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1.
Br J Oral Maxillofac Surg ; 58(1): 75-78, 2020 01.
Article in English | MEDLINE | ID: mdl-31735400

ABSTRACT

Treatment of bony tumours of the oral and maxillofacial area usually involve resection. However, access to certain areas may be difficult because of the size or site of the tumour. A poor view of the lesion during operation is another limiting factor, which can lead to incomplete resection in difficult cases. Percutaneous cryoablation is a common procedure for treating benign and malignant bony lesions outside the oral and maxillofacial area, but has to our knowledge never been used as a stand-alone treatment as we describe here. In 2016, three patients with benign bony tumours of the mandible (one a keratocyst, one an angiofibroma, and one a giant cell granuloma) were treated with one session of percutaneous cryoablation. Outcomes were monitored with computed tomography or magnetic resonance imaging at one year. No patient had a procedure-related complication, and there were no other complications. Radiological controls showed complete recovery. Percutaneous cryoablation seems to be an interesting and valuable alternative to resection for bony lesions with its limited access and high operative morbidity.


Subject(s)
Bone Neoplasms , Soft Tissue Neoplasms , Cryosurgery , Humans , Mandible , Treatment Outcome
3.
Ann Oncol ; 21(11): 2233-2239, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20444843

ABSTRACT

BACKGROUND: Erlotinib and pemetrexed are approved single agents for second-line treatment of non-small-cell lung cancer (NSCLC) and, in combination, have shown synergistic antitumor activity in NSCLC cell lines. We investigated the safety, pharmacokinetics and preliminary efficacy of combined erlotinib-pemetrexed in patients with refractory advanced NSCLC. PATIENTS AND METHODS: A nonrandomized, open-label, phase IB study was performed in patients with advanced NSCLC whose disease had progressed on or following first-line chemotherapy with a platinum-containing regimen or for whom the erlotinib-pemetrexed combination was considered appropriate. Patients received i.v. pemetrexed 500-700 mg/m² every 3 weeks and oral erlotinib 100-150 mg/day. RESULTS: Twenty patients were recruited. The most common adverse events (AEs) were rash, diarrhea and fatigue. Serious AEs occurred in eight patients (three treatment related) and there were eight deaths (none treatment related). Dose-limiting toxic effects were not experienced up to erlotinib 150 mg/day plus pemetrexed 600 mg/m². Concurrent administration did not affect pharmacokinetic parameters. Two patients achieved partial responses and nine had stable disease. CONCLUSIONS: Erlotinib-pemetrexed combination is well tolerated at doses equal to the licensed single-agent doses (150 mg/day and 500 mg/m², respectively). The good tolerability profile and promising efficacy indicate that this combination warrants further investigation for patients with advanced NSCLC.


Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Large Cell/drug therapy , Carcinoma, Neuroendocrine/drug therapy , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Squamous Cell/drug therapy , Lung Neoplasms/drug therapy , Adenocarcinoma/genetics , Adenocarcinoma/secondary , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Carcinoma, Large Cell/genetics , Carcinoma, Large Cell/secondary , Carcinoma, Neuroendocrine/genetics , Carcinoma, Neuroendocrine/secondary , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/secondary , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/secondary , Disease Progression , ErbB Receptors/genetics , Erlotinib Hydrochloride , Female , Glutamates/administration & dosage , Guanine/administration & dosage , Guanine/analogs & derivatives , Humans , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Male , Maximum Tolerated Dose , Middle Aged , Mutation/genetics , Neoplasm Staging , Pemetrexed , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins p21(ras) , Quinazolines/administration & dosage , Survival Rate , Time Factors , Tissue Distribution , Treatment Outcome , ras Proteins/genetics
5.
Lung Cancer ; 64(2): 211-8, 2009 May.
Article in English | MEDLINE | ID: mdl-19042053

