CD44-positive colorectal adenoma cells express the potential stem cell markers musashi antigen (msi1) and ephrin B2 receptor (EphB2).

The majority of colorectal adenomas contain a mutation in the APC gene activating the wnt pathway. As wnt signalling preserves stem cell functions, it would be expected that stem cells would be enriched in adenomas. We have shown expression of the wnt target gene CD44, which may characterize the expanded stem cell compartment, in colorectal tumours. To investigate this possibility, we performed an immunohistological survey of CD44 expression in relation to the proliferation marker Ki67 and apoptosis in colorectal tumour tissue, and have isolated a CD44-positive subpopulation of the human colorectal adenoma cell line LT97 for cell biological analysis. In tissues, CD44 expression was not related to Ki67, but was associated with lower apoptosis in the CD44-positive areas. CD44-positive and -negative populations isolated from LT97 cultures were identical in their Ki-ras and p53 status but differed in their growth and survival characteristics. While CD44-positive cells attached and grew to reconstitute the original culture, the CD44-negative cells rapidly underwent apoptosis and were unable to resume growth. In comparison to unsorted growing LT97 cells, the CD44-positive cells had shifted beta-catenin into the nucleus and expressed beta-catenin target genes, such as ephrin B receptor (ephB2) and musashi antigen (msi1). By contrast, CD44-negative cultures contained no cells with nuclear beta-catenin. In summary, the CD44-positive cells accumulating in colorectal tumours have increased survival capacity both in vivo and in vitro. They also express markers typical of colorectal progenitor cells, msi1 and ephB2, in the premalignant progenitor population.

Irinotecan plus raltitrexed vs raltitrexed alone in patients with gemcitabine-pretreated advanced pancreatic adenocarcinoma.

There is no established second-line treatment for advanced pancreatic cancer after gemcitabine failure. In view of the urgent need for such therapy, and since preclinical and phase I clinical data suggest an encouraging, potentially synergistic activity between raltitrexed and irinotecan, the present randomised phase II study was initiated. A total of 38 patients with metastatic pancreatic adenocarcinoma, who progressed while receiving or within 6 months after discontinuation of palliative first-line chemotherapy with gemcitabine, were enrolled in this study. They were randomised to 3-weekly courses of raltitrexed 3 mg x m(-2) on day 1 (arm A) or irinotecan 200 mg x m(-2) on day 1 plus raltitrexed 3 mg x m(-2) on day 2 (arm B). The primary study end point was objective response, secondary end points included progression-free survival (PFS) and overall survival (OS), as well as clinical benefit response in symptomatic patients (n=28). In the combination arm, the IRC-confirmed objective response rate was 16% (three out of 19 patients had a partial remission; 95% CI, 3-40%), which was clearly superior to that in the comparator/control arm with raltitrexed alone, in which no response was obtained. Therefore, the trial was already stopped at the first stage of accrual. Also, the secondary study end points, median PFS (2.5 vs 4.0 months), OS (4.3 vs 6.5 months), and clinical benefit response (8 vs 29%) were superior in the combination arm. The objective and subjective benefits of raltitrexed+irinotecan were not negated by severe, clinically relevant treatment-related toxicities: gastrointestinal symptoms (42 vs 68%), partial alopecia (0 vs 42%), and cholinergic syndrome (0 vs 21%) were more commonly noted in arm B; however, grade 3 adverse events occurred in only three patients in both treatment groups. Our data indicate that combined raltitrexed+irinotecan seems to be an effective salvage regimen in patients with gemcitabine-pretreated pancreatic cancer. The superior response activity, PFS and OS (when compared to raltitrexed), as well as its tolerability and ease of administration suggest that future trials with this combination are warranted.

Biweekly high-dose gemcitabine alone or in combination with capecitabine in patients with metastatic pancreatic adenocarcinoma: a randomized phase II trial.

