Search

In a multicenter study it is being determined, whether the use of hydroxyurea or of interferon alpha instead of busulfan prolongs the chronic phase of Philadelphia-positive CML. Additional goals are the examination, whether the types of disease evolution and the terminal phases differ between the treatment groups, and the prospective recognition of prognostic criteria for the duration of the chronic phase of CML. By September 5, 1990, 593 CML-patients had been randomized, 221 for busulfan, 228 for hydroxyurea and 144 for interferon alpha. The average age is about 51 years. By April 30, 1990, 106 patients had reached the end of the chronic phase, 126 had died. The median survival of Philadelphia-positive patients was 3.95 years, that of all patients 3.75 years. The median observation time of all patients was 1.34 years (mean 1.60 years). At present, no significant difference in survival is recognizable between the three treatment arms, although fewer adverse effects have been observed in the hydroxyurea arm.

Carboplatin is one of the most active agents in untreated small cell lung cancer (SCLC) (14% complete response [CR] and 61% CR + partial response [PR]). The combination carboplatin/etoposide/vincristine (CEV) (phase II trial) led to an overall remission rate of 84% in patients with limited disease, with 52% CR. The median survival time with this combination was 13 months in patients with limited disease and 9.5 months in those with extensive disease. The 30-month survival rates are 30% in limited disease and 10% in extensive disease with a plateau of the survival curve. This regimen is highly effective and exhibits low toxicity in SCLC. To evaluate the role of carboplatin in combination chemotherapy in patients with extensive SCLC, a phase III trial was performed. In this ongoing trial comparing CEV and etoposide/vincristine in SCLC patients with extensive disease, CR and overall response rates to date are higher in the CEV arm (CR 30% v 10%, CR + PR 90% v 75%), but as yet the differences are not statistically significant. In summary, chemotherapy regimens containing platinum compounds are among the most active in the treatment of SCLC. The use of the new compound carboplatin instead of cisplatin has led to similar or increased remission rates and is preferable because it has fewer side effects. Preliminary results from this ongoing, prospective, randomized phase III trial will be presented.

Iodo-doxorubicin belongs to the group of doxorubicin analogs with modifications at the 4'-position of the daunosamine sugar moiety. Epirubicin is the archetype of the analogs created by configurational changes at the sugar. In case of EPI, the hydroxy group at the 4'-position is equatorial instead axial. In case of I-DOX, the hydroxy group has been replaced by an iodine-atom. This exchange has a great influence on the basicity of the amino group at the 3'-position. The physico-chemical properties of I-DOX are markedly different from those of DOX and EPI. I-DOX is unprotonated at physiological pH and much more lipophilic than DOX. The preclinical screening showed greater potency of I-DOX in different tumor cell systems. Cardiotoxicity and tissue toxicity after extravasation were significantly reduced in case of I-DOX. The substance was evaluated within three phase-I-studies in Europe during 1988 to 1990. The most prominent toxicity observed was myelotoxicity. This type of toxicity was dose-dependent and reversible. Alopecia, stomatitis/mucositis were not seen at all. There was only minor nausea without vomiting. The measured thyroid parameters were not affected by administration of an iodine-containing drug, but long-term effects cannot be ruled out. No acute cardiotoxicity was observed. The pharmacokinetics and metabolism of I-DOX differ from those of DOX and EPI. The terminal half-life of I-DOX is shorter, the plasma clearance higher than of DOX. One major difference is the formation of iodo-doxorubicinol, which is much larger in case of I-DOX compared to DOX and EPI. This cytostatic metabolite has a long terminal half-life.

To investigate possible mechanisms of growth factor expression in acute myeloid leukemia, genes for granulocyte macrophage colony-stimulating factor (GM-CSF) were analyzed by Southern blots in 20 patients, for M-CSF in 13, for interleukin-6 (IL-6) in 14, for IL-6 receptor in 14 and for G-CSF in five patients. Only in one patient a complex rearrangement of the G-CSF gene with possible amplification was noted indicating rarity of direct alterations of growth factor genes in acute myelogenous leukemia (AML). Spontaneous m-RNA expression for GM-CSF was found in only one of 20 patients, and for IL-6 in eight of 11 patients. In vitro incubation of AML cells of eight patients with recombinant tumor necrosis factor for 24 hr revealed induction of GM-CSF m-RNA expression in three cases and GM-CSF protein expression in two of them. These data suggest that spontaneous GM-CSF production occurs rarely in AML and that monokines, such as tumor necrosis factor, may induce GM-CSF in AML cells. Therefore, interactions of AML cells with normal or malignant accessory cells may be important for autocrine stimulation in AML. Our data suggest that ectopic growth factor secretion is not the primary cause of generating AML but may contribute to progression of the disease. Alternatively, AML may represent a heterogenous group of leukemias with different etiology but similar phenotype.