ABSTRACT

AIM: Peritoneal mesothelioma (PM) has rarely been studied. The Expanded Access Program (EAP) provided access to 109 patients with PM. METHODS: This was a nonrandomized, open-label study conducted in chemo-naïve or previously treated patients with PM not amenable to curative surgery. Patients received pemetrexed (PEM) 500 mg/m2 alone or with cisplatin (CIS) 75 mg/m2 or carboplatin (CARBO) AUC 5 every 21 days, supplemented with standard vitamin B(12), folate, and dexamethasone. RESULTS: Response rates (95% CI) for PEM, PEM/CIS, and PEM/CARBO were 12.5% (3.5, 29.0), 20.0% (7.7, 38.6), and 24.1% (10.3, 43.5), respectively. Median survival for PEM was 10.3 months. One-year survival rates for PEM/CIS and PEM were 57.4% (95% CI: 10.3, 100) and 41.5% (95% CI: 4.6, 78.4), respectively, and were not available for PEM/CARBO. Anemia was the most common serious adverse event (6.4%). Neutropenia (34.6%) was the most frequent CTC grade 3 or 4 toxicity reported. CONCLUDING STATEMENT: PEM with or without a platinum agent was both active and well tolerated in patients with peritoneal mesothelioma.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Mesothelioma/drug therapy , Peritoneal Neoplasms/drug therapy , Adult , Aged , Carboplatin/administration & dosage , Carboplatin/adverse effects , Cisplatin/administration & dosage , Cisplatin/adverse effects , Female , Glutamates/administration & dosage , Glutamates/adverse effects , Guanine/administration & dosage , Guanine/adverse effects , Guanine/analogs & derivatives , Humans , Kaplan-Meier Estimate , Male , Mesothelioma/mortality , Middle Aged , Pemetrexed , Peritoneal Neoplasms/mortality
6.
Acta Psychiatr Scand ; 116(1): 6-9, 2007 Jul.
Article in English | MEDLINE | ID: mdl-17559595

ABSTRACT

OBJECTIVE: China's biomedical research activity is increasing and this literature is becoming more accessible online. Our aim was to survey all randomized control schizophrenia trials (RCTs) in one Chinese bibliographic database. METHOD: Chinese Academic Journals was electronically searched for RCTs and all relevant citations were also sought on PubMed to ascertain global accessibility. RESULTS: The search identified 3275 records, of which 982 were RCTs relevant to schizophrenia. A total of 71% (699) could be found by using English phrases. All the main body of text of the 982 papers was in Mandarin. On average, these trials involved about 100 people, with interventions and outcome measures familiar to schizophrenia trialists worldwide. Four of the 982 records (<1%) were identified on PubMed. CONCLUSION: Those undertaking systematic reviews should search the Chinese literature for relevant material. Failing to do this will leave the results of systematic reviews prone to random error or bias, or both.


Subject(s)
Antipsychotic Agents/therapeutic use , Randomized Controlled Trials as Topic , Schizophrenia/drug therapy , China , Humans
9.
Invest New Drugs ; 21(3): 353-8, 2003 Aug.
Article in English | MEDLINE | ID: mdl-14578684

ABSTRACT

BACKGROUND: Metastatic renal cell carcinoma (RCC) is rising in incidence but remains difficult to treat. This clinical trial evaluated the effects of pemetrexed (multitargeted antifolate, ALIMTAR) for the treatment of metastatic RCC. PATIENTS AND METHODS: Patients were required to have histological diagnosis of metastatic RCC with measurable disease and no prior chemotherapy. In addition, patients were required to have a World Health Organization (WHO) performance status of 0-2 and adequate bone marrow reserve. Patients received pemetrexed at a dose of 600 mg/m2 as a 10 min infusion every 3 weeks. Patients did not receive folic acid or vitamin B12 supplementation. RESULTS: Thirty-nine patients were enrolled and thirty two were evaluable for response. Three patients had a partial response for a response rate of 9% (95% CI 2-25%). The median time to progressive disease was 10.5 months. Of the nonresponders, twenty two had stable disease (median duration was 5.8 months; range 1.5-27.7) and seven had progressive disease (median time to progression was 5.4 months). Median time to progression for all qualified patients was 5.7 months. Common toxicities experienced were diarrhea and infection. Fatigue, stomatitis, and rash were also reported. The most common hematologic toxicity was grade 3/4 lymphopenia in 76% of patients. Leukopenia, granulocytopenia, and thrombocytopenia were also frequently reported. CONCLUSION: Single-agent pemetrexed has moderate activity in the treatment of metastatic RCC and should be investigated in combination with other potential active agents, as first-line treatment.


Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Renal Cell/drug therapy , Glutamates/therapeutic use , Guanine/analogs & derivatives , Guanine/therapeutic use , Kidney Neoplasms/drug therapy , Aged , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Carcinoma, Renal Cell/secondary , Dose-Response Relationship, Drug , Drug Administration Schedule , Drug Therapy, Combination , Female , Folic Acid/administration & dosage , Folic Acid/therapeutic use , Glutamates/administration & dosage , Glutamates/adverse effects , Guanine/administration & dosage , Guanine/adverse effects , Hematinics/administration & dosage , Hematinics/therapeutic use , Humans , Infusions, Intravenous , Kidney Neoplasms/pathology , Male , Middle Aged , Pemetrexed , Time Factors , Treatment Outcome , Vitamin B 12/administration & dosage , Vitamin B 12/therapeutic use
10.
Int J Gynecol Cancer ; 13(2): 130-7, 2003.
Article in English | MEDLINE | ID: mdl-12657112

ABSTRACT

This phase II study evaluated the activity and toxicity of gemcitabine plus cisplatin as first-line treatment of patients with advanced ovarian cancer. Chemonaive patients >/=60-year-old with FIGO stage IIIC or IV epithelial ovarian carcinoma were enrolled. Patients received cisplatin 75 mg /m2 on day 1 and gemcitabine 1250 mg /m2 on day 1 (before cisplatin) and day 8 of a 21-day cycle. Of 44 female patients (median age, 70 years), 72.7% had stage IIIC disease and 67.4% had a Karnofsky performance status >/=80. Of the 37 response-evaluable patients (35 with measurable lesion[s] >/=2 cm), there were seven (18.9%) pathologic complete responses, two (5.4%) pathologic partial responses, two (5.4%) clinical complete responses, and 12 (32.4%) clinical partial responses, for an overall response rate of 62.2% (95% CI, 44.8%-77.5%), and a pathologic response rate of 24.3% (95% CI, 11.8%-41.2%). Median survival was 27.7 months (95% CI, 14.3-40.8 months). Grade 3/4 neutropenia and thrombocytopenia occurred in 59.5% and 30.2% of patients, respectively, with neutropenic fever in one patient. Grade 3 nausea /vomiting and alopecia occurred in 25.6% and 9.5% of patients, respectively. We conclude that gemcitabine plus cisplatin is active and feasible as first-line treatment of advanced epithelial ovarian cancer in patients >/=60 years. Further clinical trials adding gemcitabine to current standard, first-line treatment seem warranted in younger as well as older patients.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma/drug therapy , Cisplatin/administration & dosage , Deoxycytidine/analogs & derivatives , Deoxycytidine/administration & dosage , Ovarian Neoplasms/drug therapy , Age Factors , Aged , Aged, 80 and over , Carcinoma/mortality , Carcinoma/pathology , Disease-Free Survival , Female , Humans , Karnofsky Performance Status , Middle Aged , Neoplasm Staging , Ovarian Neoplasms/mortality , Ovarian Neoplasms/pathology , Survival Analysis , Treatment Outcome , Gemcitabine
11.
Urology ; 61(2): 468-73, 2003 Feb.
Article in English | MEDLINE | ID: mdl-12597983

ABSTRACT

OBJECTIVES: Despite clinical use, the radiosensitizing effect of gemcitabine (2'2'-difluorodeoxycytidine) in human transitional cell carcinoma (TCC) has not been shown to date. We investigated gemcitabine as a radiosensitizer for human TCC cells. METHODS: Monolayer cultures of RT112 (G1, p53 wild type), RT4 (G1-G2, p53 wild type), T24 (G3, p53, mutant type), and SUP (G4, p53 mutant type) cells were incubated in medium with gemcitabine. Electron beam radiation was applied alone, simultaneous, or 3, 6, 12, and 24 hours after gemcitabine. Jurkat leukemia cells were used as controls for radiation toxicity. Cell survival was determined 6, 12, 24, 48, and 72 hours after radiation by microculture tetrazolium assay. DNA damage was evaluated by flow cytometric assessment of poly(ADP-ribose) polymerase, and apoptosis was determined by terminal-deoxynucleotidyltransferase-mediated dUTP nick-end labeling and flow cytometric assessment after annexin-V and propidium iodide labeling. RESULTS: In all TCC cell lines, radiation alone caused only little and insignificant growth inhibitory effects at 10 Gy. Gemcitabine alone had a dose-dependent cytotoxic and apoptosis inducing effect on all TCC cell lines independent of p53 status. Assays combining radiation with gemcitabine in different dose and time schedules demonstrated no radiosensitizing effect in TCC cells. CONCLUSIONS: Gemcitabine is effective in TCC cell lines independent of p53 status. A radiosensitizing effect could not be demonstrated. Again, p53 status was not predictive of the radioresponse in the bladder cancer cell lines. Clinical studies with gemcitabine and radiotherapy might nevertheless yield different results but should be performed with utmost caution.