BACKGROUND: Gemcitabine is an active antitumor agent in the treatment of advanced pancreatic cancer, and has shown potential synergistic activity with the oral fluoropyrimidine capecitabine in previous phase I/II trials. Based on this background and in order to define the therapeutic potential and tolerance of this combination more precisely, the present randomized multicenter phase II trial was initiated. PATIENTS AND METHODS: We prospectively randomized 83 patients to treatment with biweekly gemcitabine 2,200 mg/m(2) given as a 30 min intravenous infusion on day 1, or the same treatment plus oral capecitabine 2,500 mg/m(2) given from days 1 to 7. In both arms, chemotherapy was administered for a duration of 6 months unless there was prior evidence of progressive disease. The efficacy of the two treatment arms was evaluated according to standard criteria, i.e. objective response, progression-free survival (PFS) and overall survival (OS), as well as by analysis of clinical benefit response. RESULTS: The overall objective response rate among the 42 patients treated with gemcitabine alone was 14% compared with 7/41 (17%) among those treated with the combination arm. Similar to response rates, there was no apparent difference between the two groups in terms of median PFS (4.0 versus 5.1 months) and median OS (8.2 versus 9.5 months) in the gemcitabine and combination arm, respectively. Of 61 patients with tumor-related symptoms, who were considered evaluable for clinical benefit response, 10/30 (33%) and 15/31 (48.4%) experienced significant palliation in the gemcitabine and combination arm, respectively. Chemotherapy was well tolerated in both arms with only four versus six patients experiencing WHO grade 3 symptoms. Apart from the occurrence of hand-foot syndrome in 10 patients, no major increase in incidence and/or degree of adverse reactions was noted in the combination arm. CONCLUSIONS: Results of this trial suggest a fairly good therapeutic index for the combination of biweekly high-dose gemcitabine and capecitabine for the treatment of advanced pancreatic cancer. Despite a somewhat superior clinical benefit response rate, no advantage over single-agent gemcitabine, however, was noted in terms of objective efficacy parameters.

Second-Line Treatment of Advanced Colorectal Cancer with a Biweekly Oxaliplatin plus Irinotecan Combination Regimen.

BACKGROUND: Both oxaliplatin and irinotecan have demonstrated antitumor activity in pretreated colorectal cancer; experimental and early clinical data suggest that these two drugs may act synergistically. The aim of this study was to document the therapeutic index of a biweekly combination regimen in patients with metastatic colorectal cancer failing prior palliative first-line chemotherapy with raltitrexed. PATIENTS AND METHODS: In this study 27 patients with metastatic colorectal cancer were analyzed, who progressed while on or within 6 months after discontinuation of palliative first-line chemotherapy with raltitrexed. They received oxaliplatin 85 mg/m(2) and irinotecan 150 mg/m(2) both given on days 1 and 15 every 4 weeks. RESULTS: The confirmed overall response rate was 37% (95% confidence interval, 19.4-57.7%), including 2 complete and 8 partial remissions. 12 additional patients (44.4%) had stable disease, and in only 5 cases (18.5%) disease progression was not influenced by chemotherapy. The median progression-free survival for all 27 patients was 8 months (range, 1-16+ months), and 16 patients (59%) are still alive after a median follow-up time of 12.5 months. Hematologic adverse reactions, specifically leukocytopenia and neutropenia, were common though generally mild to moderate with grade 4 toxicity occurring in only 2 cases. The most frequent non-hematologic adverse events included gastrointestinal symptoms; severe nausea/emesis and diarrhea, however, were noted in only 2 and 3 patients, respectively. CONCLUSIONS: Our data suggest that the described biweekly combination regimen of oxaliplatin and irinotecan has substantial antitumor activity in patients with progressive, raltitrexed-pretreated metastatic colorectal cancer. Because of its favorable toxicity profile, further evaluation of this combination seems warranted.

Multicenter phase II trial of dose-fractionated irinotecan in patients with advanced colorectal cancer failing oxaliplatin-based first-line combination chemotherapy.

BACKGROUND: A multicenter phase II trial was initiated to investigate the efficacy and tolerance of a dose-fractionated administration schedule of irinotecan in patients with advanced colorectal cancer pre-treated with fluoropyrimidine/ oxaliplatin-based first-line combination chemotherapy. PATIENTS AND METHODS: 38 patients with metastatic colorectal cancer, who progressed while receiving or within six months after withholding systemic chemotherapy with oxaliplatin in combination with 5-fluorouracil/leucovorin or the specific thymidilate synthase inhibitor raltitrexed were enrolled in this study. Treatment consisted of irinotecan 175 mg/m2 given on days 1 and 10. Courses were repeated every three weeks for a total of six courses unless prior evidence of progressive disease. RESULTS: The overall objective response rate was 21% for all 38 patients (95% confidence interval (95% CI): 9.6% to 37.4%). Stable disease was noted in 19 patients (50%), whereas the tumour progressed in 11 (29%). The median progression-free survival was 4.8 months (range 1.5 to 10.5). After a median follow-up time of 10 months, 21 patients (55%) are still alive. Treatment was fairly well tolerated with only 9 of 38 patients (24%) experiencing grade 3 or 4 neutropenia. Similarly, nonhaematologic adverse reactions were generally mild; grade 3 toxicities included late-onset diarrhoea in 2 (5%), alopecia in 5 (13%), and infection in 1 case (3%), respectively. CONCLUSIONS: Our data suggest that this dose-fractionated irinotecan monotherapy schedule has substantial antitumour activity in patients with flupropyrimidine/oxaliplatin-based pre-treated colorectal cancer. Because of its favourable toxicity profile when compared to previous experiences with the European standard schedule of 350 mg/m2 every three weeks, further evaluation of this modified regimen seems warranted.

