The prognostic significance of patient-reported outcomes in pancreatic cancer cachexia

Data from a clinical study of 86 pancreatic cancer patients with involuntary, significant weight loss (cachexia) were used to explore the relationship between patient-reported outcomes (PROs) and survival. In all, 28 pancreatic cancer patients with cachexia were given gemcitabine (Gemzar) plus 3 mg/kg of infliximab (Remicade), 28 were given gemcitabine plus 5 mg/kg of infliximab, and 30 were given gemcitabine plus placebo in a double-blinded, phase II, multicenter trial. PRO endpoints included scores from the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Functional Assessment of Anorexia/ Cachexia Therapy (FAACT), Brief Pain Inventory (BPI), and the Short-Form 36 general health survey (SF-36). Population mean scores at baseline indicated fatigue problems (FACIT-F), nutritional health issues (FAACT), and mild-to-moderate pain (BPI "worst pain" score). Baseline normalized SF-36 values for physical functioning, vitality, and mental health indicated substantial impairment. Baseline fatigue and physical-functioning scores predicted survival as well as, or better than, baseline Karnofsky Performance Status or hemoglobin level. A cut-point in the FACIT-F score (median < or = 30) strongly predicted mortality; patients with greater fatigue had a lower median overall survival than did those with less fatigue. These findings supported several features of an a priori clinical-benefit model. Patient-reported fatigue provided powerful prognostic information; tracking of this symptom may be useful for treatment planning and medical monitoring of advanced-stage pancreatic cancer patients with cachexia. These results must be confirmed by larger trials.     

Herceptin and gemcitabine for metastatic pancreatic cancers that overexpress HER-2/neu

PURPOSE: To determine the response rate and toxicities of Herceptin and gemcitabine for patients with metastatic pancreatic adenocarcinomas that overexpress HER-2/neu. METHODS AND MATERIALS: Patients with metastatic pancreatic cancer with 2+/3 + HER-2/neu expression by immunohistochemistry were eligible. Patients received gemcitabine, 1 g/m2/week, for 7 of 8 weeks followed by 3 of every 4 weeks, and Herceptin, 4 mg/kg loading dose, followed by 2 mg/kg/week. RESULTS: Screening logs demonstrated the rate of HER-2/neu overexpression was 16%. Thirty-four patients were enrolled. Thirty patients (88%) had pancreatic cancers with 2+ overexpression and 4 patients (12%) had 3+ overexpression. Toxicity was similar to gemcitabine alone. Confirmed partial responses were observed in 2 of 32 patients (6%). Thirteen of 32 patients (41%) had either a partial response or a >50% reduction in CA 19-9. The median survival for all 34 patients was 7 months, and the 1-year survival was 19%. CONCLUSION: The response rate of Herceptin and gemcitabine is similar to gemcitabine alone. The 7-month median survival in patients with metastatic pancreatic cancer suggests there may be a modest benefit for some patients. Infrequent HER-2/neu overexpression limits the role of targeting the HER-2/neu gene and prevents definitive conclusions on the addition of Herceptin to gemcibine for patients with pancreatic cancer.     

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.     

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).     

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.     

Gemcitabine versus FLEC regimen given intra-arterially to patients with unresectable pancreatic cancer: a prospective, randomized phase III trial of the Italian Society for Integrated Locoregional Therapy in Oncology

Gemcitabine is considered the gold standard treatment for unresectable pancreatic adenocarcinoma. Intra-arterial drug administration had shown some interesting results in small phase II studies. In this study, patients were randomly assigned to receive gemcitabine at a dose of 1,000 mg/m2 over 30 minutes intravenously weekly for 7 weeks, followed by 1 week of rest, then weekly for 3 weeks every 4 weeks or FLEC: 5-fluoruracil 1,000 mg/m2, leucovorin 100 mg/m2, epirubicin 60 mg/m2, carboplatin 300 mg/m2 infused bolus intra-arterially into celiac axis at a 3-week interval 3 times or 5-fluorouracil 400 mg/m2 plus folinic acid 20 mg/m2 for 5 days every 4 weeks for 6 cycles. The primary endpoint was overall survival, while time to treatment failure, response rate, clinical benefit response were secondary endpoints. Sixty-seven patients were randomly allocated gemcitabine and 71 were allocated FLEC intra-arterially. Patients treated with FLEC lived for significantly longer than patients on gemcitabine (p=0.036). Survival at 1 year increased from 21% in the gemcitabine group to 35% in the FLEC group. Median survival was 7.9 months in the FLEC group and 5.8 months in the gemcitabine group. Median time to treatment failure was longer with FLEC (5.3 vs 4.2 months for FLEC vs gemcitabine respectively; p=0.013). Clinical benefit was similar in both groups (17.9% for gemcitabine and 26.7% for FLEC; p=NS). CT-scan partial response was similar in both groups (5.9% for gemcitabine and 14% for FLEC; p=NS). Toxicity profiles were different. Compared with gemcitabine, the FLEC regimen given intra-arterially improved survival in patients with unresectable pancreatic adenocarcinoma.     