Constitutive secretion of interleukin-6 (IL-6) has been proposed as a mechanism of transformation in multiple myeloma. We therefore studied 15 patients with this disease for rearrangements of the IL-6 and IL-6 receptor genes. Two patients with altered IL-6 genes were identified. Chromosome analysis revealed aberrations of chromosome 7, where the IL-6 gene resides, in only these two patients, but not in others without IL-6 rearrangements. In one of these patients, constitutive IL-6 m-RNA expression was observed. No alterations of IL-6 receptor genes were detected.

Within the framework of a multi-centre prospective randomised therapeutic trial, 150 patients with small-cell lung cancer (SCLC) were treated with cisplatin/vepesid and endoxan/vepesid. The aim of the study was to establish whether cisplatin--which although effective is commonly associated with adverse effects--can be replaced by endoxan. The sequence of treatment was oriented to the stage and course of the tumour disease. In the event of a treatment failure, cross-over to the alternative combination was effected. In terms of remission rates, the combination cisplatin/vepesid proved to be more effective than endoxan/vepesid, in particular in the case of patients with extensive disease. With respect to duration of remission and survival duration, however, no significant differences were to be seen.

In a phase II study, the combination of the new platinum derivative carboplatin with vincristine and etoposide is associated with a remission rate of 81.8 per cent (LD 84.4%, ED 79.1%). The median survival rates for patients with limited disease have not yet been reached, and, at 11.5 months in the case of patients with extensive disease, are unexpectedly high. In comparison with combinations containing cisplatin, the present combination would appear to be superior, and its toxicity is also lower. For a definitive assessment of its usefulness, it must be compared with other standard treatment regimens in prospective, randomized studies.

Carboplatin, a derivative of cisplatin, has, when administered alone, a remission rate of almost 20 per cent. Forty-six patients were treated with the combination carboplatin/vepesid. Twenty-seven per cent of the patients experienced partial remission; in 41%, no change in the size of the tumour was observed. Neither alone nor in combination does carboplatin appear to show any nephrotoxicity or otoxicity, and its neurotoxic effect is only slight.

In a prospective randomised study involving patients with inoperable non-small-cell lung cancer, no differences were to be seen in the remission rates (30.3%, 22.7% and 25%, respectively; p = 0.4) achieved by the combinations mitomycin/ifosfamide, mitomycin/vindesine and cisplatin/etoposide. Nor were any statistically significant differences to be found in terms of the duration of survival. The median survival durations were 6.5, 5.5 and 6 months, respectively (p = 0.7). With respect to toxicity, the combination mitomycin/vindesine proved to be superior, in particular since virtually no gastrointestinal toxicity was observed with this combination. On the basis of these results and the-state of our knowledge to date, the conclusion may be drawn that cisplatin-containing combinations should no longer be employed in the chemotherapeutic treatment of non-small-cell cancers.

Previous investigations in animals and one retrospective study in man suggest that verapamil can prevent anthracycline-induced cardiomyopathy. In the following study, patients with acute myeloid leukemia (AML) treated with double induction and consolidation chemotherapy (AML COOP study 1986, [3]) were randomized in a group with and without accompanying low-dose oral verapamil treatment. Since July 1986, 64 patients have been included. Thirty patients have been evaluated for pre- and posttreatment cardiological investigations. So far, no significant difference in cardiotoxicity has been observed either between the verapamil and nonverapamil group or between the two induction chemotherapy regimens (TAD/TAD - TAD/HAM).

On the basis of a considerable number of carefully designed, representative, and controlled studies adjuvant chemotherapy was considered uneffective for patients with colorectal cancer. In the light of the very recently published results obtained with the combination of 5-fluorouracil plus levamisole this option must now be reconsidered. However, the statement of the NCI that all patients with Dukes'C cancer should be offered this combination appears premature.

