Search

A study to determine if addition of gemcitabine to adjuvant fluorouracil chemoradiation increased the survival rate of patients with resected pancreatic adenocarcinoma is conducted. Results indicate an improved survival rate but were not statistically significant.

Byline: Nikolas Tsavaris (1,2), Christos Kosmas (1,2), Panagiotis Gouveris (1,2), Kostadinos Gennatas (1,3), Aris Polyzos (4), Despina Mouratidou (1,5), Heracles Tsipras (6), Helias Margaris (6), George Papastratis (6), Evanthia Tzima (1,2), Nikitas Papadoniou (7), Gavrilos Karatzas (8), Efstathios Papalambros (7) Keywords: cholangiocarcinoma; gemcitabine; biliary tract cancer; gallbladder cancer Abstract: Objectives: To evaluate the efficacy and safety of weekly administration of gemcitabine treatment in chemotherapy-naive patients with advanced biliary tract and gallbladder cancer. Patients and methods: Gemcitabine at a dose of 800mg/m.sup.2 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 naive patients with advanced cholangiocarcinoma, particularly with a gallbladder origin. Author Affiliation: (1) 'HELGO' Hellenic Group of Oncology, Athens, Greece (2) Oncology Unit, Department of Pathophysiology, 'Laiko' General Hospital, University of Athens, Athens, Greece, 11527 (3) Oncology Unit, 2nd Department Surgery, 'Areteion' General Hospital, University of Athens, Greece (4) Oncology Unit, 1st Department of Internal Medicine -- Propeduetic, 'Laiko' Hospital, University of Athens, Athens, Greece (5) 2nd Department of Medical Oncology, 'Theagenion' Cancer Hospital, Thessaloniki (6) 3rd Department of Surgery, 'G. Genimatas' General Hospital, Athens, Greece (7) 1st Department of Surgery, 'Laiko' General Hospital, University of Athens, Athens, Greece (8) 3rd Department of Surgery, 'Sotiria' Hospital, University of Athens, Athens, Greece Article History: Registration Date: 21/10/2004

Byline: Emilio Esteban (1), Joaquin Fra (1), Marian Sala (1), Juan Carrasco (1), Norberto Corral (1), Jose Maria Vieitez (1), Enrique Estrada (1), Isabel Palacio (1), Jose Mari Buesa (1), Angel J. Lacave (1) Abstract: Purpose. We determine the maximum tolerated dose (MTD) and efficacy ofgemcitabine plus vinorelbine combined withcisplatin in patients with non-small celllung cancer (NSCLC). Patients and methods. Chemo naive patientswith stage IIIA to IV non-small cell lungcancer received outpatient administrationof gemcitabine 1000 mg/m.sup.2 andvinorelbine 25 mg/m.sup.2 intravenously ondays 1 and 8 every 21 days. Doses ofgemcitabine and vinorelbine were escalatedby 250 mg/m.sup.2 and 5 mg/m.sup.2,respectively, at each dose level. Cisplatin was administered at a fixed doseof 50 mg/m.sup.2 on days 2 and 9. Afterthe MTD was reached, the study wascontinued as a phase II trial. Results. From January 1998 to March 1999, sixty-five patients were enrolled. Thefirst 38 patients participated in the phaseI evaluation. After 130 cycles, thedose-limiting toxicities were neutropenia,stomatitis, asthenia, and hepatotoxicityoccurring at the third and fourth doselevels (doses of gemcitabine/vinorelbine of1500/25 and 1000/30 mg/m.sup.2).For the subsequent phase II evaluation, 27additional patients, out of a total of 53,receiving the MTD of gemcitabine andvinorelbine (1000--1250/25 mg/m.sup.2)followed (24 hours later) by cisplatin50 mg/m.sup.2. Thirty one (58%) of 53 assessable patients responded. Objectiveresponse for patients with stages III andIV disease, respectively, were 65% and47%. The median time to progression andthe overall survival time were 9 months(95% CI: 5--12) and 11 months (95 % CI:9--13), respectively. World HealthOrganization toxicity aY= grade 3neutropenia was registered in 28 (54%) of52 assessable patients (2% with febrileneutropenia), and aY= grade 3thrombocytopenia in 15 (29%) patients (4%with bleeding). Nausea/vomiting(aY= grade 2) and asthenia (moderate tosevere) occurred in 24 (46%) and 14 (27%)patients, respectively. Conclusion. Gemcitabine1000--1250 mg/m plus vinorelbine25 mg/m.sup.2 on days 1 and 8, followed bycisplatin 50 mg/m.sup.2 24 hours later, issafe for outpatient administration andactive in patients with NSCLC. Author Affiliation: (1) Servicio de Oncologia Medica, Hospital Central de Asturias, Oviedo, Spain Article History: Registration Date: 10/10/2004

