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A phase II trial was performed to investigate the efficacy and tolerance of combined gemcitabine and liposomal doxorubicin+/-recombinant human granulocyte colony-stimulating factor (G-CSF) in patients with chemotherapeutically pretreated metastatic breast cancer. Thirty-four patients were entered in this trial. Chemotherapy consisted of gemcitabine and liposomal doxorubicin+/-G-CSF. Twenty seven patients received this regimen as 2nd line therapy, five patients as 3rd line and two patients as 4th line therapy after having failed taxane- and/or anthracycline-based chemotherapy or other drug combinations. After a median of six courses, an overall response rate of 26% (9 PR in 34 enrolled patients) was observed; 14 patients had disease stabilization (41%), and eight (24%) progressed. Three patients were not evaluable for response due to anaphylaxis after the first course and protracted thrombocytopenia. The median TTP was 7.5 months, and median overall survival was 15 months. Myelosuppression was the most frequently observed toxicity. Non-haematological side effects were generally mild to moderate. Our data suggest that gemcitabine and liposomal doxorubicin±G-CSF is an effective and fairly well tolerated regimen for chemotherapeutically pretreated patients with advanced breast cancer. [ABSTRACT FROM AUTHOR]

Background: Preclinical evidence of a positive interaction between gemcitabine and the oral 5-FU prodrug capecitabine has been confirmed in a recently reported phase II study by Hermann et al. (Proc.ASCO 2000:267a). The present trial was initiated to investigate the efficacy and tolerance of a modified dose schedule of this particular combination in patients with advanced pancreatic cancer. Methods: Between 09/99 and 10/00, thirty-two patients with metastatic pancreatic adenocarcinoma were entered in this trial. 27 pts (10 female, 17 male) are currently evaluable for response and toxicity assessment. Their median age is 63 (40-75) years, and their median WHO performance status 1 (0-2). Eighteen patients (67%) were symptomatic at the time of initiating therapy. Treatment consisted of gemcitabine 2200 mg/m² iv on day 1 plus capecitabine 2500 mg/m²/d given orally from days 1 to 7. Courses were repeated every 2 weeks. Results: A clinical benefit response (defined as a >50% eduction in pain intensity, >50% reduction in daily analgetic consumption, and/or >1 WHO score improvement in performance status that was sustained for >4 weeks) was achieved in 9/18 (50%) symptomatic patients. Objective tumor responses (as assessed by seria CT-scans) were noted in 4/27 patients (15%), and 16 (59%) had stable disease. Median time to progression is 5.8 (1.5-10) months, and median survival has not been reached yet (>7.6 months). Therapy was generally well tolerated with a low incidence of severe, i.e., >3 WHO grade hematologic (11%) or nonhematologic (4%) toxicities. Conclusions: Our findings suggest that gemcitabine + capecitabine is a tolerable and palliatively effective combination regimen for the treatment of patients with this otherwise chemorefractory and universally fatal disease. [ABSTRACT FROM AUTHOR]

Irinotecan is a topoisomerase I inhibitor with established anticancer activity in advanced colorectal cancer. This trial was initiated to investigate the efficacy and tolerance of a dose fractionated administration schedule in patients with advanced colorectal cancer pre-treated with fluoropyrimidine/oxaliplatin-based first-line combination chemotherapy. Methods: Thirty-eight patients with metastatic colorectal cancer, who progressed while receiving or within 6 months after withholding systemic chemotherapy with oxaliplatin in combination with 5-FU/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 3 weeks for a total of 6 courses unless prior evidence of progressive disease. Results: The overall objective response rate was 21% for all 38 patients (95% CI, 9.6 to 37.4%). Stable disease was noted in 19 patients (50%), whereas the tumor 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 9/38 patients (24%) experiencing grade 3 or 4 neutropenia. Similarly, nonhaematologie adverse reactions were generally mild; grade 3 toxicities included late-onset diarrhea 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 antitumor activity in patients with progressive 5-FU/leucovorin/oxaliplatin or altitrexed/oxaliplatin 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 3 weeks, further evaluation of this modified regimen seems warranted. [ABSTRACT FROM AUTHOR]

