A randomized phase II of gemcitabine and sorafenib versus sorafenib alone in patients with metastatic pancreatic cancer

Purpose Patients with metastatic pancreatic cancer have limited therapeutic options. The role of the Ras-Raf-MAPK pathway and of vascular endothelial growth factor in pancreatic carcinogenesis provided the rational to evaluate the efficacy of sorafenib with or without gemcitabine in a randomized phase II study. Methods Patients with metastatic pancreatic cancer were randomized to sorafenib alone (arm A) or sorafenib with gemcitabine (arm B). Results Arm A was closed to accrual at interim analysis due to the lack of objective response. Median PFS and OS were 2.3 and 4.3 months respectively. There was one partial response among the 37 patients in arm B. Median PFS and OS were 2.9 and 6.5 months respectively. There were more grade 3 and 4 toxicities in arm B with the most common being neutropenia (17%), thrombocytopenia (8%), alkaline phosphatase elevation (14%), venous thromboembolism (8%), diarrhea, hypokalemia and ALT elevation (5%) each. Several associations were noted between single nucleotide polymorphisms in ribonucleotide reductase, Cox-2, vascular endothelial growth factor and survival in patients treated with gemcitabine and sorafenib. Conclusions Neither sorafenib alone or sorafenib in combination with gemcitabine manifested promising activity in metastatic pancreatic cancer.     

A phase II study of the halichondrin B analog eribulin mesylate in gemcitabine refractory advanced pancreatic cancer

Background Eribulin mesylate is a halichondrin B analog that inhibits microtubule dynamics. Pre-clinical studies have suggested anti-tumor activity in pancreatic cancer. This phase II study of eribulin in patients with advanced pancreatic cancer previously treated with gemcitabine was conducted by the Princess Margaret Hospital Phase II consortium. Patients and Methods Eligibility criteria included locally advanced or metastatic pancreatic adenocarcinoma and previous treatment with gemcitabine. The study was a single arm phase II trial using a Simon 2-stage design. The primary endpoint was response rate, secondary endpoints included time to progression and overall survival. Results Fifteen patients were enrolled, 14 received treatment, and 12 were evaluable for response. The median age was 61, and the majority of patients were ECOG performance status 1. Grade 3 or greater adverse events included neutropenia (29%), fatigue (14%), peripheral neuropathy (7%) and thrombosis (7%). There were no complete or partial responses and therefore the study was closed after the first stage. The best response was stable disease in 5/12 (42%) of patients. Of these five patients, three had stable disease for 9 months or greater. Median time to progression was 1.4 months, and median overall survival was 6.1 months. Conclusion Eribulin was well tolerated but did not result in any objective responses in gemcitabine refractory pancreatic cancer. However, several patients had prolonged stable disease, suggesting that further studies of eribulin in pancreatic cancer may be warranted.     

Pilot study of irinotecan/oxalipltin (IROX) combination chemotherapy for patients with gemcitabine- and 5-fluorouracil- refractory pancreatic cancer

Background Gemcitabine- and 5-fluorouracil (5-FU)- based chemotherapy is a commonly used adjuvant or palliative treatment for patients with pancreatic cancer. However, a standard chemotherapy regimen has yet to be developed for patients refractory to gemcitabine and 5-FU treatment. We attempted to evaluate the efficacy and safety of a combination of irinotecan and oxaliplatin (IROX) as a salvage treatment for patients with gemcitabine- and 5-FU- refractory pancreatic cancer. Patients and Methods Patients with advanced pancreatic cancer who were refractory to prior gemcitabine- and 5-FU- based chemotherapy were enrolled in this study. IROX chemotherapy was administered as follows: Irinotecan, 150 mg/m² on day 1; and oxaliplatin, 85 mg/m² on day 1 over 90 min every 2 weeks. Result From Mar. 2006 to Dec. 2008, a total of 14 patients were administered 50 cycles of chemotherapy. The male-to-female ratio of the patient group was 11:3. These patients ranged in age from 48 to 73 years (median 65.5 years old). 3 patients (21.4%) evidenced partial responses. four patients (28.6%) exhibited stable disease. The median time to progression and overall survival time were 1.4 (95% CI: 1.2–1.6) months and 4.1 (95% CI: 2.0–6.2) months, respectively. Major hematologic toxicities included grade 1–2 anemia (88%), neutropenia (36%), thrombocytopenia (30%), and grade 3–4 neutropenia (10%). The most frequently detected non-hematological toxicities were grade 3 diarrheas (14%). Conclusion The IROX regimen appears to constitute a feasible and tolerable salvage therapy in patients with advanced pancreatic cancer who have been previously treated with gemcitabine- and 5-FU-based chemotherapy.     