Byline: James K. Weick (1), John J. Crowley (2), Mohamed A. Hussein (3), Dennis F. Moore (4), Bart Barlogie (5) Keywords: gemcitabine; multiple myeloma; phase II Abstract: Gemcitabine is a cytosine arabinoside(Ara-C) analog with activity in many humantumor systems. We evaluated the drug'sactivity in resistant or relapsing multiplemyeloma. Gemcitabine 1000 mg/m.sup.2 wasadministered as a 30 minute infusion ondays 1, 8, and 15 of a 28-day cycle. Nodose escalations were permitted and dosereductions were scheduled for hematologictoxicity. Twenty-nine eligible patientswere entered into Southwest Oncology Group(SWOG)-9803. One patient received notreatment and 5 patients had inadequateresponse assessments. The major toxicitywas hematologic with grade 3/4 neutropeniain 9 and grade 3/4 thrombocytopenia in 15patients. No responses were seen. Stabledisease was confirmed in sixteen patients(57%). Median survival was eight months. Gemcitabine as utilized in this trial hasshown little activity and is not to bestrongly considered for future multiplemyeloma trials. Author Affiliation: (1) Hematology Oncology Associates, Lake Worth, FL, USA (2) Southwest Oncology Group Statistical Center, Seattle, WA, USA (3) Cleveland Clinic Foundation, Cleveland, OH, USA (4) Wichita Community Clinical Oncology Program, Wichita, KS, USA (5) University of Arkansas for Medical Science, Little Rock, AR, USA Article History: Registration Date: 10/10/2004

Byline: Orhan Sezer (1), Jan Eucker (1), Christian Jakob (1), Olaf Kaufmann (2), Peter Schmid (1), Kurt Possinger (1) Keywords: gemcitabine; Hodgkin's disease; nucleoside analogues; progression; toxicity Abstract: Although, in recent decades effectivechemotherapy regimens have been developed forthe treatment of Hodgkin's disease, theprognosis of patients who experiencedisease progression is still very poor. Newtreatment approaches are urgently required tosalvage such patients. In a patient withHodgkin's disease who failed to achievecomplete remission with the escalatedBEACOPP protocol, progression with bonemarrow infiltration and B symptomsdeveloped despite further treatment.Subsequently, gemcitabine was administeredin a novel schedule as a four-hour infusion of250 mg/m.sup.2 on days 1, 8, and 15, every four weeks.After the first cycle, the dose was reducedto 200 mg/m.sup.2 because of grade 3neutropenia. The condition of the patientimproved after the second cycle and notoxicity was observed during cycles 3--6.Complete remission was achieved. Twoyears after the end of gemcitabinetherapy, the patient is in good clinicalcondition and in continuous completeremission without further treatment. Thisis the first report of the prolonged infusionof gemcitabine as a salvage therapy inHodgkin's disease. Author Affiliation: (1) Department of Oncology and Hematology, Universitatsklinikum Charite, Humboldt-Universitat, Berlin, Germany (2) Department of Pathology, Universitatsklinikum Charite, Humboldt-Universitat, Berlin, Germany Article History: Registration Date: 11/10/2004

