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Background: Docetaxel and irinotecan chemotherapy have shown good efficacy in the treatment of advanced oesophago-gastric cancer. This randomised phase II study evaluated the efficacy and toxicity profile of two non-platinum docetaxel-based doublet regimens in advanced oesophago-gastric cancer. Methods: Chemotherapy-naïve patients with advanced oesophago-gastric cancer were randomised to receive either 3-weekly DI (docetaxel 60 mg m−2 plus irinotecan 250 mg m−2 (Day 1)) or 3-weekly DF (docetaxel 85 mg m−2 (Day 1) followed by 5-fluorouracil 750 mg m−2 per day as a continuous infusion (Days 1–5)). Results: A total of 85 patients received DI (n=42) or DF (n=43). The primary endpoint was overall response rate (ORR). The ORR and time to progression (TTP) in the evaluable population (n=65) were 37.5% (DI) vs 33.3% (DF), and 4.2 months vs 4.4 months, respectively. In the intent-to-treat population, the observed ORR, TTP and median overall survival were similar between the two groups. Grade 3–4 neutropenia, febrile neutropenia and diarrhoea were more frequent in the DI arm as compared with the DF arm (83.3% vs 69.8%, 40.5% vs 18.6%, and 42.9% vs 16.3%, respectively). Conclusion: Both docetaxel-based doublet regimens show comparable efficacy; however, the DF regimen was associated with a better toxicity profile and is an alternative treatment option for patients in whom platinum-based regimens are unsuitable.

A 64-year old female had been diagnosed as having thrombotic thrombocytopenic purpura (TTP; Moschcowitz syndrome) in 1984. The initial episode and one recurrence 5 years later were successfully treated with fresh plasma transfusions without plasmapheresis. Two days before the present admission, she noticed pain in the knee and haematomas in both legs. Marked thrombocytopenia (9000/microliters), haemolytic anaemia (lactate dehydrogenase 1800 U/l, haemoglobin 7.8 g/dl, haptoglobin 5 mg/dl) and skin haemorrhages suggested a second recurrence of TTP. The blood film showed a massive increase in fragmented cells (more than 30 per field), microspherocytes and normoblasts. Thrombocyte values initially rose on daily treatment with plasmapheresis using membrane separation and fresh plasma exchange. However, after two attempts at stopping therapy, plasmapheresis and fresh plasma replacement failed to normalise thrombocyte values. The patient had a total of 44 plasmaphereses. Intravenous administration of three doses of 1.5 mg vincristine at intervals of 7 and 5 days combined with further plasmapheresis treatment soon led to normalisation of the thrombocyte count (320,000/microliters), a fall in lactate dehydrogenase (120 U/l) and a disappearance of fragment cells in the blood smear. The patient is still in complete remission 6 months after stopping treatment. Treatment with vincristine should be considered for TTP refractory to treatment.

Aktuelle Studien ergaben, dass das bis dato als chemotherapieresistent angesehene Prostatakarzinom mit Docetaxel positiv beeinflusst werden kann. Im Rahmen eines Workshops fur Internisten und Urologen zur Chemotherapie bei fortgeschrittenem hormonrefraktarem Prostatakarzinom wurden die unterschiedlichen Ansichten zur dieser noch neuen Therapieform dargelegt, Gemeinsamkeiten diskutiert und erarbeitet, aber auch Kontroversen herausgestellt. In Therapieempfehlungen werden Vorschlage gemacht zu deren praktischer Durchfuhrung (Dosierung, Anwendung), zur begleitenden Medikation und Masnahmen sowie zur Kontrolle der Behandlung und des Therapieverlaufs. Hierbei wird insbesondere auf Untersuchungen zur Erfassung des Therapieeffekts und Kriterien fur ein Ansprechen auf die Behandlung, aber auch fur einen Abbruch derselbeneingegangen.

Maligne Tumoren des Muskelskelettapparats sind selten. Die mit ihnen verbundenen Symptome sind unspezifisch. Da die Therapie — Kombination von Chemo- und/oder Radiotherapie und operativer Resektion — sehr eingreifend ist, ist eine vorherige bioptische Diagnosesicherung notwendig. Biopsien werden in Inzisions- und Exzisionsbiopsien unterteilt. Bei den Inzisionsbiopsien unterscheidet man Nadel- oder Stanz- von offenen Biopsien. Fur die Durchfuhrung einer Probenentnahme gibt es genau beschriebene Leitlinien. Die Durchfuhrungskriterien sind unter dem Uberbegriff „Vermeidung groserer Kontaminationen“ und „Berucksichtigung des spateren operativen Zugangs“ zu subsummieren. Da die Biopsiestelle durch Tumorzellen kontaminiert ist, muss diese bei der operativen Tumorresektion zusammenhangend mit dem Tumor entfernt werden. Von der Inzisions- ist die Exzisionsbiopsie zu unterscheiden. Aufgrund der multimodalen Therapie bei Sarkomen ist eine Exzisionsbiopsie nur bei kleinen, oberflachlich liegenden Weichteiltumoren oder wahrscheinlich benignen Knochentumoren indiziert. Im Zweifelsfall ist immer eine Inzisionsbiopsie vorzuziehen. Sollte eine Exzisionsbiospie durchgefuhrt werden, sind die fur eine Inzisionsbiopsie gultigen Kriterien einzuhalten. Die Durchfuhrung der Biopsie stellt prinzipiell operativ eine einfache Masnahme dar, doch ist die Fehlerquote hoch, wenn die Leitlinien nicht befolgt werden. Da die Komplikationsrate von Biopsien — egal welcher Technik —, die in einer Institution auserhalb eins Tumorzentrums durchgefuhrt wird, signifikant hoher ist, sollte der Patient im Zweifelsfall noch vor einer Biopsie in ein Tumorzentrum uberwiesen werden. Wird eine Biopsie auserhalb eines Tumorzentrums durchgefuhrt, ist fur den spateren Operateur eine Bild gebende Dokumentation zur Identifikation der Biopsiestelle zwingend notwendig.

