Phase I trial of gemcitabine in patients with advanced pancreatic cancer

BACKGROUND: Gemcitabine is the most promising new agent currently being tested in pancreatic cancer. The present study was conducted to confirm the tolerability of a weekly schedule of gemcitabine at a dose of 1000 mg/m2 in Japanese patients with advanced pancreatic cancer. METHODS: The primary end-point was to evaluate the frequency of dose-limiting toxicity. Gemcitabine 1000 mg/m2 was administered over 30 min weekly in two schedules: gemcitabine x3 every 4 weeks (Schedule 1) and gemcitabine x7 followed by a week of rest and then gemcitabine x3 every 4 weeks thereafter (Schedule 2). At least three patients entered each schedule and three additional patients were treated in the presence of dose-limiting toxicity. RESULTS: Eleven chemo-naive patients with a good Karnofsky performance status of > or =80 points and distant metastasis were entered into this trial. In Schedule 1, no dose-limiting toxicity was observed in the three patients. In Schedule 2, the evaluation of dose-limiting toxicity was complete in six of the eight enrolled patients and two patients showed dose-limiting toxicity in this Schedule; one patient experienced both grade 4 leukocytopenia and grade 4 neutropenia, and both grade 4 neutropenia and grade 3 GOT/GPT increased in another patient. Two patients (18%) showed a partial response and a clinical benefit response was also achieved in two (29%) of the seven evaluable patients. CONCLUSION: Gemcitabine 1000 mg/m2 weekly x7 followed by a week of rest and weekly x3 every 4 weeks thereafter may be tolerated in Japanese patients with advanced pancreatic cancer.     

康莱特联合吉西他滨治疗进展期胰腺癌的疗效观察

目的：观察康莱特联合吉西他滨治疗进展期胰腺癌的临床疗效、临床获益反应和不良反应.方法：40例未接受过全身化疗的进展期胰腺癌患者,至少接受2个周期的康莱特联合吉西他滨化疗方案.康莱特200ml静滴,每天1次,吉西他滨1000mg/m2,第1天和第8天,每21天为一个周期.结果：40例患者中3例临床缓解,13例部分缓解,11例稳定.总的疾病控制率为67.5％.疼痛缓解率为88.6％.骨髓抑制发生率为37.5％.无化疗相关死亡.结论：康莱特联合吉西他滨治疗进展期胰腺癌可提高疾病控制率,改善患者生活质量,减轻疼痛,减少不良反应的发生.     

Multi-center trial of gemcitabine for 49 patients with advanced pancreatic cancer

Forty-nine patients with unresectable pancreatic cancer (stage IV disease) received gemcitabine in a multi-center trial in the Fukuoka pancreatic cancer chemotherapy group, Japan. No complete remissions, 5 partial remissions (10%) and 25 no changes (51%) were obtained. Gemcitabine could maintain QOL. Main toxicities were hematologic, especially neutropenia. Neutropenia tended to appear in early administration. Non-hematologic toxicities were anorexia, nausea/vomiting, and skin rash. The mean overall survival period was 7.5 months. Carcinomatous ascites and/or pleural effusion resulted in a poor prognosis (average survival 3.1 months). Gemcitabine could be given without severe toxicities in outpatient clinics. These results suggested that gemcitabine is currently a first-line therapeutic agent for advanced pancreatic cancer.     

Phase II study of gemcitabine in patients with advanced pancreatic cancer.

