Erlotinib plus gemcitabine in patients with unresectable pancreatic cancer and other solid tumors: phase IB trial

Purpose The purpose of this phase IB trial was to evaluate the tolerability, pharmacokinetics and preliminary evidence of antitumor activity of erlotinib plus gemcitabine in patients with pancreatic cancer and other solid tumors. Patients and methods Patients included those with advanced pancreatic adenocarcinoma or other malignancies potentially responsive to gemcitabine. In the escalating phase of the trial, patients were enrolled in sequential cohorts using 100 or 150 mg oral daily dosing of erlotinib. Gemcitabine dose was 1,000 mg/m² weekly ×7 (first cycle), then weekly ×3, every 4 weeks. Results Twenty-six patients completed at least one course on study. In Cohort IA, at the 100 mg/day dose of erlotinib, three patients have developed grade 3 transaminase elevations. After stricter inclusion criteria were adopted (Cohort IB), no additional events of grade 3 transaminase elevations were observed and the dose of erlotinib was escalated to 150 mg/day (Cohorts IB and IIB) without reaching dose-limiting toxicities. The most common toxicities included diarrhea, skin rash, fatigue and neutropenia. The pharmacokinetic analyses did not reveal any significant interactions between erlotinib and gemcitabine. Objective responses were seen in two patients: cholangiocarcinoma and pancreatic cancer. Patients with unresectable or metastatic pancreatic cancer (n = 15) had a median progression-free survival of 289 days, the estimated overall survival of 389 days (12.5 months), and a 1-year survival rate of 51%. Conclusion The 150 mg/day dose of erlotinib can be safely administered in combination with standard dose gemcitabine in selected patients with pancreatic cancer and other advanced solid tumors. Promising antitumor activity has been observed in patients with pancreatic cancer. Data were previously presented at the 40th annual meeting of the American Society of Clinical Oncology, New Orleans, LA, USA, May 12–15, 2004.     

A phase I trial of gemcitabine in combination with patupilone in patients with advanced solid tumors

INTRODUCTION: Chemotherapy regimens including gemcitabine in combination with microtubule inhibitors such as docetaxel and paclitaxel have wide clinical application. Patupilone is a novel tubulin-polymerizing agent with activity against paclitaxel-resistant cell lines. We conducted a phase I trial to assess the maximum tolerated dose, dose limiting toxicity (DLT) and antitumor activity of gemcitabine and patupilone. METHODS: Patients with refractory solid tumors enrolled in cohorts of three. Cohorts received fixed doses of gemcitabine (1,000 or 750 mg/m(2)) along with escalating doses of patupilone (1.5-3 mg/m(2)) on days 1 and 8 of a 21-day cycle. RESULTS: Twenty-seven patients received a total of 99 courses of treatment on study. Hematologic toxicity in the first cohort required a modification of the protocol to decrease the gemcitabine dose. Subsequent patients received gemcitabine 750 mg/m(2) and escalating doses of patupilone from 1.5 to 3 mg/m(2). DLTs were grade 3 asthenia and grade 3 dehydration. There was also one treatment-related death due to neutropenic infection. Other clinically significant toxicities were persistent asthenia and persistent nausea. Four patients, one each with pancreatic cancer, esophageal carcinoma, cholangiocarcinoma and gallbladder carcinoma, experienced a partial response. CONCLUSIONS: The dose-limiting toxicities of gemcitabine and patupilone were asthenia and dehydration. Dose reductions also occurred due to persistent fatigue that was not dose-limiting. However, patients with advanced malignancies were able to tolerate gemcitabine and patupilone at doses that resulted in clinical benefit. The recommended phase II dose for this schedule is gemcitabine 750 mg/m(2) and patupilone 1.5 mg/m(2) on days 1 and 8 of a 21-day cycle.     