Second-line treatment with oxaliplatin + raltitrexed in patients with advanced colorectal cancer failing fluoropyrimidine/leucovorin-based chemotherapy.

BACKGROUND: To evaluate the efficacy and tolerance of combined raltitrexed and oxaliplatin in patients with advanced colorectal cancer pretreated with fluoropyrimidine leucovorin-based chemotherapy. PATIENTS AND METHODS: Thirty-six patients with metastatic colorectal cancer, who progressed while receiving or within six months after withholding palliative chemotherapy with fluoropyrimidines leucovorin +/- irinotecan, participated in this study. Treatment consisted of oxaliplatin 130 mg/m2 and raltitrexed 3.0 mg/m2 both given on day 1 every three weeks for a total of eight courses unless prior evidence of progressive disease. RESULTS: The overall objective response rate was 33.3% for all 36 evaluable patients (95% confidence interval (CI): 18.6%-51%). Seventeen additional patients (47.2%) had stable disease, and only seven (19.5%) progressed. The median progression-free survival was 6.5 months (range 1.2-14.0). After a median follow-up time of 12 months, 23 patients (63.8%) are still alive. The tolerance of treatment was acceptable with only 8 of 36 patients (22%) experiencing grade 3 or 4 neutropenia. Grade 3 non-haematological adverse reactions included peripheral sensory neuropathy in three, asthenia in one, diarrhea in two, and clinically insignificant increase in serum transaminases in two patients, respectively. CONCLUSIONS: Our data suggest that the combination of oxaliplatin and raltitrexed has substantial antitumour activity in patients with progressive fluoropyrimidine leucovorin + irinotecan pretreated colorectal cancer. Because of its favorable toxicity profile and convenient three-weekly outpatient administration schedule, further evaluation of this regimen seems warranted.

Treatment of advanced hepatocellular carcinoma with biweekly high-dose gemcitabine.

INTRODUCTION: Until today, an optimal palliative treatment regimen has not been defined for patients with advanced hepatocellular carcinoma. Since the novel cytidine analog gemcitabine has shown strong antitumor effects in vitro in a human hepatoma cell line and its therapeutic potential seems well established in several different tumors including gastrointestinal adenocarcinomas, the present phase II trial using a dose-intensified biweekly administration schedule was initiated. PATIENTS AND METHODS: 17 patients with histologically confirmed unresectable advanced or metastatic hepatoma were treated with gemcitabine 2,200 mg/m(2) given as a 30-min intravenous infusion on days 1 and 15. Treatment courses were repeated every 4 weeks. RESULTS: All patients were evaluable for response and toxicity assessment. No objective response was achieved, stable disease occurred in 8 patients (47%), and 9 progressed while on chemotherapy. The median time to progression was 4 months (range 1.5-14 months), and the median survival time was 8.5 months (range 2.5-16.0+ months). Treatment was well tolerated with mild or moderate leukopenia, thrombocytopenia and anemia representing the most common side effects. Gastrointestinal and other subjective toxicities were infrequent and also generally mild. CONCLUSIONS: In view of the disappointing treatment results, gemcitabine using this particular dose regimen should not be considered for further investigation in patients with advanced hepatocellular carcinoma.

Oxaliplatin plus raltitrexed in patients with advanced colorectal carcinoma: results of a Phase I-II trial.