The efficacy and safety of gemcitabine at a starting dose of 800 mg m2 administered once a week for 3 weeks with 1 week''s rest was investigated in chemonaive patients with advanced and/or metastatic pancreatic cancer. Of 34 patients, 32 were evaluable for efficacy, 20 patients had metastatic stage IV disease, 25 had a performance status of 1 and 26 (76%) patients has significant pain on presentation. All responses were independently validated by an external oncology review board: two patients achieved a partial response that lasted 5.8 and 5.2 months (6.3%) and six patients were stable for at least 4 weeks. The median duration of survival for evaluable patients was 6.3 months (range 1.6-19.2 months). The tumour markers, CEA, CA 19-9 and CA 195 were serially measured in 16 patients. There was a good correlation with tumour response when all three markers were significantly decreased. In 4 of 16 patients, tumour marker levels decreased by > or = 60%, including the two responders, one patient who survived for 12 months and one patient who showed objective tumour shrinkage but was deemed ineligible for response evaluation because the disease was considered not to be bidimensionally measurable. Symptomatic benefits included improvement in performance status (17.2%), analgesic requirement (7.4%), pain score (28.6%) and nausea (27.3%). The mean number of cycles administered was 2.5 and the mean dosage received was 890 mg m2 per injection. Seventy-four per cent of dose administrations were given on schedule. Toxicity, particularly haematological toxicity, reported as the maximum WHO grade experienced by patients was mild. Infective episodes were rare and limited to WHO grade 2 (6.7%). Nausea and vomiting was generally modest (WHO grade 3, 26.7%). Other side-effects included mild transient flu-like symptoms (seven patients) and peripheral oedema (three patients), which was not associated with abnormal cardiac hepatic or renal function. Gemcitabine has modest activity in pancreatic cancer, a limited positive improvement on a range of patient benefit parameters and has a mild toxicity profile. For these reasons and because of its novel mode of action, gemcitabine warrants further investigation in combination studies in pancreatic cancer.     

A pharmacological study of celecoxib and gemcitabine in patients with advanced pancreatic cancer

Purpose To evaluate whether celecoxib alters the conversion of gemcitabine into its active metabolite, difluorodeoxycytidine triphosphate (dFdCTP), in peripheral blood mononuclear cells (PBMCs).Methods Patients with advanced pancreatic cancer who had not received chemotherapy and had acceptable organ function were eligible for the study. The initial dose of gemcitabine was 750 mg/m² administered intravenously at a rate of 10 mg/m²/min on days 1, 8, and 15 every 4 weeks. Celecoxib was administered orally at 400 mg twice a day starting 2 days after the first dose of gemcitabine. Serial blood samples were taken during the first and second gemcitabine infusions and the cellular dFdCTP levels from PBMCs were analyzed.Results Five patients received gemcitabine at 750 mg/m² and six patients received it at 650 mg/m². Severe adverse events included neutropenia, thrombocytopenia, enteritis, and gastric perforation. Two patient died early during treatment. Cellular pharmacology studies showed that the conversion of gemcitabine into dFdCTP was not affected by celecoxib.Conclusion Despite the increased clinical toxicities encountered with the combination, celecoxib did not alter the conversion of gemcitabine into its active metabolites in PBMCs. Gemcitabine 650 mg/m² infusion over 65 min on days 1, 8, and 15 every 4 weeks in combination with celecoxib at 400 mg twice a day was the dose recommended for further study.     

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。     

Safety and activity of masitinib in combination with gemcitabine in patients with advanced pancreatic cancer

Purpose

To evaluate the efficacy and safety of masitinib combined with gemcitabine in patients with advanced pancreatic cancer.

Patients and methods

Twenty-two non-randomised patients with unresectable, locally advanced (n = 9) or metastatic pancreatic cancer (n = 13) received oral masitinib (9 mg/kg/day) combined with standard gemcitabine. All patients were na?ve to systemic chemotherapy or radiotherapy. The primary endpoint was time-to-progression (TTP) with efficacy and safety analyses performed on the intent-to-treat population. Secondary endpoints included overall survival (OS), as well as, subgroup analyses according to baseline disease, and performance status.

Results

Overall median TTP was 6.4 months (95% CI [2.7–11.7]); 8.3 and 2.7 months, respectively, for locally advanced and metastatic patients; 6.4 and 0.8 months, respectively, for patients with KPS [80–100] or KPS [70]. Median OS was 7.1 months (95% CI [4.8–17.0]); 8.4 and 6.8 months for locally advanced or metastatic patients, respectively; 8.0 and 4.4 months in patients with KPS [80–100] or KPS [70], respectively. The 18-month observed survival rate was similar for locally advanced (22%) and metastatic patients (23%) and reached 28% for KPS [80–100] patients. The most common suspected adverse events were nausea, vomiting, rash, diarrhoea, peripheral oedema, anaemia, lymphopenia, thrombocytopenia, pyrexia, neutropenia, asthenia, leucopoenia, and abdominal pain, and most were of grades 1–2 severity.

Conclusions

The efficacy and safety of masitinib combined with gemcitabine are encouraging, with extended survival and median TTP that support initiation of a phase 3 trial.     