A randomized phase II study of recombinant human endostatin plus gemcitabine/cisplatin compared with gemcitabine/cisplatin alone as first-line therapy in advanced non-small-cell lung cancer

Purpose Studies indicate that recombinant human endostatin (rh-endostatin) can inhibit tumor endothelial cell proliferation, angiogenesis, and tumor growth. This study assessed the efficacy of the combination of standard gemcitabine plus cisplatin chemotherapy with rh-endostatin in patients with non-small-cell lung cancer (NSCLC). Patients and Methods Chemotherapy-naive patients with stage IIIB to IV NSCLC were randomly (1:1) assigned to receive gemcitabine/cisplatin chemotherapy alone or with 7.5 mg/ m² of intravenously rh-endostatin on days 1 to 14 of each 3-week cycle. The primary end point was objective response rate (ORR). Results Baseline characteristics were similar between treatment arms. The best ORRs for rh-endostatin arm (n = 33) and chemotherapy-alone arm were 37.5% (95% CI: 21.3 to 47.2%) and 28.6% (95% CI: 19.8 to 37.6%), respectively. Median survival was 12.4 months in the rh-endostatin arm and 9.8 months in the chemotherapy-alone arm, and 1-year survival was 51.6% and 38.7%, respectively. Mild palpitions, diarrhea, and liver dysfunction were the most common rh-endostatin-related adverse events. Grade 3/4 hematological toxicities were all reported similar for patients in the two arms. Conclusion The addition of rh-endostatin to gemcitabine plus cisplatin chemotherapy for first-line treatment of NSCLC improves objective response and may improve survival.     

Phase II study of calcitriol-enhanced docetaxel in patients with previously untreated metastatic or locally advanced pancreatic cancer

Summary   Purpose: To determine the safety and efficacy of weekly high-dose oral calcitriol and docetaxel, given to patients with non-resectable, incurable pancreatic cancer. Patients and Methods: Twenty-five patients were enrolled onto this phase II study. Patients were treated with oral calcitriol 0.5 μg/kg on day 1, followed by docetaxel 36 mg/m² IV on day 2, administered weekly for three consecutive weeks, followed by 1 week without treatment. Patients followed a low-calcium diet and increased their hydration. The primary end-point of the trial was time-to-progression. Results: Three of 25 patients attained a partial response (12%, 95% CI 3 to 31) and seven (28%) achieved stable disease. Median time-to-progression was 15 weeks, and median overall survival was 24 weeks. Toxicities observed (hyperglycemia, fatigue) were mostly attributable to the docetaxel or its pre-treatment. Conclusions: This regimen of high-dose calcitriol with docetaxel may have activity in incurable pancreatic cancer, with a modest increase in TTP when compared to historical findings using single-agent docetaxel. However, results do not appear superior to those seen with gemcitabine, with or without erlotinib.     