BACKGROUND: Oxaliplatin and raltitrexed both are active anticancer agents in the treatment of patients with advanced colorectal carcinoma: They have different mechanisms of action and toxicity profiles and have shown at least additive effects in experimental and preliminary clinical studies. The aim of this disease oriented Phase I-II study was to determine the maximum tolerated dose (MTD), the dose-limiting toxicities (DLT), and the objective response rate of this combination in patients with advanced colorectal carcinoma. METHODS: Between April 1998 and March 1999, 69 patients with measurable metastatic colorectal carcinoma who previously were unexposed to palliative chemotherapy were enrolled. In the Phase I part of the study, 27 patients were treated with 3-weekly courses of a fixed dose of raltitrexed (3 mg/m(2) given as a 15-minute intravenous infusion) followed by a 2-hour infusion of oxaliplatin, which was escalated in consecutive cohorts of three to six patients from 85 mg/m(2) to 100 mg/m(2), 120 mg/m(2), 130 mg/m(2), and 140 mg/m(2). After having defined the toxic dose, 42 additional patients were entered at one dose level below to define the therapeutic index of this combination more precisely. RESULTS: In the Phase I part of the study, during the first three dose levels, only one patient each experienced DLT (Grade 3 increase in transaminases, diarrhea, and stomatitis); at level 4, two of the first six patients entered had Grade 3 neutropenic infection or peripheral neurotoxicity, whereas dose level 5 (oxaliplatin 140 mg/m(2)) constituted the toxic dose with three of three patients experiencing DLT (Grade 3 asthenia, transient amaurosis, and diarrhea with Grade 4 neutropenia). Externally reviewed objective responses were noted in 9 of these 27 patients (33%), and stable disease occurred in 12 patients (44.4%). Among the 42 patients who were treated subsequently at the MTD level (Phase II portion), 20 patients (47.6%) responded (95% confidence interval, 32-62.6%), and 21 patients (50%) had stable disease. Their median progression free survival was 9.0 months, and the median overall survival, with 42 patients (67%) currently alive, is > 14.5 months. Treatment tolerance at the MTD was acceptable, with only 9 of 42 patients (21%) experiencing Grade 3-4 neutropenia; Grade 3 nonhematologic adverse reactions included increase in serum transaminases in 6 patients, peripheral neuropathy in 3 patients, diarrhea in 3 patients, and both stomatitis and emesis in only 1 patient each. CONCLUSIONS: The described objective response and toxicity data, which are in agreement with preliminary results of other Phase I-II studies, support the promising therapeutic potential of this combination in the treatment of patients with advanced colorectal carcinoma. Due to its substantial antitumor activity, tolerance (at the recommended MTD level), and convenient 3-weekly outpatient administration schedule, further evaluation of this regimen seems warranted.

Phase II trial of two-weekly gemcitabine in patients with advanced biliary tract cancer.

BACKGROUND: Patients with advanced biliary tract carcinoma face a dismal prognosis as no effective palliative therapy has been defined. The aim of the present phase II investigation was to evaluate the therapeutic efficacy and tolerance of a two-weekly high-dose gemcitabine regimen in this patient population. PATIENTS AND METHODS: Thirty-two consecutive patients with locally unresectable or metastatic biliary tract cancer were enrolled in this multicenter phase II trial. Treatment consisted of gemcitabine 2200 mg/m2 given as a 30-min intravenous infusion every two weeks for a duration of six months unless there was prior evidence of progressive disease. RESULTS: After a median number of 12 treatment courses, 7 of 32 (22%) patients had a partial response that lasted for a median duration of 6.0 months (range 3.5-10.0). Fourteen additional patients (44%) had stable disease, whereas eleven patients (34%) progressed despite therapy. The median time to progression was 5.6 months (range 1.8-13.0); median survival time was 11.5 months (range 3.0-24.0), and the probability of surviving beyond 12 months was 44%. The tolerance of treatment was remarkable with only two patients each experiencing grade 3 leukocytopenia, granulocytopenia and/or thrombocytopenia, and one patient had grade 3 anaemia. Similarly, nonhaematologic side effects were infrequent, and generally mild to moderate. CONCLUSIONS: Two-weekly high-dose gemcitabine seems to represent a potentially effective, safe and well-tolerated regimen for the palliative treatment of patients with advanced biliary tract cancer.

Combined radiochemotherapy of locally advanced unresectable pancreatic adenocarcinoma with mitomycin C plus 24-hour continuous infusional gemcitabine.