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

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

Effects of tumor selective replication-competent herpes viruses in combination with gemcitabine on pancreatic cancer

Purpose Pancreatic cancer still has a poor prognosis, even if aggressive therapy is pursued. Currently, new modalities of oncolytic virus therapy are being tested against this cancer. The combination of one of two representative mutant herpes simplex viruses (R3616: γ₁34.5 inactivated, hrR3: UL39 inactivated) with a standard anti-pancreatic cancer chemotherapy drug (gemcitabine), was investigated in this study. Experimental design The intracellular concentration of ribonucleotide reductase was estimated by Western blotting. The effect of gemcitabine on viral replication and the total cytotoxic effect of the combination therapy were investigated on pancreatic cancer cell lines. We compared the results of two oncolytic viruses, R3616 and hrR3. A mouse model of pancreatic cancer with peritoneal dissemination was used to evaluate the in vivo effect of the combination therapy. Results Although the replication of both viruses was inhibited by gemcitabine, the combination caused more tumor cell cytotoxicity than did virus alone in vitro. The results with R3616 were more striking. Although the difference was not statistically significant, R3616 with gemcitabine had a greater effect than did R3616 alone, while hrR3 with gemcitabine had a weaker effect than did hrR3 alone in vivo experiments. Conclusion The combination of oncolytic virus with gemcitabine is a promising new strategy against advanced pancreatic cancer. Each virus has different functional characteristics, and can affect the results of the combination of viruses and chemotherapy drugs. The results indicate that there is a complicated interaction among viruses, cells, and chemotherapy drugs and that the best combination of oncolytic virus and chemotherapeutic agents should be studied more extensively before embarking on a clinical trial.     

Therapy of Smac mimetic SM-164 in combination with gemcitabine for pancreatic cancer

Pancreatic cancer (PC) is a lethal solid malignancy with resistance to traditional chemotherapy. We investigated therapy of PC with SM-164 and gemcitabine alone and in combination. Survival of PC cells was reduced as the dose of SM-164 increased. SM-164 and/or gemcitabine increased the number of apoptotic and dead PC cells, and expression of cleavage fragments of caspase-3 and PARP1, and inhibited tumor xenograft growth in nude mice. The inhibitory effect of combination treatment was greater and of longer duration than monotherapy. Neither combination nor monotherapy showed any significant toxicity in vivo. Apoptosis and necrosis, decreased expression of Ki67, and increased expression of cleaved caspase-3 were observed in xenograft tumor tissues in SM164/gemcitabine-treated mice. SM-164 could be a promising new agent for treatment of PC in combination with gemcitabine.     

Experimental study of combination therapy with S-1 against pancreatic cancer

Purpose  To determine the most effective combination chemotherapy with S-1 against pancreatic cancer and to clarify the mechanism of synergy between S-1 and the partner drug. Methods  We tested a combination of S-1 with the following antitumor drugs in an in vitro MTT assay against pancreatic cancer cell line MIA PaCa-2: gemcitabine (GEM), cisplatin (CDDP), irinotecan (CPT-11), mitomycin C, adriamycin, and paclitaxel. The efficacy of S-1, GEM, and a combination of S-1 and GEM was also tested in vivo by administering S-1 (10 mg/kg) orally to nude mice five times a week for 3 weeks, and GEM (100 mg/kg) intravenously every 2–3 days for a total of six times. A treated-to-control ratio (T/C) of relative mean tumor weight values less than 50% was determined to be effective. Furthermore, we investigated the mechanism of the synergistic effect of S-1 and GEM on the cell cycle by flow cytometry, because both S-1 and GEM are known as antimetabolic drugs. To verify cell death induced by a change in the distribution of the cell cycle phases, we investigated apoptosis by sub-G1 analysis and a TUNEL assay. Results  From classical isobolography analysis of the in vitro MTT assay, the combination of S-1 plus GEM was found to be the most effective of the combinations tested. In vivo, T/C (percentage) with the combination of S-1 plus GEM was 48.2%, which was lower than that of S-1 or GEM alone, and the combination enhanced antitumor activity. Cell cycle analysis showed greater cell cycle delay with the combination treatment (S-1 plus GEM) than for each single drug treatment, and apoptotic cells were detected only in treatments including GEM. Conclusion  The combination chemotherapy of S-1 and GEM appears to be useful for pancreatic cancer. Both cycle delay by S-1 plus GEM and apoptosis induced by GEM are involved in this synergistic mechanism.     