Subject(s)
Carcinoma, Transitional Cell/radiotherapy , Deoxycytidine/analogs & derivatives , Deoxycytidine/therapeutic use , Radiation-Sensitizing Agents/therapeutic use , Urinary Bladder Neoplasms/radiotherapy , Animals , Apoptosis/drug effects , Apoptosis/radiation effects , Carcinoma, Transitional Cell/drug therapy , Carcinoma, Transitional Cell/genetics , Cell Division/drug effects , Cell Division/radiation effects , Cell Survival/drug effects , Cell Survival/radiation effects , Deoxycytidine/pharmacology , Dose-Response Relationship, Drug , Dose-Response Relationship, Radiation , Flow Cytometry , Genes, p53/genetics , Genes, p53/physiology , Humans , In Situ Nick-End Labeling , Mutation , Radiation-Sensitizing Agents/pharmacology , Radiotherapy Dosage , Radiotherapy, Conformal , Tumor Cells, Cultured , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/genetics , Gemcitabine
12.
Onkologie ; 25(1): 47-52, 2002 Feb.
Article in English | MEDLINE | ID: mdl-11893883

ABSTRACT

OBJECTIVES: i) To evaluate objective response, toxicity, and quality of life (QoL) of gemcitabine monotherapy as second-line treatment in patients with cisplatin-refractory, metastatic transitional cell carcinoma (TCC). ii) To assess prognostic parameters for response to treatment and for improvement of QoL parameters. PATIENTS AND METHODS: 30 patients were prospectively enrolled in this open-label, nonrandomized multicenter phase II trial. Patients received up to 6 courses of gemcitabine monotherapy (1,250 mg/m(2) on day 1 and 8 of a 21-day course). 28 of 30 patients were available for response evaluation. RESULTS: Objective response (OR) was seen in 3/28 (11%) of patients (2 complete remissions, 1 partial remission). The mean time to progression (TTP) was 4.9 +/- 3.5 months and mean disease-specific survival time was 8.7 +/- 4.7 months. 13 of 28 patients did not progress (OR + 10 stable diseases), and TTP (8.0 +/- 2.7 months, p < 0.001) as well as survival time (10.2 +/- 3.8 months, p < 0.05) differed significantly from those who showed progressive disease within 18 weeks of treatment. Pain values significantly improved in the group of responders from 4.3 +/- 1.9 to 5.8 +/- 1.3 points (p < 0.05). Response to cisplatin pretreatment was the best prognosticator for the response to gemcitabine. CONCLUSIONS: Gemcitabine monotherapy as second-line treatment is justified in patients with metastatic TCC who are refractory to cisplatin treatment. Patients with initially OR to cisplatin benefit most from second-line treatment. QoL remains stable during treatment, and pain improves especially in patients with bone metastases.


Subject(s)
Carcinoma, Transitional Cell/drug therapy , Cisplatin/administration & dosage , Deoxycytidine/analogs & derivatives , Deoxycytidine/administration & dosage , Urinary Bladder Neoplasms/drug therapy , Carcinoma, Transitional Cell/mortality , Carcinoma, Transitional Cell/pathology , Cisplatin/adverse effects , Deoxycytidine/adverse effects , Dose-Response Relationship, Drug , Drug Administration Schedule , Drug Resistance, Neoplasm , Follow-Up Studies , Humans , Neoplasm Metastasis , Neoplasm Staging , Prospective Studies , Survival Rate , Urinary Bladder Neoplasms/mortality , Urinary Bladder Neoplasms/pathology , Gemcitabine
13.
Ann Oncol ; 12(6): 835-40, 2001 Jun.
Article in English | MEDLINE | ID: mdl-11484961