Despite recent advances in the treatment of gastric cancer, mortality related to this disease is still substantial. Surgery and chemotherapy represent the cornerstones of patient management. Targeted treatments that include anti-angiogenic agents and the advent of immunotherapies can contribute to improved patient prognosis. Herein, we present an Austrian consensus on the systemic treatment of patients with gastric adenocarcinoma and lower gastroesophageal junction, including those with human epidermal growth factor receptor 2 (HER2)-positive disease. The consensus considers the curative setting, as well as first-line to late-line systemic treatment options in the palliative setting. For HER2-positive disease, first-line and second-line therapies are discussed, as well as HER2 testing. Potential future therapies are also listed, with a focus on anti-angiogenic treatments and checkpoint inhibition, that might provide a further step forward in the management of patients with gastric cancer., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Cancer is among the leading causes of morbidity and mortality in the Western world. Despite recent advances, most therapeutic approaches fail to eradicate the entire neoplastic clone. The remaining cells often develop metastasis and/or recurrences and therefore may represent attractive targets of therapy. A new exciting concept in this regard suggests that each neoplasm represents a heterogeneous population of cells that pertain to long-term tumor growth both in vivo in the natural host and in experimental animals. This concept postulates the existence of small fractions of 'tumor stem cells' that exhibit a capacity for self-renewal and unlimited growth and therefore are distinct from their progeny. Based on these hypotheses, the targeting of neoplastic stem cells is considered indispensable for eradication of the entire clone and for the development of curative treatment approaches. However, tumor stem cells often may be quiescent cells and may express a different profile of targets compared with 'more mature' tumor cells. Therefore, current efforts have attempted to characterize target expression profiles in cancer stem cells in various malignancies. In the this review, the authors have provided a brief summary of the current knowledge of neoplastic stem cells and the application of respective concepts in translational oncology with the ultimate objective of improving anticancer therapy.

Background: Expression of the antiapoptotic protein myeloid cell leukemia-1 (Mcl-1) may be disordered in malignancies of the rectum. High levels of Mcl-1 may correlate with unfavourable clinical outcome., Aim of the Study: The aim of the study was to determine the biologic significance and the prognostic value of the protein Mcl-1 in a group of patients with rectal cancer using immunohistochemical staining in archival specimens., Patients and Methods: Expression of the Bcl-2 family member Mcl-1 was determined in 23 rectal malignancies. Half of the patients with rectal cancer were treated with preoperative short-term radiation therapy of 25 Gy followed by radical surgery; the other patients were treated just with radical surgery. Differences in Mcl-1 expression between irradiated and non-irradiated rectal cancer cells were analysed immunohistochemically, and Mcl-1 expression was correlated with overall survival. Induction of Mcl-1 expression by irradiation versus control in colorectal cancer cells was detected using Western blot., Results: Mcl-1 was expressed at high levels in 35% of all specimens. Significantly stronger expression was detected in specimens of irradiated rectal cancer compared with non-irradiated tissues (p-value: 0.005). No association was seen between marker expression patterns and clinicopathological data of the respective patients., Conclusion: Our findings indicate that irradiated rectal cancer produces significantly higher levels of the antiapoptotic protein Mcl-1 than non-irradiated rectal carcinoma. The data also suggest that the high level of Mcl-1 was induced by the radiotherapy. As Mcl-1 is an antiapoptotic regulator, its over-expression in irradiated rectal cancer could constitute a detrimental development antagonizing the potential benefit of adjuvant radiotherapy. Further evaluation of the correlation between Mcl-1 expression and overall survival seems warranted.

Objective: Hepatocellular carcinoma (HCC) is a late consequence of severe liver disease. Patients with genetic hemochromatosis may be at risk for HCC, but limited information is available on the relationship of HCC and heterozygosity for the HFE gene mutations., Methods: HFE mutations (C282Y and H63D) were assessed in 162 consecutive patients (131 men/31 women) with HCC. A total of 159 patients had cirrhosis. The most common etiologies of cirrhosis were chronic viral hepatitis (hepatitis C 39%, hepatitis B 9%) and alcoholic liver disease (36%)., Results: Five patients were C282Y homozygotes, four C282Y/H63D compound heterozygotes, and three H63D homozygotes. The C282Y and H63D allele frequencies in HCC were 8.3 (95% confidence limit = 5.3-11.3) and 11.1 (7.8-14.6), respectively, and not different from previously published data in healthy subjects or patients with chronic hepatitis C in Austria. Furthermore, there was no difference in the age at diagnosis in patients with or without HFE gene mutations. C282Y homozygotes had a 19-fold increased risk to develop HCC. In contrast, all other HFE allele constellations were not associated with such a risk., Conclusions: Except for C282Y homozygotes, HFE gene mutations do not increase the risk to develop HCC in patients with cirrhosis.