A randomized,placebo-controlled phase 2 study of ganitumab (AMG 479) or conatumumab (AMG 655) in combination with gemcitabine in patients with metastatic pancreatic cancer

BackgroundWe evaluated the efficacy and safety of ganitumab (a mAb antagonist of insulin-like growth factor 1 receptor) or conatumumab (a mAb agonist of human death receptor 5) combined with gemcitabine in a randomized phase 2 trial in patients with metastatic pancreatic cancer.Patients and methodsPatients with a previously untreated metastatic pancreatic adenocarcinoma and an Eastern Cooperative Oncology Group (ECOG) performance status ≤1 were randomized 1 : 1 : 1 to i.v. gemcitabine 1000 mg/m² (days 1, 8, and 15 of each 28-day cycle) combined with open-label ganitumab (12 mg/kg every 2 weeks [Q2W]), double-blind conatumumab (10 mg/kg Q2W), or double-blind placebo Q2W. The primary end point was 6-month survival rate.ResultsIn total, 125 patients were randomized. The 6-month survival rates were 57% (95% CI 41–70) in the ganitumab arm, 59% (42–73) in the conatumumab arm, and 50% (33–64) in the placebo arm. The grade ≥3 adverse events in the ganitumab, conatumumab, and placebo arms, respectively, included neutropenia (18/22/13%), thrombocytopenia (15/17/8%), fatigue (13/12/5%), alanine aminotransferase increase (15/5/8%), and hyperglycemia (18/2/3%).ConclusionsGanitumab combined with gemcitabine had tolerable toxicity and showed trends toward an improved 6-month survival rate and overall survival. Additional investigation into this combination is warranted. Conatumumab combined with gemcitabine showed some evidence of activity as assessed by the 6-month survival rate.     

Combination chemotherapy with gemcitabine and biotherapy with opioid growth factor (OGF) enhances the growth inhibition of pancreatic adenocarcinoma

Gemcitabine is the standard of care for advanced pancreatic neoplasia, and exerts its effect through inhibition of DNA synthesis. However, gemcitabine has limited survival benefits. Opioid growth factor (OGF) is an autocrine-produced peptide that interacts with the nuclear receptor, OGFr, to inhibit cell proliferation but is not cytotoxic or apoptotic. The present study was designed to examine whether a combination of chemotherapy with gemcitabine and biotherapy with OGF is more effective than either agent alone in inhibiting pancreatic cancer growth in vitro and in vivo. The combination of OGF (10^–6 M) and gemcitabine (10^–8 M) reduced MIA PaCa-2 cell number from control levels by 46% within 48 h, and resulted in a growth inhibition greater than that of the individual compounds. OGF in combination with 5-fluorouracil also depressed cell growth more than either agent alone. The action of OGF, but not gemcitabine, was mediated by a naloxone-sensitive receptor, and was completely reversible. OGF, but no other endogenous or exogenous opioids, altered pancreatic cancer growth in tissue culture. The combination of OGF and gemcitabine also repressed the growth of another pancreatic cancer cell line, PANC-1. MIA PaCa-2 cells transplanted into athymic mice received 10 mg/kg OGF daily, 120 mg/kg gemcitabine every 3 days; 10 mg/kg OGF daily and 120 mg/kg gemcitabine every 3rd day, or 0.1 ml of sterile saline daily. Tumor incidence, and latency times to tumor appearance, of mice receiving combined therapy with OGF and gemcitabine, were significantly decreased from those of the control, OGF, and gemcitabine groups. Tumor volumes in the OGF, gemcitabine, and OGF/gemcitabine groups were markedly decreased from controls beginning on days 14, 12, and 8, respectively, after tumor cell inoculation. Tumor weight and tumor volume were reduced from control levels by 36–85% in the OGF and/or gemcitabine groups on day 45 (date of termination), and the group of mice exposed to a combination of OGF and gemcitabine had decreases in tumor size of 70% and 63% from the OGF or the gemcitabine alone groups, respectively. This preclinical evidence shows that combined chemotherapy (e.g. gemcitabine) and biotherapy (OGF) provides an enhanced therapeutic benefit for 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。     

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.     