A Phase II study of celecoxib,gemcitabine, and cisplatin in advanced pancreatic cancer

Summary Background. Pancreatic cancer is amongst the most chemoresistant malignancies. Expression of the cyclooxygenase-2 (COX-2) enzyme plays a major role in tumor progression and resistance to therapy. A Phase II study was undertaken to determine the effect of gemcitabine by fixed-dose rate infusion (FDR), cisplatin and the COX-2 inhibitor, celecoxib, on the 6-month survival rate in patients with metastatic pancreatic cancer. Methods. The eligibility criteria included a pathologically or cytologically confirmed diagnosis of adenocarcinoma of the pancreas. No prior gemcitabine therapy was allowed. Patients received a combination of gemcitabine 1000 mg/m² over 100 minutes, cisplatin 35 mg/m² I.V. on days 1 and 8, and celecoxib continuously at a daily dose of 800 mg. Cycles were repeated every 21 days. Results. Twenty-two patients with metastatic pancreas cancer were enrolled (median age, 59.5 years; M:F, 13:9). The median number of cycles was 2 per patient. The median survival time was 5.8 months (90% CI, 3.6–7.6 months). The probability of survival at 6 months was 46% (90% CI, 27–62%). The major toxicity was neutropenia with grade 3 or 4 toxicities seen in 65% of patients. Conclusions. The addition of celecoxib to gemcitabine (by FDR) and cisplatin did not appear to increase activity of the chemotherapy doublet in patients with advanced pancreatic cancer. Celecoxib alone may not be sufficient to sensitize pancreatic cancer to the effects of conventional cytotoxic therapy.     

The epothilone B analogue ixabepilone in patients with advanced hepatobiliary cancers: a trial of the University of Chicago Phase II Consortium

Purpose Hepatobiliary cancers respond poorly to cytotoxic chemotherapy. We evaluated the activity and safety of ixabepilone, an epothilone B analogue which stabilizes microtubules, in a phase II trial in patients with advanced cancers of the gallbladder, bile duct, and liver. Methods Eligible patients had previously-untreated, histologically-proven unresectable hepatobiliary cancer. Ixabepilone, 40 mg/m², was administered intravenously over 3 h every 21 days. Results Between January 2002 and April 2005, 54 patients (19 hepatocelluar carcinoma, 13 cholangiocarcinomas, 22 gallbladder carcinomas) were enrolled; 47 patients were evaluable for efficacy. The objective response rate was 8.5%; 51% had stable disease. Median overall survival was 7.0 months (95% CI, 5.0 to 10.8 months) and median progression-free survival was 2.6 months (95% CI, 1.4 to 4.1 months). Grade 3/4 toxicities included neutropenia (39%), fatigue (9%), allergic/hypersensitivity reaction (4%) and sensory neuropathy (4%). Conclusion Single agent ixabepilone has limited activity in advanced hepatobiliary cancers.     

Phase I dose-finding study of sorafenib in combination with capecitabine and cisplatin as a first-line treatment in patients with advanced gastric cancer

Background To define maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and preliminary efficacy of sorafenib plus capecitabine/cisplatin in advanced gastric cancer (AGC) patients. Methods Four dose-level combinations were tested in a standard 3 + 3 dose escalation design. Level 1: sorafenib 400 mg/d, capecitabine 1,600 mg/m²/d, cisplatin 80 mg/m². Level 2: sorafenib 800 mg/d, capecitabine 1,600 mg/m²/d, cisplatin 80 mg/m². Level 3: sorafenib 800 mg/d, capecitabine 2,000 mg/m²/d, cisplatin 80 mg/m². Level 1A: sorafenib 800 mg/d, capecitabine 1,600 mg/m²/d, cisplatin 60 mg/m². Results There were 1 DLT at Level 2, and 2 DLTs at Level 3 (Level 3 was MTD). Since the relative dose intensity (RDI) of sorafenib and capecitabine could not be maintained at Level 2, Level 1A was newly investigated. As no DLT was observed and RDI remained above 80%, Level 1A is the recommended dose for the next clinical trial. Objective response rate was 62.5% (10 of 16 patients, 95% CI; 38.8–86.2%). Median progression-free survival and overall survival were 10.0 months (95% CI; 7.4–13.8) and 14.7 months (95% CI; 12.0–20.0), respectively. Conclusions Sorafenib 400 mg bid daily, capecitabine 800 mg/m² bid (days 1–14), and cisplatin 60 mg/m² (day 1) is recommended for further development in AGC.     