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。     

立体定向放射治疗联合吉西他滨与吉西他滨单药治疗局部晚期胰腺癌疗效比较

  [摘要]　　　目的 评价立体定向放射治疗联合吉西他滨与吉西他滨单药治疗局部晚期胰腺癌的疗效。方法 对治疗组56例胰腺癌患者行立体定向放射治疗(总剂量4000~4500CGY,10次分割)联合盐酸吉西他滨单药化疗(500mg/m2第1、8天)。对照组50例仅行盐酸吉西他滨单药化疗（500mg/m2第1、8、15天）。结果[给出各项主要数据] 治疗结束2个月CT复查,治疗组及化疗组局部控制率分别为98%、78%（P<0.05）,疼痛控制率分别为67%、17%（P<0.05）。治疗组中位PFS为14个月,较化疗组7.5个月明显延长（P<0.05）。治疗组与化疗组中位生存期分别为15.8、13.2个月（P>0.05）。结论 立体定向放射治疗联合吉西他滨治疗局部晚期胰腺癌较单纯化疗组近期疾病控制率较高,能延长患者无病生存期,显著提高患者的生存质量。     

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.     

Phase II study of gemcitabine, UFT and leucovorin in patients with advanced pancreatic cancer

The combination of gemcitabine with protracted 5-fluorouracil (5-FU) in the treatment of metastatic pancreatic cancer has shown activity with tolerable toxicity. The administration of UFT may simulate the effects of a protracted infusion of 5-FU. Patients with previously untreated metastatic or unresectable measurable pancreatic adenocarcinoma received gemcitabine (800 mg/m2 i.v., administered as an 80-min infusion on days 1, 8 and 15), UFT (200 mg/m2/day, on days 1 to 21), and oral leucovorin (90 mg/day, on days 1 to 21). Thirty patients were enrolled in this study. Five patients had partial responses, with an overall response rate of 17% (5/30), using the intent-to-treat principle (95% confidence interval (CI), 3-30%). Nine out of 25 (36%) patients experienced clinical benefit responses (95% CI; 17-55%). The median time to progression was 3.0 months, and the median overall survival was 7.2 months. The principal adverse event was neutropenia. The combination of gemcitabine, UFT, plus oral leucovorin shows significant antitumor activity and a beneficial clinical effect with an acceptable level of toxicity.     

吉西他滨联合奥沙利铂治疗晚期胰腺癌的临床观察

为观察吉西他滨（GEM）联合奥沙利铂（OXA）治疗晚期胰腺癌的有效性和安全性。对30例晚期胰腺癌患者,应用GEM1000mg/m2,静脉滴入30min,d1、d8;OXA100mg/m2,静脉滴入2h,d1,21d重复。至少接受2个周期的化疗。结果30例均可评价疗效,客观有效率20.00%,临床受益疗效分别为疼痛缓解率53.33%（16/30）,行为状态改善率45.33%（13/30）,体质量状态改善率36.33%（10/30）。主要不良反应为骨髓抑制、外周神经毒性及胃肠道反应,无治疗相关性死亡。初步研究结果显示,GEM联合OXA组成的GEMOX方案治疗晚期胰腺癌近期有效率较高,毒性较低,值得临床推广应用。     

Weekly full-dose gemcitabine and single-dose cisplatin with concurrent radiotherapy in patients with locally advanced pancreatic cancer

The aim of this study was to evaluate the efficacy and the toxicity of a full dose of gemcitabine and a single dose of cisplatin with concurrent radiotherapy in patients with locally advanced pancreatic cancer. Forty-one patients with locally advanced pancreatic cancer were enrolled. Patients received gemcitabine (1000 mg m(-2) on days 1, 8, 15, 29, and 36) and cisplatin (70 mg m(-2) on days 1 and 29) with concurrent radiotherapy (45 Gy in 25 fractions). Treatment was completed in 38 out of 41 patients (92.7%). The overall response rate was 24.4% (two complete and eight partial). Six patients (14.6%) underwent definite pancreatic resection and four had negative surgical margins. The intention of the treatment analysis showed that the median survival time and median time to tumour progression were 16.7 and 8.9 months. The 1- and 2-year survival rates were 63.3 and 27.9%, respectively. Overall survival was significantly longer in the low baseline CA19-9 group and therapeutic responders. Toxicities were tolerable and successfully managed by conservative treatments. The therapeutic scheme of a weekly full dose of gemcitabine and a single dose of cisplatin combined with external radiation is effective and might prolong the survival of patients with locally advanced pancreatic cancer.     

