toxicity. The 6-month survival percentage was 57.5% (95% CI, 44.9% to 73.5%) and the median survival was 6.6 months. The response rate was 10.4% (one complete response, four partial responses). Clinically significant toxicity was limited except for one fatal pulmonary embolism. CONCLUSION: This study shows a promising response rate to the combination of gemcitabine and ISIS-2503 in patients with pancreatic ACA. The observed 6-month survival rate in these patients met our protocol-defined criteria for success. This regimen is tolerable, but is of unclear benefit. Additional studies evaluating the role of gemcitabine and ISIS-2503 in the treatment of pancreatic ACA should be considered.     

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.