A phase II trial of Triapine® (NSC# 663249) and gemcitabine as second line treatment of advanced non-small cell lung cancer: Eastern Cooperative Oncology Group Study 1503

Background: The objective of ECOG 1503 was to determine the response rate of this combination in the second-line treatment of advanced NSCLC. Methods: Triapine 105 mg/m² IV on days 1, 8, and 15, and gemcitabine 1,000 mg/m² on days 1, 8, and 15, of a 28 day cycle. Results: Eighteen patients enrolled. Three patients were not eligible due to protocol violations. No objective antitumor responses were seen. Three patients (20%) experienced stable disease (90% CI 5.7–44%). Median overall survival: 5.4 months (95% CI 4.2–11.6 months); median time to progression: 1.8 months (95% CI 1.7–3.5 months). Five patients developed acute infusion reactions to Triapine? related to elevated methemoglobinemia. Patients with MDR1 variant genotypes of C3435T experienced superior overall survival compared to non-variants (13.3 vs. 4.3 months, respectively, p = 0.023). Conclusion: This regimen did not demonstrate activity in relapsed NSCLC. Prolonged survival seen with MDR1 variant genotypes is hypothesis-generating.     

Phase II study of gemcitabine and cisplatin in chemonaive patients with advanced epithelial ovarian cancer

This phase II study evaluated the activity of gemcitabine (Gemzar) plus cisplatin (Platinol) as first-line treatment of advanced epithelial ovarian cancer. Forty-two chemonaive patients with advanced (stage III and IV) epithelial ovarian cancer received gemcitabine 1,250 mg/m(2) on days 1 and 8 and cisplatin 100 mg/m(2) on day 1, every 3 weeks, up to eight cycles. The median number of cycles completed was 5 (range 2-8). Of the 41 patients evaluable for tumor response, 20 had a partial response and nine had a complete response, for an overall clinical and pathologic response rate of 70.7% (95% CI 56.8-84.6%). Median overall survival for all 42 patients was 23.4 months (95% CI 15.9-29.9 months) and the median progression-free survival time was 10.4 months (95% CI 9.4-13.5 months). The combination was generally manageable. Hematologic toxicity (grade 3/4 neutropenia: 31.0/21.4%; grade 3/4 thrombocytopenia: 9.5/4.8%; grade 3/4 anemia: 11.9/0%) and nausea and vomiting (grade 3/4: 35.7/31.0%) were the most common toxicities. There was one toxic death (septic shock due to hematologic toxicity-induced infection). We conclude that gemcitabine plus cisplatin is active and feasible as first-line treatment of advanced epithelial ovarian cancer. Further clinical trials with the addition of gemcitabine to first-line treatment appear warranted.     

吉西他滨和顺铂联合重组人血管内皮抑制素治疗晚期非小细胞肺癌临床观察

目的评价吉西他滨和顺铂联合重组人血管内皮抑制素（恩度）治疗晚期非小细胞肺癌的疗效和安全性。方法 38例病理确诊的晚期非小细胞肺癌患者给予吉西他滨和顺铂联合恩度治疗,吉西他滨1000mg/m2,第1,8天,顺铂75mg/m2,第2天,恩度注射液7.5mg/m2加入500ml生理盐水中,滴注时间3～4小时,第1～14日,每21天为一周期。结果 38例患者入组,部分缓解13例,疾病稳定17例,疾病进展8例,客观有效率为34.2%,疾病控制率为78.9%。本组中位无进展生存期为4.6个月,95%CI为2.600～6.600个月,中位生存期为13.5个月,95%CI为9.599～17.401个月,1年生存率42.1%。结论吉西他滨和顺铂联合恩度治疗晚期非小细胞肺癌,有较好的疗效和安全性,具有较好临床应用前景。     