Background: We designed a dose- and time-intensified high-dose sequential chemotherapy regimen for patients with relapsed and refractory Hodgkin lymphoma (HD). Patients and methods: Eligibility criteria included age 18 – 65 years, histologically proven primary progressive (PD) or relapsed HD. Treatment consisted of two cycles DHAP (dexamethasone, highdose cytarabine, cisplatinum); patients with chemosensitive disease received cyclophosphamide followed by peripheral blood stem cell harvest; methotrexate plus vincristine, etoposide and BEAM plus peripheral blood stem cell transplantation (PBSCT). Results: A total of 102 patients (median age 34 years, range 18– 64) were enrolled. The response rate was 80% (72% complete response, 8% partial response). With a median follow-up of 30 months (range 3 – 61 months), freedom from second failure (FF2F) and overall survival (OS) were 59% and 78% for all patients, respectively. FF2F and OS for patients with early relapse were 62% and 81%, for late relapse 65% and 81%; for PD 41% and 48%, and for multiple relapse 39% and 48%, respectively. In multivariate analysis response after DHAP (P

The overall survival of patients with advanced multiple myeloma (MM) undergoing high-dose chemotherapy and autologous stem cell transplantation (SCT) depends mainly on the quality of response. Thus, to improve the response rate, a new intensified high-dose chemoradiotherapy was evaluated in a phase I/II study. After induction chemotherapy, 89 patients (median age 51 years, range 32-60 years) with MM stage II/III received a conditioning regimen with total marrow irradiation (9 Gy), busulfan (12 mg/kg) and cyclophosphamide (120 mg/kg) followed by SCT. Regimen-related toxicity according to WHO criteria and response rates defined by EBMT/IBMTR were analyzed. The main toxicity was mucositis grade III/IV in 76%, and fever grade >I in 75% of patients. Three patients developed reversible veno-occlusive disease. Transplant-related mortality was 2%. Among patients with de novo and pretreated MM, a CR rate of 48 and 41%, respectively, was documented. With a median follow-up of 45 months, the actuarial median durations of event-free survival (EFS) and overall survival (OS) after transplant were 29 and 61 months for the whole group, 36 and 85 months for patients with de novo MM, respectively. Thus, administration of this intensified conditioning regimen was associated with tolerable toxicity, a high response rate and long EFS and OS.

Background: This study was performed to examine the efficacy and toxicity of the combination of adriamycin (ADR), methylprednisolone (solumedrol), cytarabine (Ara-C), and cisplatin (CDDP) in patients with recurrent and refractory malignant lymphomas. Patients and methods: Sixty-five patients with Hodgkin's disease (HD) (n=14) or non-Hodgkin's lymphomas (NHL) (n=51) were enrolled in the study. The ASHAP therapy consisted of ADR (40 mg/m2 by continuous infusion (CI) over 96 h), methylprednisolone (500 mg i.v., days 1–5), Ara-C (2 g/m2 as a 2-h infusion on day 5), and CDDP (100 mg/m2 by CI over 96 h). Results: Twenty-five patients (38%) achieved complete remission (CR) and 20 (31%) were taken into partial remission (PR) for an overall response rate of 69%. Thirty-two patients with CR or PR following ASHAP underwent high-dose therapy (HDT) with subsequent hematopoietic stem cell transplantation. After a median follow-up of 52 months, 13 patients are in continuous CR (CCR), the 3-year event-free survival (EFS) was 30% for responders and 21% for all patients. The median overall survival (OS) was 12 months (range 0–70 months), and the OS rate after 3 years was 32%. Unfavorable prognostic factors for EFS and OS by univariate analysis were an elevated value of the serum lactate dehydrogenase and refractory lymphoma. The most frequently observed side effects following ASHAP were leukocytopenia and thrombocytopenia of World Health Organization (WHO) grades III/IV in approximately 80% of all courses. Non-hematological toxicities such as gastrointestinal side effects, infections, mucositis, renal and neurotoxicity occurred more rarely and reached WHO grades III/IV only occasionally. No treatment-related mortality with ASHAP was observed. Conclusions: ASHAP is an effective and moderately toxic salvage therapy for patients with recurrent or refractory HD and NHL. The results in patients responding to ASHAP and afterwards undergoing HDT with stem cell support are comparable with other established protocols and indicate an improvement in survival if HDT is carried out as intensification.

Two years after the removal of an embryonic testicular tumour from a now 26-year-old man, his general health deteriorated and a holosystolic murmur was heard over the tricuspid valve area. A chest X-ray film demonstrated lung metastases. Biochemical tests were within normal limits, but the human chorionic gonadotrophin level was elevated to 81,030 mU/ml. Echocardiography revealed mild tricuspid regurgitation and a floating mass between the right atrium and ventricle, in contact with the tricuspid valve. The described findings did not support the diagnosis of embolus or inflammatory vegetation. Because of the danger of embolization and obstruction of the pulmonary outflow tract the mass was removed surgically. Enzyme-histological examination identified the tissue as a metastasis of the testicular tumour. The patient's condition at first improved, but he soon died of bleeding from the lung which was infiltrated by trophoblast-containing metastases of the testicular tumour.

Pulmonary hemorrhage is a rare cause of death in patients with acute leukemia. Within a 3-month period we observed three such cases, all of which were associated with the gram-negative opportunistic pathogen Stenotrophomonas maltophilia. Since fatal lung bleeding had previously not been observed in conjunction with this organism, we collected the data from all patients with documented S. maltophilia infections or colonizations of the past year and analyzed the risk factors for a lethal outcome. A total of eight patients were identified. In the three patients with fatal hemorrhage, the interval between first complaints (chest pain, cough, fever) and death from lung bleeding was 36-72 h. A fourth patient with acute leukemia died of nonhemorrhagic respiratory failure 9 days after developing S. maltophilia-associated pneumonia. All four patients had received intensive chemotherapy and were severely neutropenic and thrombocytopenic. Such a combination of predisposing factors was not observed in the four patients with nonfatal infections or colonizations. Pulsed-field gel electrophoresis demonstrated that the infections were unrelated. S. maltophilia was also isolated from a faucet in a patient's room, but the strain isolated was genetically different from the strain causing the patient's pneumonia. Our data suggest that severe bone marrow aplasia and a recent history of intensive chemotherapy are predisposing factors for the development of fulminant hemorrhagic S. maltophilia pneumonia. Since some of the infections and colonizations developed despite prophylactic administration of antibacterial agents with documented in vitro activity against the pathogen and none was controlled by such agents, it is clear an efficient treatment strategy needs to be developed.