ABSTRACT

BACKGROUND: Both gemcitabine and etoposide are active in the treatment of small-cell lung cancer (SCLC), and are characterised by mild toxicity profiles. The combination of both drugs was found to be feasible and active in a phase I dose-finding study in solid tumours. Therefore, a phase II trial was initiated to examine the activity and toxicity of this schedule in extensive disease SCLC. PATIENTS AND METHODS: Forty-two chemo-naïve extensive disease SCLC patients were enrolled to receive gemcitabine 1000 mg/m2, days 1, 8 and 15, and etoposide 80 mg/m2, days 8, 9 and 10 of a 28-day cycle. RESULTS: Thirty-seven patients were evaluable for efficacy (five received less than one cycle). No complete responses were observed, but partial responses were seen in 17 patients, yielding an overall response rate of 46%. The median duration of response was 5.8 months. Disease stabilisation was obtained in another 10 patients (27%). The median survival of the 37 protocol-qualified patients was 10.5 months (95% confidence interval (CI): 7.5-12.0). The levels of WHO grade 3 and 4 toxicities were low and clinically manageable. CONCLUSION: In comparison with standard platinum-based regimens, this combination of gemcitabine and etoposide resulted in a somewhat lower response rate, but a similar median survival time. Haematological toxicity was more pronounced than expected from the toxicity data of each agent individually. However, because of its mild non-haematological toxicity, and its ability to be administered in an outpatient setting, this combination provides a reasonable palliative option for patients with extensive disease SCLC.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Carcinoma, Small Cell/drug therapy , Deoxycytidine/analogs & derivatives , Deoxycytidine/administration & dosage , Etoposide/administration & dosage , Lung Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma, Small Cell/pathology , Carcinoma, Small Cell/secondary , Deoxycytidine/adverse effects , Etoposide/adverse effects , Female , Humans , Infusions, Intravenous , Lung Neoplasms/pathology , Lung Neoplasms/secondary , Male , Middle Aged , Survival Analysis , Treatment Outcome , Gemcitabine
14.
Eur J Nucl Med ; 28(4): 418-25, 2001 Apr.
Article in English | MEDLINE | ID: mdl-11357491

ABSTRACT

Apoptosis has been described as an energy-consuming process. This combined in vivo/in vitro study investigated the effects of the antineoplastic agent gemcitabine on tumour metabolism and on the induction of apoptosis. Dynamic positron emission tomography (PET) measurements of fluorine-18 fluorodeoxyglucose (FDG) uptake were done in rats bearing Morris hepatoma prior to and after therapy with 90 mg gemcitabine/kg b.w. Furthermore, thymidine (TdR) incorporation into the DNA of these tumours was determined. In vitro measurements of FDG and TdR uptake were performed immediately and 24 h after the end of gemcitabine treatment, and the amount of apoptotic cells was determined using the TUNEL reaction. In vivo an increase in FDG transport and phosphorylation occurred early after gemcitabine treatment, although TdR incorporation into the DNA of the tumours declined. In vitro, an enhanced glucose transport, an increase in TdR uptake in the cytoplasm and a decrease in TdR incorporation in the nucleic acid fraction early after treatment occurred. Inhibition of glucose transport caused an increase in the amount of apoptotic cells. The increase in glucose uptake and TdR metabolism early after therapy is interpreted as a stress reaction of the tumour cells, protecting the cells from apoptosis during this early period after exposure to cytotoxic drugs like gemcitabine.


Subject(s)
Antimetabolites, Antineoplastic/therapeutic use , Apoptosis/drug effects , Deoxycytidine/analogs & derivatives , Deoxycytidine/therapeutic use , Glucose/metabolism , Liver Neoplasms, Experimental/drug therapy , 3-O-Methylglucose/metabolism , Animals , Antimetabolites, Antineoplastic/pharmacokinetics , DNA, Neoplasm/drug effects , Deoxycytidine/pharmacokinetics , Fluorodeoxyglucose F18 , Immunohistochemistry , Liver Neoplasms, Experimental/diagnostic imaging , Liver Neoplasms, Experimental/pathology , Neoplasm Transplantation , Phosphorylation , Radiopharmaceuticals , Rats , Rats, Inbred Strains , Thymidine/metabolism , Tomography, Emission-Computed , Tumor Cells, Cultured , Gemcitabine
15.
Eur J Surg Oncol ; 26(6): 583-7, 2000 Sep.
Article in English | MEDLINE | ID: mdl-11034810