BACKGROUND: In locally advanced pancreatic cancer, the combination of chemotherapy with radiotherapy is gaining increasing importance; although, in view of the reported long-term results of several contemporary trials, further improvements are certainly warranted. The aim of the present study was to evaluate the effectiveness and safety of a combined-treatment modality consisting of systemic chemotherapy with 24-h continuous infusional gemcitabine and mitomycin C, plus external beam radiotherapy in patients with localized unresectable adenocarcinoma of the pancreas. METHODS AND MATERIALS: Systemic chemotherapy consisted of mitomycin C 8 mg/m2 given as i.v. bolus injection on day 1 and gemcitabine administered as a 24-h continous infusion once weekly for 3 of 4 weeks. The starting dose of gemcitabine was 100 mg/m2 and dose levels were escalated in consecutive cohorts of 3-6 patients to 130 and 160 mg/m2, utilizing an escalating-dose Phase I trial design. Radiation therapy using megavolt irradiation (total dose, 45 Gy, 1.8 Gy/day) of 6 MV photons or greater with a 3- or 4-field technique was delivered concurrently for 5-6 weeks. RESULTS: Between January 1997 and August 1998, a total of 15 patients were enrolled in this trial, all of whom were assessable for toxicity, response, and survival. The dose-limiting toxicities at the 160 mg/m2 gemcitabine level were myelosuppression, specifically neutropenia +/- thrombocytopenia, and gastrointestinal symptoms, including stomatitis, vomiting, and diarrhea. Only 1 partial response was observed (7%), and disease was stabilized in 10 additional patients (67%). The median time to progression was 5.5 months (range, 2-12 months). Whereas all patients developed distant metastases, locoregional failure occurred in only 3. The median survival time was 8.3 months (range, 2.5 to 22.0+ months), and the 1-year survival rate was 13.3%. CONCLUSION: The MTD of gemcitabine when given as prolonged infusion in combination with mitomycin C and radiation therapy was 130 mg/m2/week. Therapeutic results suggest that combined chemoradiation with this regimen is feasible and effective for local control of pancreatic cancer, but essentially ineffective in counteracting metastatic tumor growth.

Treatment of advanced breast cancer with vinorelbine and docetaxel with or without human granulocyte colony-stimulating factor.

PURPOSE: A multicenter phase II trial was performed to investigate the efficacy and tolerance of docetaxel, vinorelbine with or without recombinant human granulocyte colony-stimulating factor (G-CSF) in patients with metastatic breast cancer. PATIENTS AND METHODS: Between February 1998 and March 1999, 57 patients participated in this trial. Forty-two patients received this combination as first-line and 15 patients as second-line chemotherapy, including 10 patients who had failed anthracyclines. Therapy consisted of vinorelbine 30 mg/m(2) on days 1 and 15 and docetaxel 30 mg/m(2) on days 1, 8, and 15 every 4 weeks. Depending on the absolute neutrophil counts on the day of scheduled chemotherapeutic drug administration, a 5-day course of G-CSF 5 microg/kg/d was given. RESULTS: The overall response rate was 64.3% (95% confidence interval, 48.1% to 78.4%) in patients receiving docetaxel plus vinorelbine as first-line chemotherapy, including eight complete (19%) and 19 partial remissions (45.3%); 11 patients (26.2%) had disease stabilization, and only four (9.5%) progressed. Second-line treatment with this regimen resulted in eight (53.3%) of 15 objective responses, four had stable disease, and three had progressive disease. The median time to progression was 12 months in the first-line and 9.8 months in the second-line setting, respectively. After a median follow-up time of 18 months, 38 patients (65%) were still alive with metastatic disease. Myelosuppression was commonly observed; World Health Organization grade 3 or 4 neutropenia both occurred in 18 patients (32%) and was complicated by septicemia in four cases; grade 3 or 4 thrombocytopenia was seen in two patients (4%), and grade 3 anemia was seen in only one patient (2%). Severe (grade 3) nonhematologic toxicity, except for alopecia, was rarely observed and included nausea/vomiting in two patients (4%), and stomatitis, peripheral neuropathy, and skin toxicity each in one patient. CONCLUSION: Our data suggest that docetaxel and vinorelbine with or without G-CSF is an effective and fairly well tolerated regimen for the treatment of advanced breast cancer. It might be particularly useful in patients previously exposed to adjuvant or palliative anthracyclines and/or alkylating agents.