Sorafenib versus cytotoxic chemotherapy for patients with advanced hepatocellular carcinoma: a retrospective,single-institution study

Background Prior to the 2008 advent of sorafenib, traditional cytotoxic agents were the therapeutic mainstay for patients with advanced hepatocellular carcinoma (HCC). We thus undertook a clinical study of sorafinib and conventional cytotoxic therapy for HCC, comparing efficacy and safety. Methods From January, 2002 to December, 2009, 173 patients with unresectable HCC were reviewed retrospectively. Among them, 44 (25.4%) had been treated with sorafenib, and the remainder had received cytotoxic therapy (CTX). We evaluated objective response rate (ORR), progression free survival (PFS), overall survival (OS), and toxicity profiles. Results Median OS of sorafinib was 23.0 weeks (95% CI, 8.1–37.9) vs 43.6 weeks (95% CI, 34.0–53.2) for CTX. Likewise, median PFS was 11.1 weeks (95% CI, 6.5–15.8) vs 12.4 weeks (95% CI, 8.1–16.7) for sorafenib and CTX, respectively. Neither parameter differed significantly (OS, p = 0.105; PFS, p = 0.496). ORR and disease control rate for sorafenib were 2.3% and 52.3% vs 6.2% and 43.4% for CTX. CTX-treated patients experienced more Grade 3/4 neutropenia (19.7% vs 0% for sorafenib), while sorafenib therapy was more often linked to dermatologic toxicities (all grades), such as hand-foot skin reaction, rash, and pruritus. Conclusion Although sorafenib has become the treatment of choice for advanced HCC, there are still unsettled issues regarding the optimal use of sorafenib. Our analysis indicates that conventional CTX can be another option of treatment for advanced HCC. To improve clinical outcomes, further prospective investigations which define the role of CTX are needed.     

Meta-analysis of randomised trials comparing gemcitabine-based doublets versus gemcitabine alone in patients with advanced and metastatic pancreatic cancer

OBJECTIVE: To evaluate the impact on overall survival at 6, 12 and 18 months of gemcitabine-based doublets compared with gemcitabine alone in patients with advanced and metastatic pancreatic cancer. METHODS: We conducted a systematic review and meta-analysis of published data on the use of gemcitabine-based doublets compared with gemcitabine alone in chemotherapy-naive patients with advanced and metastatic pancreatic cancer treated in randomised controlled phase II-III trials with overall survival as the principal or secondary endpoint. To this end, a literature search was performed using Cochrane methodology. The relative risks with 95% confidence intervals were estimated based on adjusted number of deaths and patients at risk according to the extent of follow-up and censoring. Twenty-three randomised clinical trials including 5886 patients met the inclusion criteria. In these trials, 2932 patients were randomly assigned to receive gemcitabine-based doublets and 2954 patients to receive gemcitabine alone. RESULTS: Gemcitabine-based doublets were associated with small but significant reductions in the risk of death at 6, 12 and 18 months of 8% (95% CI 3, 13), 4% (95% CI 2, 7) and 3% (95% CI 1, 5), respectively (p<0.005 for all timepoints). No heterogeneity between studies was observed. Subgroup analyses showed an overall survival benefit for gemcitabine-based doublets in clinical trials testing the same planned dose intensity of gemcitabine in comparative arms, using platinum salt-based protocols and with survival as the primary endpoint. CONCLUSION: This meta-analysis of data obtained from randomised controlled phase II-III trials of patients with advanced pancreatic cancer showed a small but significant improvement in overall survival for patients receiving gemcitabine-based doublets compared with gemcitabine alone.     