Bone marrow malignancies are clonal disorders resulting from neoplastic transformation of hematopoietic stem or progenitor cells. Similar to their normal counterparts, transformed blood-forming cells remain dependent on signals from the hematopoiesis-regulating stromal environment for survival and proliferation. There is increasing evidence that the microenvironment may also take a more active part in the disease process. A review of the literature on stromal abnormalities in the leukemias, the myelodysplastic syndromes, and multiple myeloma reveals three principal mechanisms by which stromal derangements can contribute to the evolution of a neoplastic disease. In the simplest case, neoplastic blood-forming cells induce reversible changes in stroma function or composition which result in improved growth conditions for the malignant cells ('malignancy-induced microenvironment'). In the second setting, functionally abnormal end cells derived from the malignant clone become an integral part of the stroma system, selectively stimulating the neoplastic cells and inhibiting normal blood cell formation ('malignant microenvironment'). In the third condition, the emergence of a neoplastic cell population is the consequence of a primary stroma lesion characterized by inability to control regular blood cell formation ('malignancy-inducing microenvironment'). The perception of different stroma-related disease mechanisms may eventually lead to the development of alternative therapeutic approaches.

NK 611 is a new podophyllotoxin derivative in which a dimethyl amino group replaces a hydroxyl group at the sugar moiety of etoposide. This results in profound physico-chemical differences: NK 611 is much less hydrophobic than etoposide. Preclinical studies have shown that NK 611 is advantageous in terms of bioavailability and of the potency of its anticancer activity. A clinical phase I study was performed in cancer patients within the framework of the AIO. Additionally, its pharmacokinetics and pharmacodynamics were investigated. NK 611 was given to 26 patients at doses ranging from 60 to 140 mg/m2 [maximum tolerated dose (MTD) 120 mg/m2] in a 30-min infusion. Plasma and urine samples were collected from 25 patients and analyzed using a validated high-performance liquid chromatography (HPLC) assay procedure. The concentration versus time curve of total NK 611 in plasma samples was best described by a three-compartment model. The overall median pharmacokinetic values were as follows (ranges are given in parantheses): mean residence time (MRT) 16.5 (5.4– 42.3)h, terminal half-life 14.0 (8.2–30.5)h, volume of distribution at steady state (Vss) 11.4 (7.9–18.1) l/m2, and plasma clearance (Clp) 15.1 (3.6–36.4) ml min-1m-2. The total systemic drug exposure, represented by the area under the curve (AUC), varied between 53.4 and 532.0 μg ml-1 h. The mean AUC (±SD) increased with the dose from 78.7±3.7 μg ml-1 h at 60 mg/m2 up to 202.8±157.2 μg ml-1 h at 120 mg/m2. The mean urinary excretion (UE) fraction of unchanged drug at 48 h after the end of the infusion varied between 3.0% and 25.8% of the total dose delivered. Analysis of ultrafiltrate samples showed a protein binding of approx. 99%. The percentage reduction in white blood cells (WBC) and neutrophils (ANC) correlated with the dose, AUC, and AUCfree. The best relationship between the percentage of reduction in ANC and a pharmacokinetic parameter (AUC) took a nonlinear Hill-type form. The laboratory parameter for kidney or liver function did not correlate with the AUC. The variation of pharmacokinetic parameters within each dose level was profound. The reason for this pharmacological behavior remains unclear and should be investigated in further studies.

The multidrug resistant (MDR) phenotype has been suspected as a major cause of treatment failure in hematologic malignancies. Numerous studies have investigated the expression of the MDR1 gene product, P-glycoprotein, in leukemia, lymphoma and myeloma. Studies in myelogenous leukemia and myeloma have so far provided best evidence for a significant correlation between P-glycoprotein expression and response to chemotherapy, although large discrepancies in the proportion of positive cells limit any definite conclusion. Differences in P-glycoprotein detection techniques and methodology may account for the divergent results thus emphasizing the necessity for standardized methods of detection. Despite this, encouraging clinical results have been obtained using MDR modulators in combination with conventional chemotherapy to inhibit the activity of the P-glycoprotein pump. The paper summarizes currently available clinical data and provides guidelines for future trials aimed to reverse the MDR phenotype. The potential of idarubicin to overcome the MDR phenotype is also discussed.

Erythropoietin, alone or in combination with colony-stimulating factors, is a promising agent in the treatment of patients with cancer-related 'anemia of chronic disorders', chemo/radiotherapy-induced anemia, or anemia due to myelodysplastic or myeloproliferative syndromes. In the first two groups, at least half of the patients can be expected to respond to erythropoietin alone, with an average response delay of about 4 weeks and maximal responses at weekly doses of approximately 1000 U/kg. In myelodysplastic syndromes, only 10-20% of patients respond to conventional doses of erythropoietin, but doses exceeding 1000 U/kg weekly in combination with granulocyte colony-stimulating factor yield response rates of about 40%. Although these results show that hematopoietic growth factors can be used successfully to treat cancer-related anemias, economic constraints preclude their use at the present time.

Monoclonal antibodies Leu 11a (CD16) and Leu 19 (CD56) were tested for reactivity with cells from 36 patients with acute myelogenous leukemia (AML) using two-colour flow cytometry. Blast cells were identified by a broad panel of monoclonal antibodies. In 33% (12/36) the monoclonal antibody Leu 19, which has been demonstrated to bind to the 140 kD isoform of the human neural cellular adhesion molecule N-CAM, found on peripheral natural killer (NK)-cells, neuroectodermal cells, activated T-cells, and myeloma cells, was shown to bind strongly to the leukemic cells. The monoclonal antibody Leu 11a, which recognizes a surface differentiation antigen associated with the low affinity FcRIII for IgG, expressed on NK-cells, granulocytes and macrophages were found to bind to leukemic cells of four of the 12 Leu-19 positive cases. 50% (6/12) of Leu-19 positive patients were classified as having M4 according to the French-American-British (FAB) morphology criteria. The potential diagnostic and clinical importance of CD 56 and/or CD 16 expression in acute myelogenous leukemia is presently under investigation.