LBA8 Background: Infused irinotecan regimens have improved survival in metastatic CRC. This international, multicenter, open-label, randomized, prospective trial of adjuvant chemotherapy with IF vs. F was designed to confirm these results in pts with stage III colon cancer. Pts were given IF (Arm A) or F (Arm B) in 4 cycles of 3 infusions every 2 weeks (de Gramont regimen) or 4 cycles of the AIO regimen. Irinotecan was given as 180 mg/m2 per dose in the de Gramont regimen, and as 80 mg/m2 in the AIO regimen. Methods: Inclusion criteria were WHO performance status

Our present protocol for adult metastatic STS comprises the combination of doxorubicin 30 mg/m 2 /days 1 + 3 and ifosfamide 3 g/m 2 /days 1–3 given every 3 weeks. The first course of treatment is given without support of G-CSF. In cases of Ieukopenia grade 4 after any cycle the following cycles are given with G-CSF 5 μg/kg/day. So far, 124 courses of chemotherapy have been administered to 35 pts. After the first course 18/35 pts developed leukopenia grade 4 and 7 pts had non fatal febrile episodes necessitating antibiotic therapy. These 18 pts received additional 54 courses of chemotherapy followed by G-CSF. Although 24 episodes of leukopenia grade 4 were noticed, only one patient developed a febrile infection. 17/35 pts continued treatment after the first course without support of G-CSF. Four of them developed leukopenia grade 4 after the second and third course, respectively, so that only 13 pts received all cycles of chemotherapy without G-CSF. None of several clinical parameters, such as pts’ sex and age, performance status, localization of metastases or WBC before treatment could predict the probability of development of leukopenia grade 4. So far, response rates are: CR 6%, PR 24%, SO 38%, and PO 32%. Conclusion The above described regimen is a hematotoxic combination. However, it can be given to about 30% of adult pts with metastatic STS without support of G-CSF. With regard to the high cost of G-CSF we believe that it is justified to administer the first course of this chemotherapy without support of G-CSF. However, under these conditions, the immediate initiation of antibiotic treatment in cases of fever must be guaranteed.

Since January 1993 we are conducting a randomized phase III study in pts with metastatic colorectal carcinoma comparing 5-FU (425 mg/m2)/FA (20 mg/m2) days 1–5 as iv bolus therapy given every 4 weeks (arm A) with weekly high-dose 5-FU (2600 mg/m2) 24-hour infusion (arm B). So far, 37 pts in each arm are evaluable for response and toxicity. Pts in both arms are comparable with regard to sex, age, performance status, localizationof metastates and number of metastatic sites. Preliminary response rates are: PR 22% (A) and 27% (B), SD 32% (A) and 5l% (B), PD 46% (A) and 22% (B). Probability of median survival is 12 (A) and 15 (B) months, respectively. Moderate mucositis, diarrhea and nausea are the most frequent toxicities in both arms. Hematotoxicity is absent in arm B, but about one third of the pts develop reversible hand foot syndrome. Conclusion Although no statistically significant differences between the two treatment arms are seen so far, we believe that these preliminary results justify the continuation of the study.

Infections still remain the major cause of morbidity and mortality in neu-tropenic patients with leukemia. Especially fungal infections are critical during neutopenia. 487 febrile phases were evaluated retrospectively during 377 neutropenic episodes (leukocytes 9 /l) of 182 AML-patients treated in our institution from 1982–1993. We observed 16 neutropenic phases without fever. In 156 episodes (32%) the origin remained unknown (FUO), but 331 (68%) were clinically or microbio-logically identified infections mostly gram-positive bacterial (37%), followed by fungal (31%) and gram-negative bacterial infections (21%). Sepsis (220) and pneumonia (86) represented the major type of infections. 70% of pneumonia were caused by fungi. Urinary tract infections (27), tonsillitis (17), oesophagitis (16) and abscesses (13) turned out to be the other main infection sites. 48 patients died during neutropenia. The leading cause of death was fungal sepsis or pneumonia in 73% (29). 38% (11) of lethal fungal infections were discovered at autopsy; in 9 of these 11 patients mixed infections were observed—frequently a combination of fungal and gram-negative infection. To conclude all patients with pneumonia in neutropenia should be treated early with high dosage antimycotic therapy; in addition a mixed infection should be considered.

Two patients with acute myeloid leukemia are described in whom G- and C-banding analysis of bone marrow cells revealed, besides the translocation t(8;21), an additional structural anomaly characterized by the deletion of bands q13 to q23 of one chromosome no. 9. Findings in the literature support the proposal that this constellation represents a hitherto unreported subtype of the prototypic karyotype in AML.