Phase II trial of a 24-hour infusion of gemcitabine in previously untreated patients with advanced pancreatic adenocarcinoma

The antitumor effect of gemcitabine is not dose-response related but schedule dependent. Here we report a phase II trial of a weekly 24-hour infusion of gemcitabine in previously untreated patients with advanced pancreatic cancer. Patients with histologically proven, measurable, and irresectable pancreatic adenocarcinoma were treated with gemcitabine at a dose of 100 mg/m² infused over 24 hr on days 1, 8, and 15. Treatment was repeated every 28 days until progression of disease or limiting toxicity. All 18 patients enrolled were evaluable for response. Neutropenia and thrombocytopenia grade 3 occurred in 1 patient each. One partial response and two minor responses were observed. Median time to progression of disease was 4.4 months. Improvement of the European Organization for Research and Treatment of Cancer C30 scores was observed in 6 patients (pain and overall symptom score, respectively) and in 3 patients (overall functioning score and global quality of life, respectively). Weekly 24-hr gemcitabine was well tolerated in previously untreated patients with advanced pancreatic cancer. It shows marginal antitumor activity in terms of response rate. However, the 24-hr infusion at a dose of 100 mg/m² seems to be as active as the standard 30-min gemcitabine at a dose of 1000 mg/m². Relatively long median time to progression of disease and improvement of symptom and quality-of-life scores suggest, that patients may benefit from 24-hr gemcitabine.     

Phase I trial of weekly trabectedin (ET-743) and gemcitabine in patients with advanced solid tumors

Purpose  To determine the maximum tolerated dose (MTD) of trabectedin plus gemcitabine administered on a weekly schedule in patients with advanced solid tumors. Methods  Patients with ECOG performance status 0–1 and adequate organ function were enrolled. On days 1, 8, and 15 of a 28-day cycle, patients received gemcitabine (starting dose, 800 mg/m²) followed by trabectedin (starting dose, 0.3 mg/m²). Strict liver function test treatment criteria were employed to avoid hepatic toxicity seen in previous trabectedin studies. Plasma samples were collected during cycles 1 and 2 for pharmacokinetic analyses. Results  Fifteen patients received ≥1 dose, with a median of two treatment cycles (range 1–10). The most common drug-related toxicity was hepatic. Dose reductions were required for trabectedin in four (27%) patients and gemcitabine in six (40%) patients. Cycle delays/dose holds were required in 11 (73%) patients and doses above trabectedin 0.4 mg/m² and gemcitabine 1,000 mg/m², which is the recommended phase II dose, were not feasible. Seven patients maintained stable disease after two cycles. Gemcitabine and trabectedin pharmacokinetics were not altered substantially with concomitant administration. Conclusions  Given the lack of pharmacokinetic interaction and potential efficacy of trabectedin and gemcitabine combination therapy, further study is warranted with alternate schedules.     

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

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

Adjuvant intra-arterial 5-fluoruracil,leucovorin, epirubicin and carboplatin with or without systemic gemcitabine after curative resection for pancreatic adenocarcinoma