Recently alterations in growth factor receptors, e.g. the erythropoietin receptor, have been described which cause increased sensitivity to growth factors or even autonomous growth independent from exogenous stimuli. We therefore investigated the gene structure of the alpha and beta chains of the GM-CSF receptor using Southern blots. EcoRI and HindIII digested DNA from peripheral blood samples from 34 consecutive patients with AML were hybridized with probes specific for the GM-CSF receptor alpha and beta chains. No abnormal DNA was detected. RNA expression was investigated by Northern blots in 32 patients. Expression of the beta chain was found in 30 of 32 patients. No messenger RNAs of aberrant size were detected. PCR reactions were performed with oligonucleotide primers specific for the alpha chain; c-DNAs were identified in all 10 patients studied. Thus we conclude that gene structure and expression of both chains of the GM-CSF receptor are not altered in AML.

GM-CSF is constitutively secreted by myeloblasts of some patients with AML. Recently it has been shown that IL-1 and TNF-alpha can induce GM-CSF production in fresh leukemic cells of patients who do not release GM-CSF spontaneously. To further characterize this phenomenon we investigated GM-CSF induction by TNF-alpha in two leukemic cell lines, U 937 and KG-1a. KG-1a constitutively expresses GM-CSF mRNA as demonstrated by Northern blots and PCR analysis. Unstimulated U 937 cells contained no detectable GM-CSF transcripts. After incubation with TNF-alpha, GM-CSF specific m-RNA was found in U 937 cells. Only slight increases of GM-CSF transcripts were noted in KG-1a cells after TNF-alpha treatment. In unstimulated cultures, GMCSF concentrations were below 1 pg/ml. After 3 days of culture detectable levels of GM-CSF were found after stimulation with 1 ng/ml TNF-alpha and reached a mean of 11.9 pg/ml for U 937 and 59.3 pg/ml for KG-1a after incubation in 50 ng/ml TNF-alpha. Therefore mechanisms of GM-CSF expression are regulated differently in each of these cell lines.

Experimental data suggest that multidrug resistance in cancer may be overcome by using an increased dose of anticancer agent(s) in combination with a resistance-modifying agent (RMA). We studied the pharmacokinetics and metabolism of both epirubicin (EPI) and verapamil (VPL) to explore the possible pharmacokinetic interactions between these two drugs. Ten patients with advanced breast cancer were given EPI (40 mg/m2 in a daily i.v. bolus for 3 consecutive days), and five of them also received VPL (4 x 120 mg/daily p.o. for 4 consecutive days). The data indicated a significant interaction between these two drugs that affected their metabolism. The areas under the concentration-time curves (AUC) obtained for epirubicin glucuronide, epirubicinol glucuronide, and both of the 7-deoxy-aglycones were higher in the EPI + VPL group as compared with the EPI group. The AUC, terminal half-life, mean residence time, volume of distribution at steady state, and plasma clearance of EPI alone as compared with EPI + VPL did not differ significantly. These results suggest either an induction of enzymes necessary for drug metabolism or an increase in the liver blood flow, resulting in an enhanced generation of metabolites with time or in an inhibition of excretion processes. Comparisons of the AUC values obtained for EPI and its metabolites after the first, second, and third injections of EPI revealed a cumulative effect for the metabolites that was more pronounced in the EPI + VPL group, being significant (P0.05) for epirubicin glucuronide in both treatment groups and for epirubicinol glucuronide in the EPI + VPL group. Maximal concentrations of VPL and nor-VPL reached 705 +/- 473 and 308 +/- 122 ng/ml, respectively, with the steady-state concentrations being 265 +/- 42 ng/ml for VPL and 180 +/- 12 ng/ml for nor-VPL.

The purpose of this study was to evaluate the efficacy (progression free survival (PFS) and response rate) and safety of vinorelbine and trastuzumab combination chemotherapy in patients with HER2-overexpressing, metastatic breast cancer as a first line chemotherapy regimen. Patients with histologically confirmed, HER2-positive (immunohistochemistry (ICH) 3+, or 2+ and FISH+) metastatic breast cancer who had nor received prior vinorelbine or anti-HER2 therapy in the adjuvant setting, received at least eight weeks of vinorelbine i.v. (25 mg/g weekly) and trastuzumab (4 mg/kg on day 1 followed by 2 mg/kg weekly). Forty-one women from six participating centers were enrolled into the trial. The overall response rate, was 43.9% (18 of 41 patients), (CI 28-60.3%), 30% of patients were progression free after 1 year. Four patients reached complete remission, 14 partial remission and five had stable disease for at least 18 weeks. Six patients developed primary progression. 35 patients (85%) experienced progression after a median time of 235 days. Therapy was in general well-tolerated. There were two CTC grade 4 infusion syndromes and two patients experienced cardiotoxicity at least grade 2. This phase II trial of vinorelbine and trastuzumab demonstrated an effective and well-tolerated regimen with a favourable safety profile.