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。     

Chemotherapy for elderly patients with advanced non-small-cell lung cancer: the Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial

BACKGROUND: Vinorelbine prolongs survival and improves quality of life in elderly patients with advanced non-small-cell lung cancer (NSCLC). Some studies have also suggested that gemcitabine is well tolerated and effective in such patients. We compared the effectiveness and toxicity of the combination of vinorelbine plus gemcitabine with those of each drug given alone in an open-label, randomized phase III trial in elderly patients with advanced NSCLC. METHODS: Patients aged 70 years and older, enrolled between December 1997 and November 2000, were randomly assigned to receive intravenous vinorelbine (30 mg/m(2) of body surface area), gemcitabine (1200 mg/m(2)), or vinorelbine (25 mg/m(2)) plus gemcitabine (1000 mg/m(2)). All treatments were delivered on days 1 and 8 every 3 weeks for a maximum of six cycles. The primary endpoint was survival. Survival curves were drawn using the Kaplan-Meier method and analyzed by the Mantel-Haenszel test. Secondary endpoints were quality of life and toxicity. RESULTS: Of 698 patients available for intention-to-treat analysis, 233 were assigned to receive vinorelbine, 233 to gemcitabine, and 232 to vinorelbine plus gemcitabine. Compared with each single drug, the combination treatment did not improve survival. The hazard ratio of death for patients receiving the combination treatment was 1.17 (95% confidence interval [CI] = 0.95 to 1.44) that of patients receiving vinorelbine and 1.06 (95% CI = 0.86 to 1.29) that of patients receiving gemcitabine. Although quality of life was similar across the three treatment arms, the combination treatment was more toxic than the two drugs given singly. CONCLUSION: The combination of vinorelbine plus gemcitabine is not more effective than single-agent vinorelbine or gemcitabine in the treatment of elderly patients with advanced NSCLC.     

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.     

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.     

吉西他滨对人胰腺癌裸鼠移植瘤的放疗增敏作用

目的：评价吉西他滨对人胰腺癌移植瘤的放疗增敏作用。方法：建立人胰腺癌裸鼠移植瘤模型,36只裸鼠随机分为6组：对照组（A）、单纯放疗组（B）、吉西他滨25mg/kg组（C）、吉西他滨50mg/kg组（D）、吉西他滨25mg/kg＋放疗组（E）、吉西他滨50mg/kg＋放疗组（F）。对照组予腹腔注射生理盐水,单纯放疗组荷瘤鼠背部肿瘤局部以6MeV电子线照射。C、D组分别以25mg/kg、50mg/kg吉西他滨腹腔注射,E、F组分别以25mg/kg、50mg/kg吉西他滨腹腔注射加背部肿瘤6MeV电子线照射。然后每两天测量肿瘤的长短径、比较各组的瘤体积、肿瘤生长延缓天数、抑瘤率,利用增敏系数（EF）评价吉西他滨的增敏作用。结果：与对照组比较,25mg/kg、50mg/kg单剂量吉西他滨对移植瘤生长有明显抑制作用（P〈0.01）;两组剂量吉西他滨联合放疗组局部肿瘤生长受到明显抑制,抑瘤率分别为88.22%、91.23%,明显高于单纯放疗组（44.11%,P〈0.05）和吉西他滨两个剂量单药组（72.88%、77.53%,P〈0.05）。联合组（E、F组）肿瘤生长延缓天数（瘤体积增长2倍）分别为9、15天,高于单纯放疗组（4天,P〈0.05）和吉西他滨两个剂量单药组（4、4天,P〈0.05）。结论：吉西他滨可显著增强人胰腺癌裸鼠移植瘤放射治疗敏感性。     

Modulation of GemOx chemotherapy according to CIRS in elderly patients with advanced pancreatic cancer