ABSTRACT

AIMS: To estimate the potential activity of gemcitabine for hepatic arterial infusion (HAI) chemotherapy in pancreatic and colorectal cancer. METHODS: The anti-proliferative effects of gemcitabine were determined in MIA PaCa-2 and PMH2/89 pancreatic and HT29 and NMG64/84 colon cancer cell lines and in fresh tumours from patients with liver metastases of colon, rectal and pancreatic cancer in vitro using the human tumour colony forming assay. RESULTS: Gemcitabine showed concentration and time-dependent cytotoxic effects in all tested cell lines. The IC(50)of gemcitabine in MIA PaCa-2, PMH2/89, HT29 and NMG64/84 cells at 2 h exposure time were >100, 18, 100 and 2.5 microg/ml, respectively, at 4 h 15, 1.2, 45 and 0.5 microg/ml, respectively, and at 24 h 0.2, 0.1, 1.8 and 0.1 microg/ml, respectively. All tumours displayed concentration dependent inhibition of colony formation after exposure to gemcitabine for 2 h. The IC(50)values of gemcitabine in six of the 10 metastases were

Subject(s)
Antimetabolites, Antineoplastic/pharmacology , Colorectal Neoplasms/drug therapy , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Pancreatic Neoplasms/drug therapy , Aged , Cell Division/drug effects , Colorectal Neoplasms/pathology , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Female , Hepatic Artery , Humans , Infusions, Intra-Arterial , Kinetics , Liver Neoplasms/drug therapy , Liver Neoplasms/secondary , Male , Middle Aged , Neoplastic Stem Cells/drug effects , Pancreatic Neoplasms/pathology , Tumor Cells, Cultured/drug effects , Gemcitabine
16.
Invest New Drugs ; 18(1): 29-42, 2000 Feb.
Article in English | MEDLINE | ID: mdl-10830139

ABSTRACT

The role of chemotherapy in the treatment of non-small cell lung cancer (NSCLC) has increased greatly in the past few years. While cytotoxic drugs are currently used both as single agents and in combination for palliation in locally advanced and metastatic disease, they have also been incorporated into multi-modality treatment strategies of Stage I to Stage III NSCLC. One of the main reasons for the increased acceptance of chemotherapy is the development of new substances. Among the most promising of these new drugs is the antimetabolite gemcitabine. Several single-arm gemcitabine Phase II studies involving more than 400 patients show validated response rates in more than 20% of the patients. These positive results have also been confirmed in randomized Phase II studies. Gemcitabine's unique mechanism of action, its lack of overlapping toxicity with other agents, and its favorable toxicity profile also define it as an ideal candidate for combination therapy. The activity seen with single-agent gemcitabine therapy can be compared with that of cisplatin-etoposide combination therapy. Gemcitabine-cisplatin combination response rates range from 31% to 54%, with a median survival time between 8.4 and 15.4 months and a 1-year survival rate between 30% and 59%. In addition to the clinical research of gemcitabine-cisplatin combinations, gemcitabine has also been tested in various double and triple combinations with carboplatin, paclitaxel, docetaxel, vinorelbine, and ifosfamide. Investigations combining gemcitabine with radiation therapy are on-going. The following review will summarize results from representative Phase I/II and III studies using gemcitabine for NSCLC patients.


Subject(s)
Antimetabolites, Antineoplastic/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Deoxycytidine/analogs & derivatives , Lung Neoplasms/drug therapy , Animals , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Combined Modality Therapy , Deoxycytidine/therapeutic use , Humans , Gemcitabine
17.
Ann Oncol ; 11(4): 435-40, 2000 Apr.
Article in English | MEDLINE | ID: mdl-10847462