Preliminary data of an ongoing phase II-study in metastatic breast cancer patients are presented. Patients with metastatic breast cancer entered the study after hormone therapy had failed; prior treatment with cyclophosphamide, methotrexate and 5-fluorouracil (CMF) was also allowed. The patients were treated with three cycles of 40 mg/m2 epirubicin i.v. on days 1-3 and 4 x 120 mg oral verapamil on days 0-3, given every 3-4 weeks. After three chemotherapy courses, ifosfamide was given as a short infusion of 3 g/m2 on days 1-3. Mesna (20% of the total ifosfamide dose) was given 0, 4 and 8 h after ifosfamide administration. Response was evaluated after three cycles of epirubicin/verapamil and after the last (third) cycle of ifosfamide. The side effects of this treatment were tolerable. The epirubicin/verapamil combination was no more toxic than epirubicin alone. Despite the high dose of verapamil, systolic blood pressure remained above 80 mm Hg, and patients never had a period of strict bed rest. Alopecia was almost complete after induction therapy with epirubicin/verapamil, and nausea and vomiting were absent or mild during epirubicin/verapamil chemotherapy and were easily controlled by antiemetics during ifosfamide treatment. Stomatitis and mucositis, the main toxic effects, could be ameliorated by intensive mouth-washing procedures. The haematological toxicity was greater after epirubicin/verapamil treatment than after ifosfamide therapy, but neither bleeding nor infections due to thrombocytopenia or leucopenia were observed.

Ovarian cancer is chemosensitive, but most patients with advanced disease die from tumor progression. As 25% of the patients can be cured by chemotherapy, it is reasonable to evaluate high-dose chemotherapy (HDCT). Forty-eight patients with untreated ovarian cancer were entered in a multicenter phase I/II trial of multicycle HDCT. Median age was 46 (19–59 years); International Federation of Gynecology and Obstetrics-stage was III in 79% and IV in 21%; 31% had residual disease >1 cm after surgery. Two courses of induction/mobilization therapy with cyclophosphamide (250 mg/m2) and paclitaxel (250 mg/m2) were used to collect peripheral blood stem cells. HDCT consisted of two courses of carboplatin (area under curve (AUC) 18–22) and paclitaxel followed by one course of carboplatin and melphalan (140 mg/m2) with or without etoposide (1600 mg/m2). Main toxicity was gastrointestinal. Limiting carboplatin to AUC 20 and eliminating etoposide resulted in manageable toxicity (69% without grade 3/4 toxicity). One patient died from treatment-related pneumonitis. At 8 years median follow-up, median progression-free-survival (PFS) and overall survival (OS) is 13.3 and 37.0 months. Five-years PFS and OS is 18 and 33%. Multicycle HDCT is feasible in a multicenter setting. A European phase III trial based on this regimen is evaluating the efficacy of HDCT.

Therapy with Docetaxel for hormone-refractory prostatic carcinoma has for the first time led to an increase in the survival time. Docetaxel has become established as a standard therapy for his indication. Since hormone-refractory prostatic carcinoma is not uniformly defined and is thus for prognosis not a homogeneous entity, the prospects at the start of chemotherapy are uncertain. In the summer of 2005 these questions were addressed in an interdisciplinary consensus conference. It was agreed that the 3-week scheme with 75 mg/m (2) as standard and the indication for symptomatic patients were above question. Opinions differed with regard to the use of chemotherapy in asymptomatic patients. In addition, recommendations for the performance and monitoring of the therapy were formulated.

We report the case of a 47-year-old patient who developed acute myelogenous leukemia (AML) 18 months after receiving high-dose chemotherapy with peripheral blood progenitor cell support (PBPCT) for relapsed low-grade follicular non-Hodgkin's lymphoma (NHL). Cytogenetic analysis of the leukemic cells showed the translocation (9;22)(q34;q11). In three mitoses, an additional Philadelphia chromosome (Ph1) was present. In the literature, Philadelphia chromosome-positive secondary AML has been described only once before in a patient with multiple myeloma.

We sought to determine dynamics of BCR-ABL mRNA expression levels in 139 patients with chronic myelogenous leukemia (CML) in early chronic phase, randomized to receive imatinib (n=69) or interferon (IFN)/Ara-C (n=70). The response was sequentially monitored by cytogenetics from bone marrow metaphases (n=803) and qualitative and quantitative RT-PCR from peripheral blood samples (n=1117). Complete cytogenetic response (CCR) was achieved in 60 (imatinib, 87%) vs 10 patients (IFN/Ara-C, 14%) after a median observation time of 24 months. Within the first year after CCR, best median ratio BCR-ABL/ABL was 0.087%, (imatinib, n=48) vs 0.27% (IFN/Ara-C, n=9, P=0.025). BCR-ABL was undetectable in 25 cases by real-time PCR, but in only four patients by nested PCR. Median best response in patients with relapse after CCR was 0.24% (n=3) as compared to 0.029% in patients with continuous remission (n=52, P=0.029). We conclude that (i) treatment with imatinib in newly diagnosed CML patients is associated with a rapid decrease of BCR-ABL transcript levels; (ii) nested PCR may reveal residual BCR-ABL transcripts in samples that are negative by real-time PCR; (iii) BCR-ABL transcript levels parallel cytogenetic response, and (iv) imatinib is superior to IFN/Ara-C in terms of the speed and degree of molecular responses, but residual disease is rarely eliminated.

We assessed the effect of rabbit antithymocyte globulin manufactured by Fresenius (ATG-F) on the hemostatic system in patients (n=12) with various hematological malignancies undergoing hematopoietic stem cell transplantation (HSCT) from HLA-matched unrelated donors. For this purpose, we monitored different parameters of coagulation before, during and after the administration of ATG-F. As a control group, we recruited patients (n=10) undergoing HSCT from their HLA-identical siblings who did not receive ATG-F as part of their preparative regimens. At 24 and 48 h after ATG-F treatment had been initiated, we found a temporary rise in D-Dimer, tissue factor, soluble thrombomodulin and thrombin-antithrombin III complex levels and a significant decrease of platelet counts in patients treated with ATG-F as compared to the control group. No differences between the two groups could be detected with regard to global coagulation tests as well as the incidence of bleeding manifestations, thromboembolic complications or the development of vascular-occlusive-disease of the liver. This temporary state of a stressed but compensated coagulation system under ATG-F therapy can be addressed as nonovert disseminated intravascular coagulation (DIC). The effect was independent from the different conditioning regimens and eased off after cessation of ATG-F. We conclude that ATG-F can induce nonovert DIC in patients receiving antithymocyte globulin as part of their conditioning regimen for HSCT.