A phase II study of cell cycle inhibitor UCN-01 in patients with metastatic melanoma: a California Cancer Consortium trial

Background Genetic abnormalities in cell cycle control are common in malignant melanoma. UCN-01 (7-hydroxystaurosporine) is an investigational agent that exhibits antitumor activity by perturbing the cancer cell cycle. A patient with advanced melanoma experienced a partial response in a phase I trial of single agent UCN-01. We sought to determine the activity of UCN-01 against refractory metastatic melanoma in a phase II study. Patients and methods Patients with advanced melanoma received UCN-01 at 90 mg/m² over 3 h on cycle 1, reduced to 45 mg/m² over 3 h for subsequent cycles, every 21 days. Primary endpoint was tumor response. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). A two-stage (17 + 16), single arm phase II design was employed. A true response rate of ≥20% (i.e., at least one responder in the first stage, or at least four responders overall) was to be considered promising for further development of UCN-01 in this setting. Results Seventeen patients were accrued in the first stage. One patient was inevaluable for response. Four (24%) patients had stable disease, and 12 (71%) had disease progression. As there were no responders in the first stage, the study was closed to further accrual. Median PFS was 1.3 months (95% CI, 1.2–3.0) while median OS was 7.3 months (95% CI, 3.4–18.4). One-year and two year OS rates were 41% and 12%, respectively. A median of two cycles were delivered (range, 1–18). Grade 3 treatment-related toxicities include hyperglycemia (N = 2), fatigue (N = 1), and diarrhea (N = 1). One patient experienced grade 4 creatinine elevation and grade 4 anemia possibly due to UCN-01. No dose modification was required as these patients had disease progression. Conclusion Although well tolerated, UCN-01 as a single agent did not have sufficient clinical activity to warrant further study in refractory melanoma.     

A Phase II trial of epothilone B analogue BMS-247550 (NSC #710428) ixabepilone, in patients with advanced pancreas cancer: A Southwest Oncology Group study

Summary Purpose: The purpose of this Phase II multi-institutional study was to define the efficacy and toxicity of ixabepilone in patients with advance pancreatic adenocarcinoma. Patients and methods: Patients were required to have pancreatic adenocarcinoma and metastatic or recurrent disease that was not amenable to curative resection. Performance status was 0-1, and patients could not have had prior chemotherapy, or chemoradiation therapy for their advanced disease although prior local palliative radiation was allowed. Ixabepilone was administered iv as a 3 hour infusion every 21 days. Initially, the dose was 50 mg/m² but this was lowered to 40 mg/m² shortly after the trial opened because of concerns about neurotoxicity. Results: Sixty-two patients were registered however 2 were ineligible because they did not have recurrent or metastatic disease. For the 60 eligible patients, 22 had performance status of 0 and 38 performance status of 1. The estimated 6-month survival was 60% (95% CI 48%–72%) with a median survival of 7.2 months and an estimated time to treatment failure of 2.3 months. Out of 56 patients with measurable disease there were 5 confirmed partial responses for a confirmed response probability of 9% (95% CI 3%–20%) and 7 unconfirmed partial responses for an overall response probability of 21% (95% CI 12%–34%). Common toxicities were neutropenia/granulocytopenia, nausea and vomiting and neuropathy. There was one death, cause not determined but judged “possibly” related to treatment. Conclusion: Ixabepilone shows encouraging activity in patients with advanced pancreatic cancer and should be investigated further in this disease. This investigation was supported in part by the following PHS Cooperative Agreement grant numbers awarded by the National Cancer Institute, DHHS: CA38926, CA32102, CA20319, CA35090, CA52654, CA12644, CA45560, CA35431, CA45807, CA16385, CA76447, CA46441, CA35178, CA11083, CA46282, CA58686, CA76429, CA46368, CA04919, CA45377, CA67663, CA35176, CA63848, CA27575, CA35281, CA35119.     