ABSTRACT

BACKGROUND: To evaluate the activity of MTA plus cisplatin in chemotherapy-naive patients with non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Thirty-six chemotherapy-naïve patients with NSCLC received 500 mg/m2 MTA plus 75 mg/m2 cisplatin every 21 days, with 4 mg dexamethasone orally twice daily on the day before, of, and after MTA administration. RESULTS: Median age was 58 years. WHO performance status was 0-2. Eighteen patients each had stage IIIB and IV disease. Seventeen patients each had squamous-cell and adenocarcinoma; two had undifferentiated disease. Fourteen patients (39%; 95% confidence interval: 23%-57%) showed partial response; seventeen (47%) had stable disease. Median survival was 10.9 months. Twenty-one patients (59%) experienced grade 3 or 4 granulocytopenia without fever or infection. Five (14%) and six (17%) patients experienced grade 3 anemia and grade 3 or 4 thrombocytopenia, respectively. Nonhematological toxicities included grade 3 nausea in two patients (6%), and grade 3 and 4 diarrhea in one patient (3%) each. One patient each experienced grade 4 ALT and grade 3 bilirubin and AST elevations. CONCLUSIONS: MTA plus cisplatin is well tolerated and active against NSCLC. Further studies of this combination are warranted.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Adult , Aged , Anemia/chemically induced , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma, Non-Small-Cell Lung/pathology , Cisplatin/administration & dosage , Dexamethasone/administration & dosage , Female , Glutamates/administration & dosage , Guanine/administration & dosage , Guanine/analogs & derivatives , Humans , Infusions, Intravenous , Lung Neoplasms/pathology , Male , Middle Aged , Pemetrexed , Survival Analysis , Thrombocytopenia/chemically induced
18.
Semin Oncol ; 26(2 Suppl 6): 89-93, 1999 Apr.
Article in English | MEDLINE | ID: mdl-10598561

ABSTRACT

MTA (multitargeted antifolate, LY231514) is a novel antimetabolite resulting from structure/activity studies of the lometrexol-type antifolates. It has been shown to inhibit various enzymes of folate pathways and has broad antitumor activity in a variety of in vitro and in vivo tumor models. Clinical phase 1 studies have been performed using different administration schedules, and subsequently the every-21-days schedule has been selected for further development. We report the preliminary findings from a combination phase I study of MTA and cisplatin administered every 21 days. In the first cohort (34 patients), both agents were administered on day 1 with a starting dose of 300 mg/m2 MTA and 60 mg/m2 cisplatin. In a second cohort (10 patients), MTA (500 or 600 mg/m2) was administered on day 1 followed by cisplatin (75 mg/m2) on day 2. The maximum tolerated doses were reached at 600 mg/m2 MTA/100 mg/m2 cisplatin (cohort 1) and 600 mg/m2 MTA/75 mg/m2 cisplatin (cohort 2). In cohort 1, dose-limiting toxicities consisted of reversible myelosuppression with leukopenia and neutropenia. In addition, delayed fatigue also was of clinical significance. Pharmacokinetic analyses indicated that hydration administered before the administration of cisplatin did not influence the major pharmacokinetic parameters of MTA. Eleven objective remissions were observed, including one complete response in a patient with relapsed squamous cell carcinoma of the head and neck and partial responses in four of seven patients with mesothelioma In contrast, the dose-limiting toxicities in patient cohort 2 consisted of neutropenic sepsis, diarrhea, and skin toxicity with two possibly treatment-related deaths on study. No objective remissions are presently observed in cohort 2. We conclude that the combination of MTA and cisplatin is feasible and clinically active when both agents are administered on day 1 and that it should be pursued for further clinical development.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Glutamates/administration & dosage , Guanine/analogs & derivatives , Head and Neck Neoplasms/drug therapy , Lung Neoplasms/drug therapy , Mesothelioma/drug therapy , Adult , Aged , Cisplatin/administration & dosage , Enzyme Inhibitors , Female , Folic Acid Antagonists , Guanine/administration & dosage , Humans , Male , Middle Aged , Pemetrexed
19.
J Clin Oncol ; 17(10): 3009-16, 1999 Oct.
Article in English | MEDLINE | ID: mdl-10506594

