Gemcitabine in advanced pancreatic cancer: a phase II trial

The 5-year survival for pancreatic cancer is usually less than 5%, and no treatment has demonstrated consistent effect on patient survival and disease-related symptoms. Early studies with gemcitabine suggested a modest antitumor activity with significant improvement in disease-related symptoms. This phase II study reports the activity of gemcitabine on 33 consecutive patients with unresectable pancreatic carcinoma. Twenty-three patients had metastatic and 10 locally advanced unresectable disease. Twenty-six patients had not received any previous treatment and seven had received first-line chemotherapy with 5-fluorouracil. Gemcitabine 1,000 mg/m2 was administered intravenously in 30 minutes in the first cycle once weekly for up to 7 weeks followed by 1 week rest; then in subsequent cycles, once weekly for 3 of every 4-week cycle. Four patients obtained partial response (12%). Fifteen patients (45%) had stable disease with a median duration of 32 weeks (range: 16-75 weeks), and 14 patients experienced progressive disease. Median duration of response was 34.5 weeks (range: 19-50 weeks). Median survival was 33 weeks (range: 2-91 weeks). All 4 responding patients and 14 of 15 (93%) patients with stable disease had improvement in performance status and decrease in daily analgesic requirement. Toxicity was mild and mainly consisted of moderate and rapidly reversible myelosuppression. We conclude that gemcitabine chemotherapy was very well tolerated and determined a significant clinical improvement with modest antitumoral activity in patients with advanced pancreatic cancer.     

A phase I trial of weekly gemcitabine and concurrent radiotherapy in patients with locally advanced pancreatic cancer

This study investigated the maximum-tolerated dose of gemcitabine based on the frequency of dose-limiting toxicities of weekly gemcitabine treatment with concurrent radiotherapy in patients with locally advanced pancreatic cancer. Fifteen patients with locally advanced pancreatic cancer that was histologically confirmed as adenocarcinoma were enrolled in this phase I trial of weekly gemcitabine (150-350 mg x m(-2)) with concurrent radiotherapy (50.4 Gy in 28 fractions). Gemcitabine was administered weekly as an intravenous 30-min infusion before radiotherapy for 6 weeks. Three of six patients at the dose of 350 mg x m(-2) of gemicitabine demonstrated dose-limiting toxicities involving neutropenia/ leukocytopenia and elevated transaminase, while nine patients at doses of 150 mg x m(-2) and 250 mg x m(-2) did not demonstrate any sign of dose-limiting toxicity. Of all 15 enrolled patients, six patients (40.0%) showed a partial response. More than 50% reduction of serum carbohydrate antigen 19-9 level was observed in 13 (92.9%) of 14 patients who had pretreatment carbohydrate antigen 19-9 levels of 100 U x ml(-1) or greater. The maximum-tolerated dose of weekly gemcitabine with concurrent radiotherapy was 250 mg x m(-2), and this regimen may have substantial antitumour activity for patients with locally advanced pancreatic cancer. A phase II trial of weekly gemcitabine at the dose of 250 mg x m(-2) with concurrent radiation in patients with locally advanced pancreatic cancer is now underway.     

Phase I study of fixed dose rate infusion of gemcitabine in patients with unresectable pancreatic cancer

OBJECTIVE: The purpose of this study was to determine the feasible dose of gemcitabine when administered as a fixed dose rate infusion (10 mg/m(2)/min) on a weekly schedule to Japanese patients with unresectable advanced pancreatic cancer. METHODS: Patients were required to have histologically or cytologically proven locally advanced or metastatic pancreatic cancer for which they had received no previous chemotherapy. Gemcitabine was administered intravenously weekly for three consecutive weeks every 4 weeks. Patients at three dose levels were scheduled to receive escalating doses of gemcitabine: 1000 mg/m(2) over 100 min (Level 1), 1200 mg/m(2) over 120 min (Level 2) and 1500 mg/m(2) over 150 min (Level 3). RESULTS: A total of 16 patients were enrolled in this study between December 2003 and September 2004. Maximum-tolerated dose was not reached during the first course. Dose-limiting toxicity was Grade 4 neutropenia. Grade 3 or 4 neutropenia was observed at Level 3 in all six patients in the first course, and administration of gemcitabine on Day 8 or 15 was skipped in all six patients. Non-hematologic toxicity was mild and the most common symptoms were anorexia, nausea and vomiting. Partial response was achieved in 1 of the 17 patients (7%). Median overall survival was 7.3 months. CONCLUSIONS: Gemcitabine administered at a rate of 10 mg/m(2)/min was tolerated up to 1500 mg/m(2), but 1200 mg/m(2) represented a more appropriate recommended dose in further studies owing to neutropenia in Japanese patients with advanced pancreatic cancer.     