The present study evaluated activity and toxicity of modulated doses of gemcitabine associated to oxaliplatin in patients with secondary CIRS and with locally advanced pancreatic adenocarcinoma (LAPC) and metastatic pancreatic adenocarcinoma (MPC). Since January 2006, untreated LAPC and MPC patients have been assessed with ADL, IADL, CIRS to modulate chemotherapy dosages according to co-morbidity stage. Patiens aged<75 years, co-morbidity stage primary/intermediate, or ≥75 years and co-morbidity stage primary, received gemcitabine 1,000 mg/m2 as a 10 mg/m2/min infusion on day 1 and oxaliplatin 70 mg/m2 as a 2-h infusion on day 2 every 2 weeks. Patiens aged<75 years, co-morbidity stage secondary or ≥75 years and co-morbidity stage intermediate/secondary patients received gemcitabine 800 mg/m2. Primary endpoint was the overall response rate (ORR). Secondary endpoints were disease control rate (DCR), PFS, OS and toxicity. Thirty-one patients were recruited: 26% (8/31) LAPC and 74% (23/31) MPC; median age 69 years. Co-morbidity stage primary/intermediate, 19; secondary, 12. Twenty-seven valuable patients: ORR 30% (CI±0.14); disease control rate 85% (CI±0.18). Median follow-up 13 months: median PFS and OS were 6 and 15 months, respectively. Valuable cycles 140. Grade 3/4 toxicity per patient: leukopenia, 18.5%; neutropenia, 55,5%; thrombocytopenia, 7.4%; SGOT/SGPT, 7.4%; gamma-GT, 7.4%; fever without neutropenia, 3.7%. Median received dose intensity: gemcitabine 400 mg/m2/w; oxaliplatin 35 mg/m2/w. Modulation of GemOx chemotherapy according, to CIRS stage in advanced pancreatic cancer confirms reported efficacy and tolerability.     

国产吉西他滨联合重组人血管内皮抑制素二线治疗晚期胰腺癌的临床观察

目的：观察国产吉西他滨（泽菲）联合重组人血管内皮抑制素（恩度）二线治疗晚期胰腺癌的近期疗效及毒性反应。方法：15例患者均经病理学或影像学确诊为胰腺癌，全组病例均采用泽菲联合恩度治疗：泽菲1000mg／m^2，静滴30分钟，每周1次，连用2周；恩度7．5mg／m^2，一般为15rag／次，加入生理盐水500ml中缓慢静脉滴注，滴注时间为3～4小时，第1～14天连续给药。每3周重复。结果：15例患者中，可评价疗效患者14例，无CR病例，PR1例，SD4例，PD9例，疾病控制率35．7％（5／14）。临床受益反应率40．0％（6／15）。主要毒副反应为骨髓抑制，恶心呕吐以及心电图异常。结论：泽菲联合恩度方案治疗晚期胰腺癌疗效较好，毒副反应轻，耐受性良好，值得进一步研究。     

A clinical study assessing the tolerability and biological effects of infliximab, a TNF-alpha inhibitor, in patients with advanced cancer

BACKGROUND: Tumour necrosis factor-alpha (TNF-alpha) is an important regulator of the chronic inflammation contributing to tumour progression. Infliximab, an anti-TNF-alpha monoclonal antibody was investigated in this trial of patients with advanced cancer. The primary objectives were to determine the safety profile and biological response of infliximab in a cancer population. Clinical response was a secondary objective. PATIENTS AND METHODS: Forty-one patients received infliximab at 5 mg/kg (n = 21) or 10 mg/kg (n = 20) i.v. at 0 and 2 weeks and then every 4 weeks. Post-treatment samples were measured for changes in plasma and serum TNF-alpha, CCL2, IL-6 and C-reactive protein (CRP). RESULTS: Infliximab was well tolerated with no dose-limiting toxic effects. At both doses of infliximab, neutralisation of serum TNF-alpha was observed after 1 h while plasma CCL2, IL-6 and serum CRP were decreased 24 and 48 h following infliximab administration. Seven patients experienced disease stablisation (range 10-50+ weeks). There was no evidence of disease acceleration in any patient. CONCLUSIONS: Infliximab treatment was safe and well tolerated in patients with advanced cancer. There was evidence of biological activity with baseline TNF-alpha and CCL2 being correlated with infliximab response.     