Background: The role of adjuvant therapy in pancreatic cancer remains controversial. Gemcitabine given systemically seems to be effective; intra-arterial chemotherapy (IAC) has a deep rationale. Patients and methods: The goal was to evaluate the impact of postoperative IAC followed or not by systemic gemcitabine in patients after curative resection for pancreatic adenocarcinoma. 5-fluoruracil 750 mg sqm⁻¹, leucovorin 75 mg sqm⁻¹, epirubicin 45 mg sqm⁻¹, carboplatin 225 mg sqm⁻¹ were administered every 3 weeks into celiac axis for three cycles (FLEC regimen), then gemcitabine at the dosage of 1 g sqm⁻¹ on days 1, 8 and 15 every 4 weeks for 3 months (FLECG regimen). Results: Forty-seven patients entered the study. The first 24 received only IAC (FLEC regimen), the other 23 received the same intra-arterial regimen followed by systemic gemcitabine (FLECG regimen). After a median follow-up of 16.9 months, 29 patients recurred (61.7%). Median disease free survival (DFS) was 18 months and median overall survival (OS) was 29.7 months. One-year DFS was 59.4% and 1-year OS was 75.5%. Main grade 3 toxicity related to IAC was only nausea/vomiting in 4%; regarding gemcitabine, grade 3 toxicities were anaemia 8%, leukopenia 8%, thrombocitopenia 17%, nausea/vomiting 4%. Conclusions: FLEC regimen with or without gemcitabine is active with a very mild toxicity and results are very encouraging in an adjuvant setting.     

Combination chemotherapy of carboplatin and gemcitabine against solid tumors: a phase I trial

Background. Some trials have suggested that the combination of gemcitabine and platinum compounds can have a synergistic effect on several solid tumors, but, at present, the data concerning carboplatin-gemcitabine combinations are not sufficient to allow the planning of phase II trials. The present phase I trial was planned to define the maximum tolerated dose and the dose-limiting toxicity of a carboplatin-gemcitabine combination. Methods. Thirty-two patients with advanced, pretreated solid tumors were treated with carboplatin on day 1 and gemcitabine on days 1, 8, and 15 every 28 days. The starting doses of carboplatin and gemcitabine were 3.5 mg/ml per min (area under the curve; AUC), and 600 mg/m², respectively. The doses of the two agents were alternately increased to 4, 4.5, and 5 mg/ml per min and to 800 and 960 mg/m², respectively. At each dose level, three patients were initially enrolled. If one of them experienced grade IV hematological toxicity or grade III–IV nonhematological toxicity (with the exception of alopecia), an additional three patients were enrolled at the same dose level. If two or more patients experienced grade IV hematological toxicity or grade III–IV non-hematological toxicity (with the exception of alopecia), the maximum tolerated dose was considered to have been reached, and the dose below this was recommended for further studies. All patients were evaluated weekly for toxicity and after every two courses of chemotherapy for response. Results. Dose-limiting toxicity was hematological, and the maximum tolerated doses were 4.5 mg/ml per min for carboplatin and 800 mg/m² for gemcitabine. The activity of the carboplatin/gemcitabine combination was encouraging, with a 21.9% response rate (7/32), three complete disease regressions, and a median time to progression of 30 weeks. The gemcitabine doses of day 15 or days 8 and 15 were omitted for hematological toxicity in 57 (50%) and 17 (14.9%) courses of chemotherapy, while no courses of chemotherapy were delayed for grade III–IV hematological or nonhematological toxicity. Conclusion. The maximum tolerated doses suggested by this trial are lower than those in other similar phase I trials, but they are consistent with those reported by most of the trials investigating gemcitabine either in combination with cisplatin or in heavily pretreated patients. Carboplatin 4.5 mg/ml per min on day 1 plus gemcitabine 800 mg/m² on days 1, 8, and 15 every 28 days may represent a promising schedule for further phase II trials. Received: January 29, 2001 / Accepted: September 13, 2001     

Phase 1 Study of Erlotinib and Metformin in Metastatic Triple-Negative Breast Cancer