A phase II trial of the Src kinase inhibitor saracatinib (AZD0530) in patients with metastatic or locally advanced gastric or gastro esophageal junction (GEJ) adenocarcinoma: a trial of the PMH phase II consortium

Purpose The Src family of kinases may play a role in the development and progression of gastric cancer. We evaluated the activity and safety of saracatinib an oral, anilinoquinazolone, non-receptor tyrosine kinase inhibitor targeting Src kinases, in patients with metastatic or locally advanced gastric carcinoma. Methods Eligible patients who had received ≤1 prior line of chemotherapy for metastatic disease received saracatinib 175 mg/day of a 28 day cycle until progression. The primary endpoint was the objective response and/or prolonged stable disease rate (pSD ≥ 16 weeks). Results Ten patients with gastric carcinoma and 11 with adenocarcinoma of the gastroesophageal junction received a median of 2 cycles (range 1–10 cycles) of treatment per patient. 17 patients were evaluable for response. No objective response was seen. One patient experienced prolonged Stable disease (pSD). Three patients had SD and 13 progressive disease. Median overall survival was 7.8 months (95% CI, 3.9–12.2 months) and median time to progression was 1.8 months (95% CI: 1.5–1.9 months). Grade 3 events possibly related to saracatinib included: fatigue (2 patients), hypoxia (2) anemia (3) and lymphopenia (2). Conclusion Saracatinib has insufficient activity as a single agent in patients with advanced gastric adenocarcinoma to warrant further investigation. Further development in gastric cancer would require rational drug combinations or identification of a tumor phenotype sensitive to Src inhibition.     

A Phase II study of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) and gemcitabine in advanced pancreatic carcinoma. A trial of the Princess Margaret Hospital Phase II consortium

3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapine, Vion Pharmaceuticals, New Haven, CT) is an inhibitor of the M2 subunit of ribonucleotide reductase (RR). Preclinical testing demonstrates synergy between 3-AP and gemcitabine. Phase I studies of the combination have suggested tolerability and some initial evidence of efficacy. Therefore, a phase II study of gemcitabine plus 3-AP in advanced pancreatic carcinoma was undertaken. In this two-step phase II trial, patients with advanced pancreatic adenocarcinoma who had not received prior chemotherapy for advanced disease were treated with 3-AP 105 mg/m(2) given over 2 h. Four hours after the 3-AP infusion was completed, gemcitabine 1,000 mg/m(2) was given over 30 min. Both drugs were given on days 1, 8 and 15 of a 28-day cycle.Twenty-six patients were enrolled to the study. One patient withdrew consent prior to receiving any treatment and is excluded from all further analyses. Four patients discontinued treatment due to adverse effects. Grade 3/4 hematological adverse events included neutropenia, thrombocytopenia, lymphopenia, leukopenia and anemia and the most frequent non-hematological adverse events were fatigue and pain. No objective responses were observed. Eleven patients had stable disease (SD). In five of these eleven patients, SD lasted for more than 6 months. The median time to progression was 4.1 months and the 6 month progression-free survival rate was 29%. The median survival was 9.0 months with a 1-year survival of 28.0%. The combination of 3-AP and gemcitabine is associated with moderate toxicity in patients with advanced pancreatic cancer. This two-stage trial was stopped after stage I due to lack of antitumour activity. On the basis of this clinical trial, the combination of gemcitabine and 3-AP at this dose and schedule does not warrant further study in this patient population.     