Gemcitabine combined with gefitinib in patients with inoperable or metastatic pancreatic cancer: a phase II Study of the Hellenic Cooperative Oncology Group with biomarker evaluation

The combination of gemcitabine and gefitinib was evaluated in advanced pancreatic cancer. Totally, 53 patients were treated with a 7 week cycle of gemcitabine (1,000 mg/m(2) given weekly) followed by six 4 week cycles of gemcitabine given on days 1, 8 and 15. Gefitinib 250 mg was administered daily. Responses were seen in 6, and stabilization of the disease in 12 patients. The main toxicity was myelotoxicity (92%). The 6-month progression-free survival (PFS) was 30%. Median PFS was 4.1 months and median survival 7.3 months with a 1 year survival rate of 27%. The above combination demonstrated promising activity in advanced pancreatic cancer.     

Phase II study of radiotherapy combined with gemcitabine for locally advanced pancreatic cancer

Gemcitabine has been reported to be a potent radiosensitiser in human pancreatic cell lines. This study was conducted to evaluate the efficacy and toxicity of radiotherapy combined with gemcitabine for locally advanced pancreatic cancer. In all, 42 patients with pancreatic cancer that was unresectable but confined to the pancreatic region were treated with external-beam radiation (50.4 Gy in 28 fractions over 5.5 weeks) and weekly gemcitabine (250 mg m(-2), 30-min infusion). Maintenance gemcitabine (1000 mg m(-2) weekly x 3 every 4 weeks) was initiated 1 month after the completion of the chemoradiotherapy and continued until disease progression or unacceptable toxicity. Of the 42 patients, 38 (90%) completed the scheduled course of chemoradiotherapy. The major toxicity was leucopenia and anorexia. There was one death attributed to duodenal bleeding and sepsis. The median survival time was 9.5 months and the 1-year survival rate was 28%. The median progression-free survival time was 4.4 months. In 35 patients with documented disease progression at the time of analysis, 34 (97%) showed distant metastasis as the cause of the initial disease progression. The chemoradiotherapy used in this study has a moderate activity against locally advanced pancreatic cancer and an acceptable toxicity profile. Future investigations for treatment with more systemic effects are warranted.     

Gemcitabine plus oxaliplatin (GEMOX) combined with cetuximab in patients with progressive advanced stage hepatocellular carcinoma: results of a multicenter phase 2 study

BACKGROUND: The authors conducted a phase 2 trial of the antiepidermal growth factor receptor (EGFR) monoclonal antibody cetuximab in combination with the gemcitabine plus oxaliplatin (GEMOX) regimen in patients with documented progressive hepatocellular carcinoma (HCC). METHODS: Forty-five untreated patients with advanced-stage progressive HCC were prospectively enrolled. Treatment consisted of cetuximab at a dose of 400 mg/m2 initially then 250 mg/m2 weekly, plus gemcitabine at a dose of 1000 mg/m2 on Day 1 and oxaliplatin at a dose of 100 mg/m2 on Day 2, every 2 weeks. Treatment was continued until disease progression, unacceptable toxicity, or patient refusal. RESULTS: Overall, 306 cycles were administered. Grade 3 to 4 hematologic toxicity consisted of thrombocytopenia (24%), neutropenia (20%), and anemia (4%). Grade 3 oxaliplatin-induced neurotoxicity occurred in 5 patients (11%) and grade 3 cutaneous toxicity in 7 patients (16%). There were no treatment-related deaths. The confirmed response rate was 20% and disease stabilization was obtained in 40% of patients. The median progression-free and overall survival times were 4.7 months and 9.5 months, respectively. The 1-year survival rate was 40%. CONCLUSIONS: In poor-prognosis patients with progressive advanced-stage HCC, the GEMOX-cetuximab combination appears to be active and to have manageable toxicity. A comparative randomized trial is now being planned.     

Phase I/IIa study of cetuximab with gemcitabine plus carboplatin in patients with chemotherapy-naive advanced non-small-cell lung cancer.