Byline: Christian Manegold (1), Petr Zatloukal (2), Kurt Krejcy (3), Johannes Blatter (4) Keywords: gemcitabine; NSCLC; review; efficacy; toxicity; randomization Abstract: The role of chemotherapy in the treatment of non-smallcell lung cancer (NSCLC) has increased greatly in the past fewyears. While cytotoxic drugs are currently used both as singleagents and in combination for palliation in locally advanced andmetastatic disease, they have also been incorporated intomulti-modality treatment strategies of Stage I to Stage IIINSCLC. One of the main reasons for the increased acceptance ofchemotherapy is the development of new substances. Among the most promising of these new drugs is theantimetabolite gemcitabine. Several single-arm gemcitabine PhaseII studies involving more than 400 patients show validatedresponse rates in more than 20% of the patients. Thesepositive results have also been confirmed in randomized Phase IIstudies. Gemcitabine's unique mechanism of action, its lack ofoverlapping toxicity with other agents, and its favorabletoxicity profile also define it as an ideal candidate forcombination therapy. The activity seen with single-agent gemcitabine therapy canbe compared with that of cisplatin-etoposide combination therapy.Gemcitabine-cisplatin combination response rates range from31% to 54%, with a median survival time between 8.4and 15.4 months and a 1-year survival rate between 30% and59%. In addition to the clinical research ofgemcitabine-cisplatin combinations, gemcitabine has also beentested in various double and triple combinations withcarboplatin, paclitaxel, docetaxel, vinorelbine, and ifosfamide.Investigations combining gemcitabine with radiation therapy areon-going. The following review will summarize results fromrepresentative Phase I/II and III studies using gemcitabine forNSCLC patients. Author Affiliation: (1) Thoraxklinik der LVA, University Teaching Hospital, Heidelberg, Germany (2) Faculty Hospital Na Bulovce, Charles University and Postgraduate Medical School, 3rd Faculty of Medicine, Prague, Czech Republic (3) Eli Lilly GmbH, Area Medical Center, Vienna, Austria (4) Lilly Deutschland GmbH, Bad Homburg, Germany Article History: Registration Date: 05/10/2004

Byline: Elizabeth Poplin (1,2), John Roberts (1,2), Marybeth Tombs (1,2), Steven Grant (1,2), Eric Rubin (1,2) Keywords: gemcitabine; fluorouracil; Phase I study Abstract: Gemcitabine is a chemotherapy agent with efficacy in the treatment of lung, pancreas, bladder and breast cancer. It inhibits DNA synthesis by interfering with cytidine triphosphate production and also inhibits the activity of ribonucleotide reductase. Gemcitabine may potentiate fluorouracil's inhibition of thymidylate synthase. This inhibition would be expected to be sequence dependent, occurring only if gemcitabine were administered following fluorouracil (5FU). The combination of leucovorin, 5-FU, and gemcitabine was assessed in this phase I trial. Eligibility requirements included refractory solid tumor malignancy adequate hematologic, renal and hepatic reserve no prior therapy with the combination of leucovorin and 5FU, or with gemcitabine ECOG performance status 0--2, and signed informed consent. Eleven men and nine women were eligible. The median age was 52.5 years and the median performance status was 1. All but three patients had prior chemotherapy. The starting doses were leucovorin 20 mg/m.sup.2, 5FU 255 mg/m.sup.2 and gemcitabine 600 mg/m.sup.2. 5FU and gemcitabine were escalated in tandem to 340 mg/m.sup.2 and 800 mg/m.sup.2 and thereafter to 425 mg/m.sup.2 and 1000 mg/m.sup.2, respectively. Gemcitabine administration always followed that of 5FU by 30 minutes. The median number of cycles was 2 (range 1--32). Two patients at the starting dose had disease progression within the first cycle with one death on day 28. One patient with cholangiocarcinoma had a partial response and remained on study for 40 months. There were no other responses. The maximum tolerated dose is leucovorin 20 mg/m.sup.2, 5FU 340 mg/m.sup.2, and gemcitabine 800 mg/m.sup.2. The impact of drug sequence remains undetermined. Author Affiliation: (1) The Massey Cancer Center of the Medical College of Virginia, Virginia Commonwealth University, Richmond, VA, USA (2) The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ, USA Article History: Registration Date: 14/10/2004