Treatment of advanced, refractory breast cancer with alternating docetaxel and epirubicin/cyclophosphamide plus human granulocyte colony-stimulating factor.

PURPOSE: A phase II study was performed to investigate the efficacy and tolerance of alternating docetaxel and epirubicin/cyclophosphamide plus recombinant human granulocyte colony-stimulating factor (G-CSF) in patients with advanced breast cancer who failed previous non-anthracycline/taxane-containing palliative chemotherapy. PATIENTS AND METHODS: Between November 96 and June 98, a total of 45 patients participated in this trial. Chemotherapy consisted of docetaxel 100 mg/m2 given as a 1-h infusion on day 1, and epirubicin 100 mg/m2 plus cyclophosphamide 800 mg/m2 both administered on day 21. G-CSF 5 microg/kg/day was given subcutaneously from days 22-28 during each cycle. Treatment courses were repeated every 42 days for a total of three courses unless prior evidence of progressive disease. RESULTS: The overall response rate was 57.8% (95% confidence interval, 42.1-72.3%), including seven complete (15.5%) and 19 partial remissions (42.3%); nine patients (20%) had stabilization of disease and 10 (22.3%) progressed. The median time to treatment failure was 7.0 months (range 1.5-26.0), and the median overall survival time 15.0 months (range 2.0-37.0+) with 12 patients (27%) currently still alive with metastatic disease. Myelosuppression was commonly observed with WHO grade 3/4 neutropenia in 20 patients (44%) complicated by septicemia in five (11%). Severe nonhematologic toxicity included stomatitis in five patients (11%), skin and peripheral neurotoxicity each in one patient; alopecia was seen in all 45 patients with complete hair loss in 26 (58%). CONCLUSIONS: Our data suggest that alternating docetaxel and epirubicin/cyclo-phosphamide plus G-CSF is an effective and tolerable second-line combination regimen for the treatment of advanced breast cancer.

Oxaliplatin-induced fever and release of IL-6.

BACKGROUND: Oxaliplatin is a novel cytotoxic agent with documented activity in colorectal cancer. Side effects are generally moderate, and include peripheral neuropathy along with mild bone marrow suppression and gastrointestinal side effects. To our knowledge, induction of febrile episodes by this agents has not been described in the literature. CASE REPORT: We present the case of a 74-year-old male patient admitted to our institution for palliative treatment of metastatic colorectal carcinoma. Due to progression during treatment with 5-fluorouracil and leucovorin, chemotherapy consisting of oxaliplatin 85 mg/m(2) on days 1 + 15 plus mitomycin C 8 mg/m(2) on day 1 repeated every 28 days was initiated. The first cycle of this combination was tolerated without side effects, but the patient experienced fever up to 39 degrees C starting 2 h after oxaliplatin administration on day 15 of the second cycle, which persisted for 3 days. Fever again recurred at the same interval following administration of oxaliplatin on day 1 of the next cycle. Blood samples taken at regular intervals disclosed an increase in IL-6 serum levels parallel to the body temperature curve, with the peak corresponding to the highest temperature, while C-reactive protein values remained unchanged. In spite of intensive premedication with steroids, antipyretics and clarithromycin, fever promptly recurred during the third cycle of treatment. CONCLUSION: Our data suggest a clear- cut correlation between fever, the release of IL-6 and oxaliplatin administration. Whether IL-6 release is directly triggered by the application of oxaliplatin or is a bystander phenomenon, however, remains unclear at the moment.

Treatment of patients with advanced nonsmall cell lung carcinoma using docetaxel and gemcitabine plus granulocyte-colony stimulating factor.