Colorectal cancer represents one of the most common malignant diseases worldwide. Because of the expanding understanding of the biology of this disease entity, and the development/availability of a number novel antitumor agents, therapeutic options have considerably improved within the past few years. As for new drug development, therapeutic advances comprise the oral fluoropyrimidine prodrugs, specific thymidilate synthase inhibitors, irinotecan, oxaliplatin, and signal transduction inhibitors such as the anti-EGF-receptor monoclonal antibody Cetuximab. Compared to the area of conventional 5-fluorouracil therapy, much higher objective response rates and major improvements in overall survival can be achieved today, even in the case of disseminated disease. The aim of this review article is to provide the reader with an overview of presently available treatment options in the palliative, neoadjuvant and postoperative adjuvant setting in colon and rectal cancer, respectively. Furthermore, actual clinical-practice oriented and future perspectives in the management of this disease will be addressed.

Radiolabeled human non-specific polyclonal immunoglobulin G (HIG), is used for the diagnosis of inflammation/infection. Focal uptake of HIG in malignant lesions has also been reported. We investigated the diagnostic value of In-111-HIG in patients with known pancreatic cancer. Fourteen consecutive patients with histologically verified pancreatic cancer were included in this prospective study. Four of them had undergone potentially curative surgery for their primary cancer. Eight patients had liver metastases. Planar and SPECT images of the abdomen were performed after administration of In-111-HIG (74-92 MBq). Scintigraphic results were compared to conventional imaging by means of CT scanning. In addition, In-111-HIG uptake was investigated in a panel of four representative human pancreatic cancer cell lines. Primary pancreatic tumors were visualized by In-111-HIG in 6 out of 10 patients (sensitivity 60%), while 1 was false positive. In comparison, CT scanning was true positive in 9 out of 10 patients (sensitivity 90%), and no false positive. Visualization of liver lesions by means of In-111-HIG was possible in 6 out of 8 patients (sensitivity 75%), while 1 was false positive. In vitro studies revealed only minimal uptake of In-111-HIG into cells (about 3% of activity). Our data demonstrate that In-111-HIG is able to visualize pancreatic primary cancers as well as liver metastases. However, the minimal uptake into tumor cells, as shown in vitro, suggests non-specific tumor related inflammatory reactions, increased vascular permeability, release of indium from In-111-DTPA-labeled antibody and local retention to be responsible for visualization of the tumor site.

Purpose: Irinotecan and oxaliplatin are two new agents with promising activity in advanced colorectal cancer. Based on preclinical and clinical evidence that both drugs act synergistically, a randomized phase II study was initiated to investigate the therapeutic potential and tolerance of this combination in the front-line setting., Patients and Methods: Ninety-two patients with previously untreated, measurable disease were randomized to receive biweekly oxaliplatin 85 mg/m(2) plus irinotecan 175 mg/m(2) or raltitrexed 3 mg/m(2) given on day 1 every 3 weeks. Upon development of progressive disease, second-line treatment with the opposite arm was effected., Results: Patients allocated to oxaliplatin/irinotecan had a significantly better radiologically confirmed response rate (43.5% v 19.6%; P =.0025) and longer progression-free survival (median, 7.1 v 5.0 months; P =.0033). Improvement in overall survival, however, did not reach the level of significance (median, 16.0 v 16.5 months; P =.3943). The response rate after cross-over was 33.3% (eight of 24) for assessable patients treated with oxaliplatin/irinotecan compared with 14.2% (three of 21) for those treated with second-line raltitrexed. Oxaliplatin/irinotecan caused more hematologic and gastrointestinal toxicities, necessitating dose reductions in 10 of the first 20 patients. After adjustment of the irinotecan starting dose from 175 to 150 mg/m(2), tolerance of treatment was acceptable; the most commonly encountered events (all grades) were neutropenia (81%), alopecia (65%), nausea/emesis (62%), peripheral sensory neuropathy (62%), and diarrhea (46%)., Conclusion: Oxaliplatin/irinotecan seems beneficial as first-line therapy in advanced colorectal cancer, with an acceptable toxicity profile at the reduced irinotecan dose level. Its promising therapeutic potential is supported by the high response activity noted in the raltitrexed control arm after cross-over, which may also explain the lack of a difference in overall survival.

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.

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., (Copyright 2001 S. Karger AG, Basel.)

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.

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., (Copyright 2000 S. Karger AG, Basel.)

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., (Copyright 2000 American Cancer Society.)

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.