Inhibitor development is often associated with an increased bleeding tendency, which May result in spontaneous, life-threatening bleeding episodes and requires immediate intervention using an established therapeutic agent such as aPCC or rFVIIa. But even bleeding complications following a simple surgical procedure with supposed absence of inhibitor May quickly develop into a dramatic situation for the patient.

A 51-year-old female patient suffered from recurrent ischemic strokes and venous thromboembolism although treated with ASS and phenprocoumon, which mainly occurred after diagnosis and treatment of an invasive-ductal mamma carcinoma. The severely ill patient presented with right-sided hemiparesis and dysarthria, a swollen leg, a painful necrotic-ulcerative lesion at the left-lateral ankle and a systolic heart murmur.Laboratory data revealed a haemoglobin of 8,4 g/dl, a leucocyte count of 3,1 x 10 (9)/l and a platelet count of 87 x 10 (9)/l. C-reactive protein, ESR and plasma fibrinogen were markedly increased. Levels of antinuclear, IgG-anticardiolipin and anti-doublestranded-DNA antibodies were excessively elevated. A test for lupus anticoagulant was strongly positive. Sonographic examinations showed deep vein thrombosis and significant mitral valve regurgitation. Suspected pulmonary embolism was demonstrated by CT scan. We diagnosed systemic lupus erythematosus with secondary antiphospholipid antibody syndrome (APAS).Phenprocoumon was stopped and full-dose anticoagulation with low-molecular-weight heparin initiated. Additional immunosuppressive therapy consisted of cyclophosphamide, azathioprin and prednisone resulting in prevention of further thromboembolism and significant improvement of clinical symptoms. The observed severe interference of LA with the prothrombin time after cessation of phenprocoumon (INR 3,6; FII activity 81 %) suggested that the effect of oral anticoagulation had been overestimated in the past.APAS may present as an acute and life-threatening disorder. In this case interdisciplinary co-operation and a highly individualised treatment strategy are mandatory.

The purpose of this phase II trial was to investigate the efficacy and safety of a combination chemotherapy with gemcitabine, vinorelbine and cisplatin in the first-line treatment of advanced non-small cell lung cancer (NSCLC). Patients with NSCLC stage IIIB or IV disease received 1000 mg/m(2) gemcitabine and 25 mg/m(2) vinorelbine on days 1 and 8 and 75 mg/m(2) cisplatin on day 2, every 3 weeks. From December 1998 to May 1999, 31 patients (21 stage IV and 10 stage IIIB disease), with a median age of 59 years (range 40-72 years) were enrolled. The overall intent-to-treat response rate was 45% (95% confidence interval (CI): 27-64%) with 2 complete responders (CR) and 12 partial responders (PR), 7 patients had stable disease and 10 progressed. Median survival was 12.8 months (95% CI: 6.5-12.8+ months), median time to progression was 5.1 months (95% CI: 3.5-7.7 months), and the 1-year survival rate was 52.9% (95% CI: 36.7-76.2%). Patients with stage IIIB disease had a significantly longer overall survival than patients with stage IV disease (P=0.05). Transient World Health Organization (WHO) grade IV leucopenia, anaemia and thrombocytopenia occurred in 3 (10%), 2 (6%) and 3 (10%) patients, respectively. The predominant non-haematological toxicities were alopecia and nausea/vomiting. 15 patients (48%) had WHO grade II and III alopecia and 14 patients (45%) nausea/vomiting. The combination of gemcitabine, vinorelbine and cisplatin has demonstrated major antitumour efficacy in advanced NSCLC with a manageable toxicity profile.

Neovascularization is increasingly recognized as an important factor in the pathogenesis of hematologic malignancies as well as solid tumors. The complex interactions between several cell types and numerous cytokine mediators suggest the involvement of autocrine and paracrine signaling mechanisms. Vascular endothelial growth factor (VEGF) in particular is critical to both stimulation of leukemic growth and proliferation of endothelial cells. Tyrosine kinase receptors specific for certain growth factors represent attractive target molecules for anticancer therapy. SU5416 is a competitive inhibitor of VEGF receptor subtypes VEGFR-1 and VEGFR-2 and stem cell factor receptor c-kit. Preclinical evidence shows that SU5416 effectively inhibits VEGF-induced endothelial cell proliferation and slows growth of subcutaneous solid tumor xenografts. This agent is in late-stage clinical trials in patients with solid tumors, and a Phase 2 study was recently initiated to evaluate its utility in the treatment of acute myeloid leukemia. In this Phase 2 study, investigators are seeking to determine the response rate to the antiangiogenic agent SU5416. Translational research in this study is intended to aid our understanding of the precise mechanisms by which SU5416 affects acute myeloid leukemia cells and the bone marrow microenvironment.

IgM myeloma is a rare disease, accounting for approximately 0.5% of multiple myelomas (MM). Here we report four cases of IgM multiple myeloma. Two were diagnosed in advanced clinical stages with multiple osteolytic lesions, leading to hypercalcemia in one patient. Bone marrow morphology showed a variable degree of infiltration with mainly mature plasma cells. An immunophenotypic analysis performed in one case showed expression of CD38 and monoclonal cytoplasmatic immunoglobulin. Interphase fluorescence in situ hybridization performed in one case did not reveal any aneuploidies or deletions of the retinoblastoma, P16, or P53 tumor suppressor genes. While one patient with a smoldering IgM myeloma did not need specific therapy, the others received cytotoxic treatment based on standard chemotherapy for MM. The outcomes were one stable disease, one sustained complete remission, and one progressive disease. All four patients were alive 1 year after diagnosis. One died due to progressive disease after 31 months. We conclude that IgM myeloma shares clinical and histological features with other MM rather than with Waldenstrom's macroglobulinemia, which is most commonly diagnosed in cases with IgM monoclonal gammopathy. Since MM and Waldenstrom's macroglobulinemia differ in prognosis and treatment strategies, the two disease entities should be distinguished based on clinical criteria, bone marrow morphology, and immunophenotypic analysis.