A phase 3 randomized,double-blind,placebo-controlled trial of ganitumab or placebo in combination with gemcitabine as first-line therapy for metastatic adenocarcinoma of the pancreas: the GAMMA trial

This double-blind, phase 3 study assessed the efficacy and safety of ganitumab plus gemcitabine as first-line treatment of metastatic pancreatic cancer. The study was stopped after a preplanned futility analysis indicated a positive outcome was unlikely at primary analysis. Ganitumab plus gemcitabine had manageable toxicity but did not improve OS versus gemcitabine alone in unselected patients.BackgroundThis double-blind, phase 3 study assessed the efficacy and safety of ganitumab combined with gemcitabine as first-line treatment of metastatic pancreatic cancer.Patients and methodsPatients with previously untreated metastatic pancreatic adenocarcinoma were randomly assigned 2 : 2 : 1 to receive intravenous gemcitabine 1000 mg/m² (days 1, 8, and 15 of each 28-day cycle) plus placebo, ganitumab 12 mg/kg, or ganitumab 20 mg/kg (days 1 and 15 of each cycle). The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), safety, and efficacy by levels of circulating biomarkers.ResultsOverall, 322 patients were randomly assigned to placebo, 318 to ganitumab 12 mg/kg, and 160 to ganitumab 20 mg/kg. The study was stopped based on results from a preplanned futility analysis; the final results are reported. Median OS was 7.2 months [95% confidence interval (CI), 6.3-8.2] in the placebo arm, 7.0 months (95% CI, 6.2-8.5) in the ganitumab 12-mg/kg arm [hazard ratio (HR), 1.00; 95% CI, 0.82-1.21; P = 0.494], and 7.1 months (95% CI, 6.4-8.5) in the ganitumab 20-mg/kg arm (HR, 0.97; 95% CI, 0.76-1.23; P = 0.397). Median PFS was 3.7, 3.6 (HR, 1.00; 95% CI, 0.84-1.20; P = 0.520), and 3.7 months (HR, 0.97; 95% CI, 0.77–1.22; P = 0.403), respectively. No unexpected toxicity was observed with ganitumab plus gemcitabine. The circulating biomarkers assessed [insulin-like growth factor-1 (IGF-1), IGF-binding protein-2, and -3] were not associated with a treatment effect on OS or PFS by ganitumab.ConclusionGanitumab combined with gemcitabine had manageable toxicity but did not improve OS, compared with gemcitabine alone in unselected patients with metastatic pancreatic cancer.Clinical trial registrationClinicalTrials.gov NCT01231347.     

Ceravolo

Abstract

Gemcitabine is considered the gold standard treatment for unresectable pancre-atic adenocarcinoma. Intra-arterial drug administration had shown some interesting results in small phase II studies.

In this study, patients were randomly assigned to receive gemcitabine at a dose of 1,000 mg/m² over 30 minutes intravenously weekly for 7 weeks, followed by 1 week of rest, then weekly for 3 weeks every 4 weeks or FLEC: 5-fluoruracil 1,000 mg/m², leucovorin 100 mg/m², epirubicin 60 mg/m², carboplatin 300 mg/m² infused bolus intra-arterially into celiac axis at a 3-week interval 3 times or 5-fluor-ouracil 400 mg/m2 plus folinic acid 20 mg/m2 for 5 days every 4 weeks for 6 cycles. The primary endpoint was overall survival, while time to treatment failure, response rate, clinical benefit response were secondary endpoints. Sixty-seven patients were randomly allocated gemcitabine and 71 were allocated FLEC intra-arterially. Patients treated with FLEC lived for significantly longer than patients on gemcitabine (p=0.036). Survival at 1 year increased from 21% in the gemcitabine group to 35% in the FLEC group. Median survival was 7.9 months in the FLEC group and 5.8 months in the gemcitabine group. Median time to treatment failure was longer with FLEC (5.3 vs 4.2 months for FLEC vs gemcitabine respectively; p=0.013). Clinical benefit was similar in both groups (17.9% for gemcitabine and 26.7% for FLEC; p=NS). CT-scan partial response was similar in both groups (5.9% for gemcitabine and 14% for FLEC; p=NS). Toxicity profiles were different.

Compared with gemcitabine, the FLEC regimen given intra-arterially improved survival in patients with unresectable pancreatic adenocarcinoma.