PURPOSE: This multicenter, open-label, phase I/IIa study was undertaken to establish the safety/toxicity profile of cetuximab in combination with gemcitabine and carboplatin in patients with chemotherapy-na?ve, epidermal growth factor receptor-positive, stage IV non-small-cell lung cancer. Secondary objectives were to gather preliminary evidence of efficacy including tumor response rate, time to progression, and overall survival. PATIENTS AND METHODS: Thirty-five patients received a total of 264 3-week cycles of treatment with cetuximab, carboplatin, and gemcitabine. An initial dose of cetuximab 400 mg/m2 intravenously was administered the first week, followed by weekly doses of 250 mg/m2. Carboplatin (area under the curve = 5, day 1) and gemcitabine 1,000 mg/m2 on days 1 and 8 were administered every 3 weeks. Patients were evaluated for tumor response after every two cycles of therapy. RESULTS: The most frequently reported adverse events related to cetuximab included an acne-like rash (88.6%), dry skin (34.3%), asthenia and skin disorders (31.4%), mucositis/stomatitis (25.7%), fever/chills (20%), and nausea/vomiting (17.1%). The majority of these toxicities were mild to moderate. One patient withdrew from the study because of a grade 3 allergic reaction. Myelosuppression was the most frequently observed toxicity related to chemotherapy. Responses among 35 assessable patients included 10 partial responses (28.6%). Twenty-one patients had stable disease. The median time to progression was 165 days, and the median overall survival was 310 days. CONCLUSION: The combination of cetuximab, carboplatin, and gemcitabine was well tolerated with an acceptable toxicity profile. Most grade 3 adverse events were attributable to chemotherapy. The response rate and median survival are encouraging and warrant additional investigation.     

A phase II trial of weekly paclitaxel and gemcitabine in non-small cell lung cancer patients previously treated with platinum and vinorelbine

This study evaluated the activity and toxicity of a weekly paclitaxel plus gemcitabine combination as second-line treatment in patients with advanced non-small cell lung cancer (NSCLC). Paclitaxel 80 mg/m2 on days 1, 8 and 15 and gemcitabine 1000 mg/m2 on days 1 and 8 every 3 weeks were administered to 34 consecutive, advanced NSCLC patients uniformly pretreated with cisplatin or carboplatin and vinorelbine. The median time interval from first- to second-line treatment was 8 weeks (range 1-72). A total of 124 cycles with a median of 3 cycles per patient were administered (range 1-6). Four patients (12%) achieved a partial response (95% confidence interval: 1-23%), 17 had stable disease (50%) and 12 progressed (37%). Three responses were observed in 14 patients showing disease response or stabilization to previous platinum therapy. The median survival was 28 weeks (range 3-91), the median progression-free survival was 12 weeks (range 3-50) and the 1-year survival rate was 23%. The toxicity profile was favorable. In conclusion, a weekly schedule of paclitaxel plus gemcitabine as a second-line regimen has moderate activity and good tolerability in NSCLC patients not refractory to previous platinum-vinorelbine treatment.     

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。     

Phase I-II study of gemcitabine and fluorouracil as a continuous infusion in patients with pancreatic cancer.