It has been unequivocally demonstrated that hyperthermia (40-44 degrees C) has an potentiating effect on radiotherapy and chemotherapy. Technical improvements have facilitated the application of both local and whole-body hyperthermia, and have thus made this form of treatment available to large numbers of patients. Randomized phase III studies performed in patients with breast cancer, malignant melanoma and cervical cancer have convincingly confirmed the increased efficacy of the combination of radiotherapy with local or regional hyperthermia in comparison with radiotherapy alone. The effectiveness of other procedures such as the combination of radio- and chemotherapy with regional hyperthermia, regional thermochemotherapy and whole-body hyperthermia has so far been investigated mainly in phase II studies focusing on head and neck cancer, cervical and ovarian cancer, sarcoma, malignant germ cell tumors, and rectal carcinoma. However, the actual place of hyperthermia as a permanent element in a multimodal therapeutic concept has yet to be shown in prospective phase III studies.

The purpose of this phase II study was to investigate the efficacy and safety of gemcitabine plus vinorelbine as first-line chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). Eligibility criteria included cytologically or histologically confirmed NSCLC (stage IIIB or IV), no previous chemotherapy, and bidimensionally measurable disease. Patients received 1000 mg/m(2) gemcitabine and 30 mg/m(2) vinorelbine on days 1, 8 and 15 every 4 weeks up to eight courses. From December 1997 to November 1998, 70 patients (59 stage IV and 11 stage IIIB disease), with a median age of 59 years (range 38-74 years) were enrolled. The intent-to-treat response rate was 41% (95% confidence interval (CI) 30-54%) with 1 complete responder (CR) and 28 partial responders (PRs), 15 patients had stable disease (SD) and 26 progressed (PD). Median survival was 8.3 months (95% CI 6.0-9.9 months), median progression-free survival (PFS) was 4.8 months (95% CI 3.9-5.5 months), and 1-year survival rate was 33.5% (95% CI 24.0-46.8%). Patients received a total of 229 cycles. Haematological and non-haematological toxicities were moderate. Transient World Health Organization (WHO)-grade IV leucopenia and thrombocytopenia occurred in 13 (6%) and two (1%) cycles, respectively. The predominant non-haematological toxicity was local reactions of the veins in 19 (27%) patients (WHO-grade II and III). Neurotoxicity was infrequent, non-cumulative, and reversible. The combination of gemcitabine and vinorelbine has demonstrated activity in metastatic NSCLC, with response and survival rates similar to those of cisplatin-based regimens and a more favourable toxicity profile that is well tolerated in an outpatient setting.

This is an open-label, nonrandomized phase I trial to determine the safety and maximum tolerated dose of irinotecan with a fixed dose of UFT plus oral leucovorin in patients with advanced or metastatic colorectal cancer. A secondary objective of the study is to determine the response rate in this patient population. Adult patients with histologically confirmed advanced or metastatic colorectal carcinoma and no prior chemotherapy for advanced or metastatic disease, or those patients who have received adjuvant chemotherapy (6 months prior to the study entry) will be eligible to participate. All patients must have measurable or evaluable lesions. Symptoms will be evaluated at baseline and every 6 weeks thereafter. Computed tomography scans will be performed at baseline and every three cycles of treatment to assess tumor response. A total of six cycles of treatment may be given, depending on patient tolerance. Patients will be followed for a maximum of 12 months for time to progression, following the last dose of the study drug. Tumor response will be defined using standard World Health Organization criteria.

The genetic mechanisms underlying the genesis, disease progression, and high-grade transformation of marginal zone B-cell lymphoma (MZBCL) are poorly understood. We analyzed 33 cases of histologically and immunophenotypically well-characterized MZBCL (12 extranodal, 11 nodal, and 10 splenic MZBCL; 27 at primary diagnosis and six during the course of disease) by dual-color interphase fluorescence in situ hybridization (FISH) for deletions of tumor suppressor genes. We investigated loci known to play a role in the genesis or disease progression of other subtypes of lymphoid malignancies, namely the P53 gene (17p13), the retinoblastoma gene (RB, 13q14), the D13S25 locus (13q14), and the P16(INK4A) gene (9p21). Heterozygous deletions of P53 were detected in three out of the 33 cases, including two splenic and one extranodal MZBCL. One of these patients was analyzed at primary diagnosis and two during the course of disease. Heterozygous deletions of the RB gene (nodal MZBCL) and D13S25 (splenic MZBCL) were found in one case each. P16 deletions were not detected in any of our cases. We conclude that deletions of the analyzed tumor suppressor genes are relatively rare in MZBCL, which contrasts with the findings in some other subtypes of NHL.

Marginal zone cell lymphomas of the mucosa-associated lymphoid tissue (MALT) are the most common subtype of lymphoma arising at extranodal sites. The t(11;18)(q21;q21) appears to be the key genetic lesion and is found in approximately 50% of cytogenetically abnormal low-grade MALT lymphomas. We show that the API2 gene, encoding an inhibitor of apoptosis also known as c-IAP2, HIAP1, and MIHC, and a novel gene on 18q21 characterized by several Ig-like C2-type domains, named MLT, are recurrently rearranged in the t(11;18). In both MALT lymphomas analyzed, the breakpoint in API2 occurred in the intron separating the exons coding respectively for the baculovirus IAP repeat domains and the caspase recruitment domain. The breakpoints within MLT differed but the open reading frame was conserved in both cases. In one case, the translocation was accompanied by a cryptic deletion involving the 3' part of API2. As a result, the reciprocal transcript was not present, strongly suggesting that the API2-MLT fusion is involved in the oncogenesis of MALT lymphoma.

In order to develop new strategies for the treatment of relapsed or refractory acute myeloid leukemia, the German AML Cooperative Group performed a prospective multicenter phase II study to evaluate the antileukemic efficacy of aclarubicin 60 mg/m2/day and etoposide 100 mg/m2/day each given for 5 days. Of 37 heavily pretreated evaluable patients (median age 42 years, range 18-81) 15 (40%) achieved a remission after one or two courses of treatment consisting of nine complete (24%) and six partial remissions (16%). Fourteen (38%) cases were non-responders and eight (22%) patients suffered from early deaths. Disease-free survival for patients in remission and overall survival were 3.2 months each. The median duration of critical neutropenia500/microl was 27 days. The most frequent non-hematologic side-effects were stomatitis (WHO III/IV, 48%), infections (40%), nausea/vomiting (26%) and diarrhea (24%). Cardiac toxicity was mild. This study suggests a substantial antileukemic efficacy and an acceptable toxicity of aclarubicin in combination with etoposide in heavily pretreated patients with advanced acute myeloid leukemia, and warrants further evaluations in a more favorable stage of the disease.