ABSTRACT

PURPOSE: Multitargeted antifolate (MTA; LY231514) has broad preclinical antitumor activity and inhibits a variety of intracellular enzymes involved in the folate pathways. This study was designed to (1) determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of MTA combined with cisplatin; (2) determine a recommended dose for phase II studies; and (3) collect anecdotal information on the antitumor activity of MTA combined with cisplatin. PATIENTS AND METHODS: Patients with solid tumors received MTA intravenously over 10 minutes and cisplatin over 2 hours once every 21 days. In cohort 1, both agents were administered on day 1 starting with MTA 300 mg/m(2) and cisplatin 60 mg/m(2). In cohort 2, MTA (500 or 600 mg/m(2)) was administered on day 1, followed by cisplatin (75 mg/m(2)) on day 2. RESULTS: In cohort 1, 40 assessable patients received 159 courses of treatment. The MTD was MTA 600 mg/m(2)/cisplatin 100 mg/m(2). DLTs were reversible leukopenia/neutropenia and delayed fatigue. Hydration before cisplatin therapy did not influence MTA pharmacokinetics. Eleven objective remissions included one complete response in a patient with relapsed squamous cell head and neck carcinoma, and partial responses in four of ten patients with epithelial pleural mesothelioma. In cohort 2, 11 assessable patients received 23 courses of treatment. The MTD was MTA 600 mg/m(2) and cisplatin 75 mg/m(2). DLTs were neutropenic sepsis, diarrhea, and skin toxicity. Two patients died of treatment-related complications during the study. Two patients had objective remissions (one mesothelioma patient, one colon cancer patient). CONCLUSION: The combination of MTA and cisplatin is clinically active, and administering both agents on day 1 is superior to a split schedule. Further development of this combination for mesothelioma is warranted.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Folic Acid Antagonists/pharmacokinetics , Glutamates/pharmacokinetics , Guanine/analogs & derivatives , Neoplasms/drug therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Cisplatin/administration & dosage , Dose-Response Relationship, Drug , Female , Folic Acid Antagonists/administration & dosage , Folic Acid Antagonists/adverse effects , Glutamates/administration & dosage , Glutamates/adverse effects , Guanine/administration & dosage , Guanine/adverse effects , Guanine/pharmacokinetics , Humans , Infusions, Intravenous , Male , Mesothelioma/drug therapy , Middle Aged , Pemetrexed , Treatment Outcome
20.
Int J Radiat Oncol Biol Phys ; 41(4): 875-82, 1998 Jul 01.
Article in English | MEDLINE | ID: mdl-9652852

ABSTRACT

PURPOSE: Gemcitabine (2',2'-difluorodeoxycytidine; dFdCyd) is a new deoxycitidine analog which exhibits substantial activity against solid tumors and radiosensitizing properties in vitro. To examine cell cycle-specific effects of a combined treatment with gemcitabine and radiation, the in vitro clonogenic survival of two different cell lines was measured for cells from log-phase culture, G1 and S-phase cells. METHODS AND MATERIALS: Chinese hamster (V79) and human colon carcinoma (Widr) cells were exposed to different radiation doses and for different points of time relative to gemcitabine treatment (2 h). Experiments were also carried out with different cell-cycle populations obtained after mitotic selection (V79) or after serum stimulation of plateau-phase cells (Widr). The resulting survival curves were analyzed according to the LQ model, and mean inactivation doses (MID) and the cell cycle-specific enhancement ratios (ER) were calculated from the survival curve parameters. RESULTS: Effectiveness of combined treatment of log-phase cells was greatest when cells were irradiated at the end of the gemcitabine exposure [ER: 1.28 (V79), 1.24 (Widr)]. For later times after the removal of the drug, radiosensitization declined, approaching independent toxicity. From the time course of interactive-type damage decay half-life values of 75 min (V79) and 92 min (Widr) were derived. Gemcitabine did not radiosensitize G1 Widr cells or V79 cells from the G1/S border, but substantial radiosensitization was observed for the S-phase cell preparations [ER: 1.45 (V79-lateS), 1.57 (Widr)]. CONCLUSIONS: Treatment of cells with gemcitabine immediately before irradiation eliminates, or at least greatly reduces, the variation in radiosensitivity during the cell cycle that is manifested by radioresistance during S phase. This reversal of S-phase radioresistance could imply that gemcitabine interferes with the potentially lethal damage repair/fixation pathway. Other approaches have been taken to overcome S-phase radioresistance, such as hyperthermia or densely ionizing radiation, and combined treatments with dFdCyd could prove of value to complement such efforts.


Subject(s)
Cell Cycle/drug effects , Cell Cycle/radiation effects , Deoxycytidine/analogs & derivatives , Radiation-Sensitizing Agents/pharmacology , Animals , Cell Line/drug effects , Cell Line/radiation effects , Cell Survival , Combined Modality Therapy , Cricetinae , Cricetulus , Deoxycytidine/pharmacology , Dose-Response Relationship, Drug , Humans , Radiation Dosage , S Phase/drug effects , S Phase/radiation effects , Tumor Cells, Cultured/drug effects , Tumor Cells, Cultured/radiation effects , Gemcitabine
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