PURPOSE: To determine the maximum-tolerated dose (MTD), dose-limiting toxicities, and efficacy of gemcitabine combined with fluorouracil (5-FU) in patients with pancreatic cancer. PATIENTS AND METHODS: Patients with measurable, locally advanced, nonresectable or metastatic pancreatic cancer were candidates for the study. 5-FU was given via protracted venous infusion (PVI) at a fixed dosage of 200 mg/m2/d, and gemcitabine was administered weekly for 3 consecutive weeks every 4 weeks. The initial dose of gemcitabine was 700 mg/m2 and was escalated in increments of 100 mg/m2/wk until the appearance of severe toxicity. Measurements of efficacy included the following: response rate; clinical benefit response, which is a composite measurement of pain, performance status, and weight loss; time to disease progression; and survival. RESULTS: Twenty-six patients received a total of 109 courses. Dose-limiting toxicity, which consisted of grade 4 neutropenia with fever (one patient) and grade 4 thrombocytopenia (one patient), was observed in two of three patients treated with 1,100 mg/m2/wk of gemcitabine. On the basis of these results, the MTD of gemcitabine with 5-FU via PVI on this schedule was 1,000 mg/m2. Sixteen patients developed grade 3-4 neutropenia, and three patients developed grade 3-4 thrombocytopenia. Grade 3-4 nonhematologic toxicity consisted of diarrhea (two patients) and cutaneous toxicity, asthenia, edema, mucositis, and nausea and vomiting (one patient each). The delivered dose-intensity of gemcitabine was similar at the 1,000 mg/m2 dose level (599 mg/m2/wk) as at the 900 mg/m2 (601 mg/m2/wk) dose level. For this reason, the recommended dose of gemcitabine for phase II evaluation on this schedule was 900 mg/m2. Five patients had objective responses (one complete response and four partial responses; response rate, 19.2%; 95% confidence interval [CI], 6.5 to 39.3), and 10 patients had improvement of disease-related symptoms (45%; 95% CI, 24 to 67). After a median follow-up of 17.7 months (range, 7.8 to 24.8 months), the median progression-free survival and overall survival times were 7.4 months (95% CI, 3.3 to 11.4) and 10.3 months (95% CI, 8.1 to 12.5), respectively. CONCLUSION: The MTD of gemcitabine when combined with 5-FU via PVI on this schedule was 1,000 mg/m2/ wk; however, on the basis of administered dose-intensity, the recommended dose for additional investigation is 900 mg/m2. This combination chemotherapy regimen was well tolerated and showed promising antitumor activity in the treatment of pancreatic cancer.     

A phase I study of erlotinib in combination with gemcitabine and radiation in locally advanced, non-operable pancreatic adenocarcinoma.

PURPOSE: To determine the maximum tolerated dose (MTD) of erlotinib when administered concurrently with twice weekly gemcitabine and radiation therapy (RT) for locally advanced pancreatic cancer, assess the safety and toxicity profile of this combination and secondarily evaluate response, time to tumor progression and overall survival. METHODS: Patients with untreated locally advanced pancreas cancer were treated with daily erlotinib in combination with gemcitabine 40 mg/m(2)/30 min twice weekly and RT delivered at 180 cGy/day in 28 fractions over 5.5 weeks for a total of 5040 cGy. Erlotinib was dose escalated in successive cohorts (100 mg, 125 mg). When the MTD was determined, the cohort was expanded to better define toxicity and preliminarily efficacy. All patients were surgically staged. After chemoradiation, patients received maintenance weekly gemcitabine 1000 mg/m(2) on days 1 and 8 of a 21 day cycle and daily erlotinib for four cycles. RESULTS: Three patients were treated at dose level 1 (erlotinib 100 mg) without limiting toxicity. Two of six patients at dose level 2 (erlotinib 125 mg) had dose-limiting toxicities, neutropenia and thrombocytopenia, causing dose delay and elevated liver enzymes. The MTD for erlotinib in combination with twice weekly gemcitabine-based chemoradiation was 100 mg/day. Eleven additional patients were treated at dose level 1. All twenty patients were assessable for toxicity. Seventeen patients were assessable for response. The partial response rate was 35% and 53% had stable disease. The median survival for all patients was 18.7 months. CONCLUSION: In combination with fixed dose gemcitabine at 40 mg/m(2) twice weekly and radiation at 180 cGy/day, the MTD of erlotinib was found to be 100 mg/day. This is a relatively well tolerated, biologically active combination in a poor prognostic cancer.     

Epidermal Growth Factor Receptor Antagonists in Pancreatic Cancer

Pancreatic cancer is the fourth leading cause of cancer-related death in North America and is associated with an extremely bleak prognosis. Advances in the treatment of this devastating disease will require novel approaches. A key therapeutic strategy is inhibition of the epidermal growth factor receptor (EGFR). The EGFR is overexpressed in pancreatic cancer and is associated with poor prognosis. This article summarizes current knowledge of the role of EGFR antagonists in pancreatic cancer and focuses on the preclinical background and EGFR inhibitors in clinical development including erlotinib, gefitinib, cetuximab, and matuzumab. Erlotinib in combination with chemotherapy and radiation has encouraging antitumor activity in locally advanced pancreatic cancer. A phase II trial of cetuximab and gemcitabine in advanced pancreatic cancer showed promising activity and 1-year survival. Proof of principle for EGFR inhibition in this disease was provided by a phase III trial in advanced pancreatic cancer that demonstrated a survival advantage with erlotinib in combination with gemcitabine compared with placebo plus gemcitabine. Current research efforts are aimed at determining predictive factors for response to EGFR inhibitors, defining the role of EGFR blockade in early stages of disease, and exploring combinations with other molecular-targeted approaches.     

Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma: Eastern Cooperative Oncology Group Trial E2297.

PURPOSE: Gemcitabine is generally considered to constitute first-line therapy for pancreatic cancer. To determine whether the addition of fluorouracil (5-FU) improves on the results from single-agent gemcitabine, the Eastern Cooperative Oncology Group (ECOG) compared gemcitabine plus bolus 5-FU with gemcitabine alone for patients with advanced pancreatic carcinoma. PATIENTS AND METHODS: This trial involved patients with biopsy-proven, advanced carcinoma of the pancreas not amenable to surgical resection. Patients were randomized to receive either gemcitabine alone (1,000 mg/m(2)/wk) weekly for 3 weeks of every 4 or to receive gemcitabine (1,000 mg/m(2)/wk) followed by 5-FU (600 mg/m(2)/wk) weekly on the same schedule. The primary end point of the trial was survival, with secondary end points of time to progression and response rate. RESULTS: Of 327 patients enrolled over 18 months, 322 were eligible. Overall, the median survival was 5.4 months for gemcitabine alone and 6.7 months for gemcitabine plus 5-FU (P =.09). Progression-free survival for gemcitabine alone was 2.2 months, compared with 3.4 months for gemcitabine plus 5-FU (P =.022). Objective responses were uncommon and were observed in only 5.6% of patients treated with gemcitabine and 6.9% of patients treated with gemcitabine plus 5-FU. Most toxicities were hematologic or gastrointestinal; no significant differences were noted between the two treatment arms. CONCLUSION: 5-FU, administered in conjunction with gemcitabine, did not improve the median survival of patients with advanced pancreatic carcinoma compared with single-agent gemcitabine. Further studies with other combinations of gemcitabine and 5-FU are not compelling, and clinical trial resources should address other combinations and novel agents.     

A phase I study evaluating the role of the anti-epidermal growth factor receptor (EGFR) antibody cetuximab as a radiosensitizer with chemoradiation for locally advanced pancreatic cancer

Purpose

(1) To determine the safety of the epidermal growth factor receptor (EGFR) antibody cetuximab with concurrent gemcitabine and abdominal radiation in the treatment of patients with locally advanced adenocarcinoma of the pancreas. (2) To evaluate the feasibility of pancreatic cancer cell epithelial?Cmesenchymal transition (EMT) molecular profiling as a potential predictor of response to anti-EGFR treatment.

Methods

Patients with non-metastatic, locally advanced pancreatic cancer were treated in this dose escalation study with gemcitabine (0?C300?mg/m²/week) given concurrently with cetuximab (400?mg/m² loading dose, 250?mg/m² weekly maintenance dose) and abdominal irradiation (50.4?Gy). Expression of E-cadherin and vimentin was assessed by immunohistochemistry in diagnostic endoscopic ultrasound fine-needle aspiration (EUS-FNA) specimens.

Results

Sixteen patients were enrolled in 4 treatment cohorts with escalating doses of gemcitabine. Incidence of grade 1?C2 adverse events was 96%, and incidence of 3?C4 adverse events was 9%. There were no treatment-related mortalities. Two patients who exhibited favorable treatment response underwent surgical exploration and were intraoperatively confirmed to have unresectable tumors. Median overall survival was 10.5?months. Pancreatic cancer cell expression of E-cadherin and vimentin was successfully determined in EUS-FNA specimens from 4 patients.

Conclusions

Cetuximab can be safely administered with abdominal radiation and concurrent gemcitabine (up to 300?mg/m²/week) in patients with locally advanced adenocarcinoma of the pancreas. This combined therapy modality exhibited limited activity. Diagnostic EUS-FNA specimens could be analyzed for molecular markers of EMT in a minority of patients with pancreatic cancer.     