Byline: Jordan D. Berlin (1), Dona B. Alberti (1), Rhoda Z. Arzoomanian (1), Chris A. Feierabend (1), Kris J. Simon (1), Kim A. Binger (1), Rebecca M. Marnocha (1), George Wilding (1) Keywords: gemcitabine; 5-fluorouracil; leucovorin; phase I study Abstract: Introduction: This was a dose escalation phase I trial designed to establish the MTD (maximum tolerated dose) and toxicity profile of the combination of gemcitabine, leucovorin and 5-fluorouracil (5-FU). Methods: Standard eligibility criteria were required for patients with advanced malignancy to enrol. Gemcitabine was escalated from an initial dose of 800 mg/m.sup.2. Gemcitabine was administered prior to leucovorin (25 mg/m.sup.2) followed by bolus 5-FU (600 mg/m.sup.2) every week for 3 weeks followed by 1 week of rest. Results: Of 21 patients enrolled, 20 were eligible for MTD determination. Patients received a median of three 4-week cycles of chemotherapy (range: 1 to 8 cycles). Toxicity was predominantly hematologic or gastroenterologic. Four dose levels were studied. At a gemcitabine dose of 1,500 mg/m.sup.2 systemic symptoms of fatigue accompanied hematologic toxicity and patients refused further therapy. At 1,250 mg/m.sup.2, full dose intensity was not delivered during the first cycle in 7 of 8 patients treated. Therefore, 1,000 mg/m.sup.2 was established as the recommended phase II dose for gemcitabine in this study. Antitumor activity was seen at all dose levels. Conclusions: The combination of gemcitabine, leucovorin and 5-FU was tolerable at full doses of all 3 drugs with an expected toxicity profile. Recommended phase II dose for gemcitabine was 1,000 mg/m.sup.2. Initial evidence of clinical activity was seen in a variety of tumor types. Author Affiliation: (1) Division of Oncology, University of Wisconsin, WI, USA Article History: Registration Date: 29/09/2004

Byline: Diana Luftner (1), Bernd Flath (1), Costa Akrivakis (1), Hans-Gunther Mergenthaler (1), Ute Ohnmacht (2), Michael Arning (2), Kurt Possinger (1) Keywords: gemcitabine; epirubicin; phase I study; metastatic breast cancer Abstract: Gemcitabine has shown single-agent activity in metastatic breast cancer. Epirubicin is also widely used for the adjuvant and treatment of metastatic breast cancer. The toxicity profiles and modes of action are different which provides a good rationale for studying both drugs in combination. In a phase I study gemcitabine at a fixed dose of 1000 mg/m2 on days 1, 8, 15 of a 28 day cycle was combined with escalated weekly doses of epirubicin starting with an initial dose of 10 mg/m2. Patients had stage IV metastatic disease without previous chemotherapy except as adjuvant treatment. Nineteen patients were included in the study which defined the maximum tolerated dose (MTD) of epirubicin at 20 mg/m2. Myelosuppression was the dose limiting toxicity with leucopenia WHO grade 3 and 4 in 40.0% and 20.0%, neutropenia WHO grade 3 and 4 without neutropenic fever in 20.0% and 40.0% and thrombocytopenia WHO grade 4 in 20.0%. At the epirubicin 15 mg/m2 dose level, leucopenia (11.1% WHO grade 3) and neutropenia (12.5 and 37.5% WHO grade 3 and 4) were reported. Symptomatic toxicity was generally mild: nausea/vomiting in about 20% of patients (WHO grade 3 or 4) on both 15 and 20 mg/m2 epirubicin dose levels. Alopecia WHO grade 3 and 4 was seen in 2 patients at MTD. Four of 19 evaluable patients had a partial response. We conclude that the combination of gemcitabine and epirubicin is well tolerated and has promising activity. A phase II study is underway with gemcitabine 1000 mg/m2 and epirubicin 15 mg/m2 on days 1, 8 and 15 of a 28 day cycle. Author Affiliation: (1) Medizin. Klinik II, Charite, Humboldt-Universitat, Berlin (2) Eli Lilly Germany, Bad Homburg, Germany Article History: Registration Date: 29/09/2004