BackgroundEpidermal growth factor receptor (EGFR) is frequently overexpressed in metastatic triple-negative breast cancer (mTNBC). One strategy for overcoming resistance to EGFR inhibition is concomitant inhibition of downstream signaling. The antidiabetic drug metformin inhibits both MAPK and PI3K/mTOR pathway signaling. We evaluated the combination of erlotinib and metformin in a phase 1 study of patients with mTNBC.Patients and MethodsPatients with mTNBC who had received at least one prior line of therapy for metastatic disease were eligible. Erlotinib dose was fixed at 150 mg daily. Metformin dose escalation was planned according to a 3 + 3 design. Dose-limiting toxicities (DLT) were assessed during the first 5 weeks of therapy. The primary objective was to determine the maximum tolerated dose of metformin with fixed-dose erlotinib. Secondary endpoints were response rate, stable disease rate, and progression-free survival.ResultsEight patients were enrolled. The median number of prior therapies for metastatic disease was 2.5 (range, 1-6). No DLT events were reported during the DLT assessment period. Most adverse events were grade 1/2. Grade 3 diarrhea despite maximum supportive care required dose reduction of metformin in one patient. Grade 3 rash led to study withdrawal in one patient. No grade 4 adverse events were reported. The best observed response was stable disease in 2 patients (25%). Median progression-free survival was 60 days (range, 36-61 days).ConclusionErlotinib and metformin were well tolerated in a population of pretreated mTNBC patients but did not demonstrate efficacy in this population.     

Phase I clinical trial of intrathecal gemcitabine in patients with neoplastic meningitis

PURPOSE: A phase I study of intrathecal (IT) gemcitabine was performed to define a safe dose and characterize the toxicity profile and CSF pharmacokinetics of gemcitabine and its major metabolite 2',2'-difluoro-deoxyuridine (dFdU) in patients 3 years of age and older with neoplastic meningitis. EXPERIMENTAL DESIGN: Gemcitabine was administered via Ommaya reservoir or lumbar puncture at three dose levels: 5 mg weekly, 5 mg twice-weekly, and 10 mg twice-weekly using a standard phase I dose escalation design. Serial CSF samples were obtained for pharmacokinetic studies in seven patients with Ommaya reservoirs. Serial blood samples for pharmacokinetic studies were also obtained from three patients. RESULTS: Ten patients were enrolled in this study. Significant neurological toxicities occurred in two patients including myelitis in a patient at the 5 mg twice-weekly dose level and somnolence in a patient at the 10 mg twice-weekly dose level. No complete responses were seen; however, three patients had stable disease. Gemcitabine was rapidly eliminated from the CSF with a terminal half-life of 61 +/- 50 min. No gemcitabine or dFdU was detected in plasma. CONCLUSIONS: IT gemcitabine was associated with significant neurotoxicity; therefore, its further development for IT use is not recommended.     

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

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

PHASE II CLINICAL TRIAL OF LASTET CAPSULE IN COMBINATION CHEMOTHERAPY OF MALIGNANT TUMORSIN CHINA

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吉西他滨联合顺铂与单药吉西他滨治疗晚期胰腺癌的疗效比较

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

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

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

A phase IB study of the pharmacokinetics of gemcitabine and pemetrexed, when administered in rapid sequence to patients with advanced solid tumors

Background We have previously demonstrated that pemetrexed is clinically active when administered 90 min after gemcitabine in a phase I study. The present study was undertaken to evaluate the efficacy, toxicity, and pharmacokinetics of gemcitabine and pemetrexed when pemetrexed is administered immediately after gemcitabine.Patients and Methods A total of 14 patients received 84 cycles of treatment. Gemcitabine 1250 mg/m² was administered on days 1 and 8 of each 21-day cycle, and pemetrexed 500 mg/m² on day 8 immediately following gemcitabine administration. Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria and recorded as maximum grade per patient for all treatment cycles. Pharmacokinetic analyses of plasma gemcitabine and pemetrexed concentrations were performed.Results Neutropenia was the most common severe toxicity. Non-hematologic toxicities, which included nausea, vomiting, fatigue, diarrhea, rash, and elevated transaminases were of mild-to-moderate severity. No increased toxicity was observed with this schedule in comparison to the previous phase I schedule. There was no pharmacokinetic interaction between the two drugs. One partial response was documented in a patient with non-small-cell lung cancer. Eight patients had disease stabilization for five or more cycles.Conclusion Gemcitabine immediately followed by pemetrexed is well tolerated and clinically active, and deserves further evaluation in phase II trials.