Phase II study of gemcitabine plus docetaxel in advanced pancreatic cancer: a Hoosier Oncology Group study

OBJECTIVE: To determine the response rate, duration of response and survival with weekly gemcitabine plus docetaxel in metastatic or unresectable pancreatic cancer. METHODS: Forty patients were enrolled, and 38 patients were evaluable for survival and toxicity. Thirty-seven patients were evaluable for response. Nine patients (24%) had locally advanced disease and 29 (76%) had metastatic disease at the time of enrollment. Median Eastern Cooperative Oncology Group performance status was 1. Patients received gemcitabine 750 mg/m(2) i.v. and docetaxel 35 mg/m(2) i.v. weekly for 3 out of 4 weeks for a maximum of 6 cycles. RESULTS: Patients received a median of 4 cycles (range 1-6) of chemotherapy. An objective response was obtained in 10 patients (27%) with a median duration of 17 weeks. Median survival was 7 months, and 1-year survival was 19.3%. Eight patients experienced at least one form of grade 4 toxicity and 27 patients experienced at least one type of grade 3 toxicity. CONCLUSIONS: The combination of gemcitabine and docetaxel is a well-tolerated regimen with clinical efficacy. The ultimate role of this combination versus single-agent gemcitabine can only be determined by a randomized phase III trial.     

A phase I study of weekly gemcitabine and docetaxel in patients with advanced cancer: a Hoosier Oncology Group Study

PURPOSE: To determine the maximum tolerated dose (MTD) of weekly gemcitabine plus docetaxel, a dose escalation trial of both drugs was developed with each administered weekly for 3 weeks out of 4. PATIENTS AND METHODS: Dose levels for gemcitabine (mg/m(2)) and docetaxel (mg/m(2)) were as follows: level 1: 600/25; level 2: 600/35; level 3: 750/35; and level 4: 900/35. Sixteen patients with adequate renal, hepatic, and hematologic function and an Eastern Cooperative Oncology Group performance status of 0-2 were treated. Primary sites included pancreas (12) and others (4). RESULTS: Three patients were treated at each dose level from level 1 through level 4. The dose-limiting toxicity (DLT) was neutropenia, the maximum tolerated dose being 750 mg/m(2) of gemcitabine and 35 mg/m(2) of docetaxel. No grade 4 nonhematologic toxicity was seen. Three patients had grade 4 neutropenia. Of the 12 patients with pancreatic cancer, 1 had a partial remission and 7 had stable disease with a median duration of 8 weeks. CONCLUSIONS: Gemcitabine and docetaxel can be safely administered weekly at a dose of 750 and 35 mg/m(2), respectively. The DLT was neutropenia. Disease stabilization suggests that this may be an active regimen in patients with metastatic pancreatic cancer.     

Neoadjuvant cetuximab,twice-weekly gemcitabine,and intensity-modulated radiotherapy (IMRT) in patients with pancreatic adenocarcinoma

BackgroundNeoadjuvant therapy has been investigated for localized and locally advanced pancreatic ductal adenocarcinoma (PDAC) but no standard of care exists. Combination cetuximab/gemcitabine/radiotherapy demonstrates encouraging preclinical activity in PDAC. We investigated cetuximab with twice-weekly gemcitabine and intensity-modulated radiotherapy (IMRT) as neoadjuvant therapy in patients with localized or locally advanced PDAC.Experimental designTreatment consisted of cetuximab load at 400 mg/m² followed by cetuximab 250 mg/m² weekly and gemcitabine 50 mg/m² twice-weekly given concurrently with IMRT to 54 Gy. Following therapy, patients were considered for resection.ResultsThirty-seven patients were enrolled with 33 assessable for response. Ten patients (30%) manifested partial response and 20 (61%) manifested stable disease by RECIST. Twenty-five patients (76%) underwent resection, including 18/23 previously borderline and 3/6 previously unresectable tumors. Twenty-three (92%) of these had negative surgical margins. Pathology revealed that 24% of resected tumors had grade III/IV tumor kill, including two pathological complete responses (8%). Median survival was 24.3 months in resected patients. Outcome did not vary by epidermal growth factor receptor status.ConclusionsNeoadjuvant therapy with cetuximab/gemcitabine/IMRT is tolerable and active in PDAC. Margin-negative resection rates are high and some locally advanced tumors can be downstaged to allow for complete resection with encouraging survival. Pathological complete responses can occur. This combination warrants further investigation.     

Weekly gemcitabine and cisplatin chemotherapy: a well-tolerated but ineffective chemotherapeutic regimen in advanced pancreatic cancer patients. A report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD).