Weekly Gemcitabine for the Treatment of Biliary Tract and Gallbladder Cancer

Objectives: To evaluate the efficacy and safety of weekly administration of gemcitabine treatment in chemotherapy-naïve patients with advanced biliary tract and gallbladder cancer. Patients and methods: Gemcitabine at a dose of 800?mg/m² was administered weekly as a 30-min infusion to patients with previously operated, histologically confirmed, metastatic, or unresectable locally advanced cholangiocarcinoma. Treatment was continued until unacceptable toxicity or disease progression. Results: A total of 30 patients (median age 66 years; range 54–72 years) were included in the study. A median of 14 (range, 4–33) weekly doses was administered. Out of 30 patients evaluable for response, nine partial responses were observed (30.0%), while a further 11 patients demonstrated stable disease (36.7%). The median time to disease progression was 7 months (range, 5–34). Overall response rate was superior in patients with cancer of the gallbladder (ORR=35.7%) compared with those patients with biliary duct cancer (ORR=27.3%). This correlated to a significantly longer time to progression of 6.4 months (95% confidence interval (CI), 5.6–7.1 months) versus 3.6 months (95% CI, 2.9–4.3 months; p=0.03) and a significantly better overall survival of 17.1 months (95% CI, 15.8–18.5 months) versus 11.4 months (95% CI, 10.2–12.6 months, p=0.021). Toxicities were generally mild with only one case of grade 3 neutropenia. There were no cases of febrile neutropenia and no treatment-related deaths. Conclusions: Weekly administration of gemcitabine provides a safe, well-tolerated, and effective treatment for chemotherapy naïve patients with advanced cholangiocarcinoma, particularly with a gallbladder origin.     

Arsenic trioxide in patients with hepatocellular carcinoma: a phase II trial

Summary Background: Arsenic trioxide induces growth inhibition and apoptosis in human hepatocellular carcinoma (HCC) cell lines. A phase II trial was conducted to evaluate the efficacy and toxicity of single-agent arsenic trioxide in patients with HCC. Methods: Inclusion criteria included advanced HCC patients to whom no standard palliative treatment can be offered, good organ function and liver function reserve. Patients received arsenic trioxide 0.16–0.24 mg/kg per day for 5–6 days per week for 3–4 weeks, followed by one-week rest. Tumor response was assessed every 2 cycles. Primary endpoint was the percentage of patients with 6-month disease stabilization. Results: Twenty-nine patients (median age, 59) with locally advanced or metastatic HCC received a total of 61 cycles (median, 2; range, 1–6). One patient had partial response. Three patients had disease stabilization for at least six months. The 6-month tumor stabilization rate was 14% (95% CI, 1–27). The median overall survival was 4.8 months (95% CI, 1.4–8.2) and one-year survival was 30%. Conclusion: Single-agent arsenic trioxide using this dose schedule is not active against advanced HCC.     

Neoadjuvant chemotherapy with gemcitabine and cisplatin in stage IIIA/B non-small cell lung cancer

Purpose. We studied cisplatin plusgemcitabine as induction (neoadjuvant)therapy in patients with stage IIInon-small cell lung cancer (NSCLC) toassess its objective remission rate,resectability, survival, and toxicity. Patients and methods. Patients with stageIII NSCLC received 2 cycles of gemcitabine1250 mg/m² on days 1, 8, and 15,plus cisplatin 100 mg/m² on day 2.Subsequently, patients were assigned tolocal therapy – surgery or radiotherapy. Results. Twenty-nine eligiblepatients (male/female: 21/8) with a medianage of 59 years (range, 43–71 years) wereenrolled between October 1996 and February1999. A total of 80 cycles were given,with a median of 3 per patient (range, 1–4cycles). Overall, toxicities were mild;only one patient had febrile neutropenia,and there were no grade 4 non-hematologicaltoxicities. There was one toxic deathfollowing afebrile grade 4 neutropenia.Overall clinical response rate (2 completeresponses [CRs] + 16 partial responses[PRs]) was 62% (95% CI, 45%–79%);10 patients had stable disease and noneprogressed; one patient was not evaluable.Eight of the 18 operated patients hadpathological response: 1 CR and 7downstagings to N(–); 14 patients wereresected. Median survival was 17 months(95% CI, 13–21 months), with 1-year and2-year actuarial survival rates of 61%and 29%, respectively. Conclusions. Gemcitabine pluscisplatin is a very active andwell-tolerated induction regimen in stageIII NSCLC. Comparative studies with otherstandard regimens are warranted.