Phase I study of olaparib plus gemcitabine in patients with advanced solid tumours and comparison with gemcitabine alone in patients with locally advanced/metastatic pancreatic cancer

We identified olaparib 100 mg b.i.d. (intermittent) with gemcitabine 600 mg/m² as a tolerated dose combination, which could be considered for future evaluation. Given the encouraging response observed in patients with aBRCAm in previous olaparib trials, further investigation of clinical benefit in this patient subset compared with chemotherapy alone is warranted.BackgroundOlaparib (Lynparza™) is an oral poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitor that induces synthetic lethality in cancers with homologous recombination defects.Patients and methodsIn this phase I, dose-escalation trial, patients with advanced solid tumours received olaparib (50–200 mg capsules b.i.d.) continuously or intermittently (days 1–14, per 28-day cycle) plus gemcitabine [i.v. 600–800 mg/m²; days 1, 8, 15, and 22 (cycle 1), days 1, 8, and 15 (subsequent cycles)] to establish the maximum tolerated dose. A separate dose-escalation phase evaluated olaparib in tablet formulation (100 mg o.d./b.i.d.; days 1–14) plus gemcitabine (600 mg/m²). In an expansion phase, patients with genetically unselected locally advanced or metastatic pancreatic cancer were randomised 2 : 1 to the tolerated olaparib capsule combination dose or gemcitabine alone (1000 mg/m²).ResultsSixty-six patients were treated [dose-escalation phase,n = 44 (tablet cohort,n = 12); dose-expansion phase,n = 22 (olaparib plus gemcitabine,n = 15; gemcitabine alone,n = 7)]. In the dose-escalation phase, four patients (6%) experienced dose-limiting toxicities (raised alanine aminotransferase,n = 2; neutropenia,n = 1; febrile neutropenia,n = 1). Grade ≥3 adverse events were reported in 38/47 patients (81%) treated with olaparib capsules plus gemcitabine; most common were haematological toxicities (55%). Tolerated combinations were olaparib 100 mg b.i.d. capsule (intermittently, days 1–14) plus gemcitabine 600 mg/m² and olaparib 100 mg o.d. tablet (intermittently, days 1–14) plus gemcitabine 600 mg/m². There were no differences in efficacy observed during the dose-expansion phase.ConclusionsOlaparib 100 mg b.i.d. (intermittent dosing; capsules) plus gemcitabine 600 mg/m² is tolerated in advanced solid tumour patients, with no unmanageable/unexpected toxicities. Continuous dosing of olaparib or combination with gemcitabine at doses >600 mg/m² was not considered to have an acceptable tolerability profile for further study.ClinicalTrials.govNCT00515866.     

The role of second-line chemotherapy after gemcitabine failure in patients with advanced pancreatic cancer

Systemic chemotherapy with single-agent gemcitabine or a gemcitabine-based regimen still remains a standard of care for the treatment of patients with locally advanced and metastatic pancreatic cancer. To date, no standard treatment approach for patients that show progressive disease during gemcitabine therapy is defined. Several clinical trials have evaluated the safety and efficacy of second-line chemotherapy after gemcitabine failure in this patient population. Based on the currently available data, there is increasing evidence that selected patients may derive clinical benefit from salvage chemotherapy, also with regard to survival. However, results from large randomized Phase III trials are still lacking and therefore no evidence-based treatment recommendation can be given for patients with advanced pancreatic cancer after failure of first-line gemcitabine.     

Phase II trial of gemcitabine and S-1 for patients with advanced pancreatic cancer

Purpose

To evaluate the efficacy and safety of combined gemcitabine and S-1 as first-line chemotherapy for patients with locally advanced or metastatic pancreatic cancer.

Methods

This study included patients who had been diagnosed with unresectable, locally advanced or metastatic adenocarcinoma arising from the pancreas, which was histologically or cytologically confirmed and involved at least 1 unidimensionally measurable lesion. The regimen consisted of intravenous 1,000 mg/m² gemcitabine on day 1 and 8 combined with oral S-1 on days 1–14 every 21 days. The dosage of S-1 was based on the body surface area (BSA) as follows: 40 mg bid (total 80 mg/day) for a BSA of <1.25, 50 mg bid (total 100 mg/day) for a BSA of ≥1.25 but <1.5, and 60 mg bid (total 120 mg/day) for a BSA of ≥1.5. Treatment consisted of at least 2 courses unless rapid disease progression was noted. The primary end points were the response and disease control rates, and the secondary end points were toxicity and survival.