BACKGROUND: This phase II study was initiated to determine the activity and toxicity of a combination of gemcitabine (GEM) and cisplatin (CDDP) in patients with pancreatic cancer. PATIENTS AND METHODS: CDDP 35 mg/m(2) was given as a 30-min infusion and GEM 1000 mg/m(2) as a 30-min infusion. Both drugs were administered once weekly for 2 consecutive weeks out of every 3 weeks to chemonaive patients with locally advanced or metastatic pancreatic cancer. RESULTS: Forty-five advanced pancreatic cancer patients received this regimen for a total of 180 cycles of chemotherapy. One complete and four partial responses have been observed for an overall response rate of 9% (95% confidence interval 10% to 11%). Twenty-one patients (46%) had stable disease and 19 progressed on therapy. The median time to progression was 3.6 months, with a median survival of 5.6 months. A clinical benefit was obtained in nine of 37 patients (24%). Side-effects were mainly represented by hematological toxicity. Grade 3/4 WHO toxicities included neutropenia (6% of the patients) and thrombocytopenia (11%). The dose of GEM and CDDP was reduced in 14 patients (31%) and treatment was delayed in 10 patients (22%). CONCLUSIONS: Our results in terms of response rate, clinical benefit and survival do not support an advantage for the combination of GEM and CDDP given by this schedule.     

Phase I trial of sorafenib and gemcitabine in advanced solid tumors with an expanded cohort in advanced pancreatic cancer.

BACKGROUND: With its potent inhibitory effects against Raf-1 kinase and vascular endothelial growth factor receptor-2, sorafenib is a novel oral anticancer agent targeting signal transduction and angiogenic pathways. This study is designed to combine sorafenib and gemcitabine due to their compatibility in preclinical models and nonoverlapping clinical toxicities. EXPERIMENTAL DESIGN: An initial dose-escalation part of the study enrolled patients with advanced solid tumors, followed by an expanded cohort at the recommended dose for patients with advanced unresectable or metastatic pancreatic cancer. Sorafenib is administered continuously, whereas gemcitabine is given at 1,000 mg/m2 weekly x 7 followed by 1 rest week, then weekly x 3 every 4 weeks. RESULTS: Forty-two patients have been enrolled overall, including 19 in the dose-escalation part and 23 in the extended pancreatic cancer cohort. Demographics were as follows: male-to-female ratio = 26:16; median age = 61 years (range 39-83 years); Eastern Cooperative Oncology Group performance status 0:1:2 ratio = 16:21:5. The recommended dose of this combination is sorafenib 400 mg twice daily and gemcitabine 1,000 mg/m2. The most frequent grade 3 or 4 adverse events of all causalities were thrombocytopenia (28.6%), lymphopenia (21.4%), lipase elevation (19%), neutropenia (16.7%), and fatigue (14.3%). Antitumor activity was observed in both groups, with 2 (10.5%) confirmed partial responses in ovarian cancer and 12 patients (63.2%) with disease stabilization in the dose-escalation part; 13 patients (56.5%) achieved disease stabilization in the pancreatic cohort. There was no consistent pharmacokinetic drug-to-drug interaction between sorafenib and gemcitabine. CONCLUSIONS: Sorafenib and gemcitabine are well tolerated in combination; further evaluations in pancreatic and ovarian cancers are warranted.     

Gemcitabine plus epirubicin in advanced pancreatic cancer: a phase II multicenter trial

The aim of this phase II multicenter trial was to evaluate the activity of a novel combination of gemcitabine (GEM) and epirubicin (EPI) in advanced pancreatic cancer patients. Clinical benefit and response rate were the main efficacy end-points. From December 1997 to October 1999, 30 consecutive patients with measurable advanced pancreatic cancer were enrolled. Gemcitabine was administered intravenously in 30 min at a dose of 800 mg/m2 on days 1, 8, 15 followed by i.v. injection of epirubicin 25 mg/m(2); treatment was repeated every 28 days. With regard to clinical benefit response, 8/21 patients (38%) experienced significant palliation of tumor-related symptoms; the median symptom control time was 25 weeks. No complete responses were recorded while 6 patients achieved a partial remission, for an overall response rate of 20%; 10 patients (30%) had a stable disease and 14 (46%) had progressive disease. The median time to progression was 14 weeks. Median survival was 26 weeks, with 6 patients (20%) having long-term survival at 46 weeks. In general, chemotherapy was well tolerated; 9 patients (30%) suffered from WHO grade 3-4 haematological toxicity and 5 patients (16.6%) suffered from grade 3 non-haematological toxicity. In conclusion, the GEM plus EPI regimen represent a feasible approach for improvement of clinical benefit in advanced pancreatic cancer patients, but confirmatory investigations are required.