Summary ESMO has designed a programme of certification and training in medical oncology. In this paper the background of these programmes is given, and the programme of graduate education is described in greater detail. The standard requirements are a total training period of six years, beginning with a common internship in internal medicine of at least two years, followed by a training programme in oncology for three to four years, which must include at least one year of full-time clinical training in the diagnosis and management of neoplastic diseases, accompanied by one year of experience in an ambulatory care setting.

With the use of a cisplatin-based chemotherapy, metastatic testicular cancer has become a model for a highly curable malignant disease. Current data show that 70% to 80% of patients with this disease will achieve long-term survival following cisplatin/etoposide/bleomycin therapy. The role of high-dose chemotherapy with autologous stem cell support is being investigated in metastatic germ cell cancer in attempts to improve outcome for patients whose disease relapses after standard-dose chemotherapy and for those who present initially with advanced metastatic disease. Prognostic categories for patients receiving high-dose salvage chemotherapy have recently been developed: cisplatin-refractory disease, beta-human chorionic gonadotropin values greater than 1,000 U/L, and primary mediastinal germ cell tumors are factors characterizing patients who will derive less benefit from high-dose chemotherapy than those with chemosensitive disease at relapse. While standard-dose salvage chemotherapy achieves only a 20% long-term survival rate, high-dose salvage chemotherapy may yield a cure rate of approximately 40%. A randomized study comparing high-dose therapy with conventional-dose therapy (IT94 coordinated by the European Group for Blood and Marrow Transplantation) in patients with relapsed disease is ongoing to substantiate this observation. The use of dose-intensive therapy as first-line treatment is currently being studied by several institutions. High-dose therapy may be better tolerated when used first line compared with its use in the salvage situation, and may also achieve a rapid initial cell kill before cytostatic drug resistance develops. The German Testicular Cancer Study Group has developed a sequential high-dose combination regimen of cisplatin/etoposide/ifosfamide given with granulocyte colony-stimulating factor and peripheral blood stem cell support for four cycles every 3 weeks. This ongoing study, started in 1990, had accrued 218 patients with advanced testicular germ cell tumors as of June 1997. Of 141 evaluable patients receiving dose levels 1 through 5, 82 (58%) have achieved complete remission with no evidence of disease and 32 (23%) have achieved partial remission with marker normalization. The early death rate was 8%. Overall and event-free survival rates at 2 years are 78% and 73%, respectively, with a projected 5-year overall survival rate of 74%. Despite favorable preliminary results, this approach cannot be considered standard treatment. Currently, high-dose chemotherapy with peripheral blood stem cell transplantation should be administered to patients with testicular cancer only within controlled clinical trials to allow long-term cure rates and treatment-related late side effects to be evaluated.

The destruction of hematopoiesis and lymphopoiesis by total body irradiation or high dose chemotherapy for the treatment of malignancy can be reversed by the transplantation of allogeneic or autologous hematopoietic stem cells. In primary disorders of bone marrow or immune system, allogeneic stem cells replace deficient cells. Acute leukemias can be cured, with in 50 to 80% disease free survival after 5 to 8 years. The allogeneic graft versus leukemia effect by immunoreactive cells reduces the relapse rate in myeloid and lymphoid malignancies. 40 to 70% of patients with chronic myeloid leukemia remain disease free after more than 5 years. Patients with malignant lymphoma have a 40 to 70% chance of cure with autologous transplantation, which is not increased by allogeneic cells, because of a higher incidence of severe complications. An increasing number of patients without option for cure is treated with the aim of prolonging remission or retarding disease progression, such as in chronic myeloid leukemia, multiple myeloma and certain solid tumors. New studies suggest in breast cancer with axillary lymph node metastases, that adjuvant high dose chemotherapy with autologous stem cell support will significantly improve disease free survival from 30 to over 60% after 3 to 5 years. In congenital metabolic and storage diseases deficient enzymes are substituted by the allogeneic cells. Clinical trials explore the use of stem cell transplantation after myeloablative therapy in autoimmune disorders as well as in gene therapy with transfected hematopoietic stem cells.

Trisomy 8 is the most frequent numerical chromosome aberration in acute myeloid leukaemia (AML). It occurs either as the sole anomaly or together with other clonal chromosome aberrations. We investigated whether accompanying chromosome anomalies influence the clinical outcome in patients with trisomy 8 and de novo AML. Since 1986, in 713 AML cases treated according to the protocols of the German AMLCG trials, chromosome analyses have been successfully performed. The overall incidence of trisomy 8 was 7.6%. Complete clinical follow-up data were available for 51 patients who were divided into three different categories: group 1: trisomy 8 as the sole cytogenetic anomaly (n = 20); group 2: trisomy 8 in addition to favourable chromosome aberrations (t(8;21)(q22;q22), t(15;17)(q22;q21), inv(16)(p13q22)) (n = 10); and group 3: trisomy 8 accompanied by other anomalies, in most cases of complex type (n = 21). Complete remission (CR) rates were 70%, 90% and 67% for groups 1, 2 and 3, respectively. Event-free survival (EFS) at 3 years differed significantly between patients with trisomy 8 only (37.5%), patients with trisomy 8 in combination with favourable aberrations (55.0%) and patients with trisomy 8 and other accompanying anomalies, mostly complex chromosome aberrations (9.0%) (group 1 v group 2: P=0.12; group 1 v group 3: P=0.005; group 2 v group 3: P=0.05). In this study patients with +8 as the sole cytogenetic anomaly had an intermediate prognosis, patients with +8 in addition to favourable chromosome aberrations maintained a good clinical outcome, and patients with +8 in combination with other abnormalities showed the worst prognosis.