Results

Thirty-seven patients were enrolled between August 2005 and December 2010. The median number of chemotherapy cycles was 4 (range 1–28 cycles). Response to treatment could be evaluated in 31 patients. None of the patients showed complete response, but 5 achieved partial response. The response rate was thus 13.5 % [95 % confidence interval (CI) 2.7–24.3 %] in the intent-to-treat population. Sixteen patients (43.2 %; 95 % CI 27–59.5 %) showed stable disease, and the overall disease control rate was 56.8 % (95 % CI 40.6–72.9 %). For all 37 patients, the median progression-free survival was 4.6 months (95 % CI 1.8–7.6 month), and the median overall survival was 9.4 month (95 % CI 5.8–12.6 month). Chemotherapy-related grade 3/4 hematological toxicities were neutropenia (36.1 %), leucopenia (22.2 %), and anemia (13.9 %). The non-hematological toxicities were generally mild.

Conclusions

Combination chemotherapy with gemcitabine and S-1 was effective, convenient, and safe in patients with advanced pancreatic cancer.     

Phase II study to evaluate combining gemcitabine with flutamide in advanced pancreatic cancer patients

A phase II study was undertaken to determine the safety of combining flutamide with gemcitabine, with response rate being the primary end point. Twenty-seven patients with histologically proven, previously untreated, unresectable pancreatic adenocarcinoma received gemcitabine, 1 g m(-2) intravenously on days 1, 8 and 15 of a 28 day cycle, and flutamide 250 mg given orally three times daily. Treatment was halted if there was unacceptable toxicity, or evidence of disease progression. Toxicity was documented every cycle. Tumour assessment was undertaken after cycles 2 and 4, and thereafter at least every additional four cycles. One hundred and seventeen cycles of treatment were administered, median four cycles per patient (range 1-18). Gemcitabine combined with flutamide was well tolerated, with most toxicities being recorded as grade 1 or 2 and only nine treatment cycles associated with grade 3 toxicity. The most frequent toxicity was myelosuppression. One case of transient jaundice was recorded. The commonest symptomatic toxicity was nausea and vomiting. The response rate was 15% (four partial responses), median survival 6 months and 22% of patients were alive at 1 year. These results suggest antitumour activity of the combination therapy to be equivalent to single agent gemcitabine.     

A case of advanced pancreatic cancer treated with gemcitabine hydrochloride

We report the case of 75-year-old man with advanced pancreatic cancer who was successfully treated with gemcitabine. The patient was admitted to our hospital suffering from anorexia and body weight loss. CT and ERCP showed pancreatic tail cancer with Schnitzler metastasis. We judged that a curative operation was impossible. Gemcitabine was infused over 30 minutes on an outpatient basis (1,000 mg/m2/week x 3/4 weeks). After 4 courses, the tumor was reduced and the tumor markers decreased. Furthermore, the patient can take sufficient meals without any adverse effects. The patient continues to undergoing the therapy with gemcitabine, and his quality of life has been preserved.     

Combination chemotherapy with gemcitabine and S-1 for advanced pancreatic cancer

The incidence and mortality of pancreatic cancer has increased very rapidly in Japan. The five-year survival rate is still poor at less than 10%, because it is commonly considered to be linked to a high incidence of distant metastasis even at the initial diagnosis as well as to the tumor's resistance to anticancer agents. Although gemcitabine has been the most widely used chemotherapeutic agent in patients with advanced pancreatic cancer (APC), gemcitabine monotherapy has obvious limitations. Therefore, various combinations with other agents have been investigated to improving the survival of patients with APC. Under these circumstances, we conducted a phase I /II trial of gemcitabine with S-1, an oral fluorouracil derivative, to determine the maximum tolerated dose and to evaluate the activity and toxicity of such a combination in patients with APC. S-1 was administered orally twice daily each day for 14 days and gemcitabine on days 8 and 15 of each cycle, and this cycle was repeated every 21 days. As a result, S-1 30 mg/m2 orally twice daily and gemcitabine 1,000 mg/m2 were selected as the recommended dose. The toxicities observed were mainly hematological ones with mild non-hematological toxicities. An encouragingly high response rate was observed. This result is very promising, but the survival benefit in comparison with gemcitabine monotherapy needs to be confirmed in a future randomized clinical trial.