BACKGROUND: A combination regimen comprised of docetaxel, gemcitabine, and granulocyte-colony stimulating factor (G-CSF) was studied in patients with advanced nonsmall cell lung carcinoma (NSCLC) to determine its antitumor efficacy and tolerance. METHODS: Thirty-four patients with advanced measurable NSCLC (3 patients with Stage IIIB and 31 patients with Stage IV disease) were treated with an intravenous combination chemotherapy regimen comprised of docetaxel, 80 mg/m(2), on Day 1 and gemcitabine, 1000 mg/m(2), on Days 1 and 10; G-CSF, 5 microg/kg, was administered subcutaneously between Days 2 and 8. Treatment cycles were repeated every 3 weeks. All patients were evaluable for toxicity and response assessment. A total of 163 courses was administered. RESULTS: Objective tumor response was noted in 17 patients (50%; 95% confidence interval, 32. 5-67.5%), including 2 complete responses (6%) and 15 partial responses (44%). There was no change in 10 patients (29%) and 7 patients developed progressive disease. The median duration of response was 6.5 months (range, 3-15 months) and the median time to disease progression for all patients was 6.8 months (range, 1.8-18 months). The median overall survival time was 13.0 months (range, 2. 5-23+ months) with a 1-year survival rate of 55.8%. Myelosuppression was the most frequently encountered adverse reaction, although World Health Organization Grade 3 or 4 leukocytopenia and/or granulocytopenia occurred in only 18% and 24% of patients, respectively. Other toxicities generally were mild to moderate, and always fully reversible. CONCLUSIONS: With a response rate of 50% and a median survival time of 13 months, the drug combination described in the current study appears to have significant activity against advanced metastatic NSCLC. Due to its fairly good tolerance and ease of administration, further investigation of this regimen appears warranted.

Distribution of patients with Wilson disease carrying the H1069Q mutation in Austria.

BACKGROUND/AIMS: More than 100 different mutations of the Wilson disease (WD) gene have been reported so far, but only the H1069Q mutation is frequently found in patients of North and East European origin. We wanted to know if there is a connection between the migration pattern in Central Europe and the geographical distribution of this mutation in Austria. METHODS: One hundred and nine patients (91 index patients and 18 asymptomatic siblings) with WD diagnosed in Austria were included in this study. Eighty-one of the 91 index patients were born in Austria. Evaluation criteria included the place of birth of each member of the study group, as well as of his parents and grandparents. RESULTS: Out of the 81 index patients born in Austria, 72 were tested for the H1069Q mutation. Twelve (16.7%) were homozygous carriers of the H1069Q mutation, 29 (40.3%) were compound heterozygous and 31 (43.0%) had an unknown mutation on both chromosomes. Eight of the twelve H1069Q homozygotes were born close to the northeastern border of Austria (neighboring the Czech Republic, Slovakia and Hungary). Compound heterozygous patients showed a more variable geographical distribution with respect to their birthplace. The patients with unknown mutation were scattered all over Austria. CONCLUSION: These data provide further evidence that the H1069Q mutation originates from Eastern Europe. In patients from these countries the PCR-based testing for this mutation may be useful for differential diagnosis and family studies.

A phase II trial of biweekly high dose gemcitabine for patients with metastatic pancreatic adenocarcinoma.

BACKGROUND: Although the novel cytidine analog gemcitabine has shown superior antitumor activity compared with weekly bolus 5-fluorouracil in patients with advanced pancreatic carcinoma, further improvements of therapeutic results are warranted. The current Phase II study was initiated to investigate whether this might be achieved by dose intensification. METHODS: Between August 1997 and September 1998, 43 consecutive patients with metastatic pancreatic adenocarcinoma were enrolled in this multicenter Phase II trial. Patients received 4 weekly courses of gemcitabine 2200 mg/m((2)) given as intravenous infusion during 30 minutes on Days 1 and 15 for a duration of 6 months unless there was prior evidence of progressive disease. The efficacy of treatment was assessed according to standard criteria, i.e., objective response, progression free survival, and overall survival, as well as by analysis of clinical benefit response (defined as >/= 50% reduction in pain intensity, >/= 50% reduction in daily analgesic consumption, and/or >/= 20 point improvement in Karnofsky performance status that was sustained for >/= 4 consecutive weeks). RESULTS: Of 43 patients evaluable for objective response, 1 achieved complete and 8 partial remissions, for an overall response rate of 21% (95% confidence interval, 10-36%); 18 additional patients (42%) had stable and 16 (37%) progressive disease. The median time to progression was 5.3 months. Median survival was 8.8 months, and the probability of surviving beyond 12 months was 26.3%. Of 36 patients with tumor-related symptoms who were considered evaluable for clinical benefit response, 16 (44%) experienced significant palliation. The median time to achieve a clinical benefit response was 6 weeks, and its median duration was 27 weeks. Chemotherapy was well tolerated, with leukopenia/granulocytopenia representing the most common side effect. Gastrointestinal and other subjective toxicities were infrequent and generally mild. CONCLUSIONS: Biweekly high dose gemcitabine seems to represent a safe, tolerable, and effective regimen for the palliative treatment of patients with advanced pancreatic carcinoma.