Analyses of the cystic fluid from a patient with massive tissue calcification showed a significant amount of acid mucopolysaccharides (mainly hyaluronic acid) and phospholipid-polypeptide complexes. The possible role of those molecules in this type of calcinosis is discussed.

Between July 1974 and December 1976 a total of 69 patients were treated for acute nonlymphoblastic leukaemia. The mean age was 42 years. Seven had been previously treated. Induction treatment with daunoblastin and cytarabine was given to 67 patients. It produced complete remission in 37 (55.2%) and partial remission in two. Twelve patients received a minimum of two courses of induction treatment without remission (definite treatment failures). Sixteen patients died during the first 30 days after onset of treatment. Treatment to maintain remission consisted of cytarabine and alternating 6-thioguanine, cyclophosphamide, lomustin and daunoblastin. Treatment could be continued as planned in only a quarter of the patients, because of serious side effects in the others. One year after conclusion of the study (31. 12.77) the median remission period was 42, median survival time for all patients 33 weeks (73.5 weeks for those responding and 8 weeks for those not responding to treatment). Age, fever, and chromosomal status of bone-marrow cells had an effect on prognosis.

Ein Uberblick einschlagiger Therapiestudien bei AML des Erwachsenen zeigt keine durchbruchartigen, wegweisenden Therapiefortschritte in den 80er Jahren. Diese liegen bereits in den 70er Jahren, etwa bei einigen wirksamen Induktionsregimen. Fortschritte in diesem Jahrzehnt sind nur in kleinen Schritten zu erwarten. Der klinischen Forschung obliegt es, die einzelnen Therapiekomponenten und neue Elemente sorgfaltig auf ihre Wirksamkeit zu prufen, um diese besser additiv einsetzen zu konnen. Eine Standardisierung der Therapie ist dabei unumganglich, vielfach auch ein randomisierter Vergleich. So konnte in unserer multizentrischen Studie erstmals die Rolle der monatlichen Erhaltungstherapie geklart werden. Ebenso konnte eine bessere Beurteilung einer speziellen Immuntherapie ermoglicht werden.

Two patients with acute lymphocytic leukemia are described in whom G- and R-banding analysis revealed in bone marrow cells a translocation t (4; 11) (q21; q23). The clinical data are compared to the other four cases with t (4; 11) reported so far in the literature. The anomaly seems to be characteristic for ALL. In addition it appears to be associated with a very high number of circumlating blasts and other poor prognostic factors.

Two patients with extramedullary manifestation of the blastic phase of chronic myelocytic leukemia (CML) are reported. 100% of the metaphases derived from extranedullary sites were aneuploid. Despite the absence of blastic changes in the bone marrow and the peripheral blood, a significant proportion of the metaphases derived from these tissues also showed aneuploidy. It is suggested that maturation and differentiation of aneuploid myeloblasts are influenced by their environment.

Surface marker analyses and TdT assays were performed on cells from 31 patients. A variety of diagnoses were made and categorized as follows: acute leukemia (group I), non-Hodgkin lymphoma (group II) and diverse diagnoses (group III). Levels of TdT in the range from 0 to 7.9 U/mg lyophilized blasts from the peripheral blood were found in AL. This corresponds to 0-95 U/10(8) cells. Preparations of mononuclear cells from the peripheral blood of healthy donors showed TdT values up to 0.88 U/mg or 10.6 U/10(8) cells. High TdT activity was observed in a patient with AML, type M1 according to the FAB classification. In a patient with ALL (L1) cytostatic treatment effected the clearance of TdT activity from the peripheral blood cells and at the same time induced a significant increase of E rosette forming cells. Combined studies of the TdT activity and cell surface markers may enable us to define remissions and relapses of AL more precisely than it is possible by conventional cytological methods. Within the group II two patients with moderate TdT activities of 1.2 and 1.28 U/mg, respectively, were observed whose cells were of prolymphocytic or unclassifiable appearance, respectively. The TdT assay may be helpful to identify such cells of unknown origin and in addition may provide the means of discrimination between such cases and ALL patients who mostly show high TdT activities. Another result of our studies was the finding of moderate TdT activity of 1.2 U/mg with cells from the pleural effusion of a patient with Hodgkin's disease. Cells from malignant effusions from a patient with melanoma and a patient with teratoid carcinoma showed no TdT activity. Cells form the peripheral blood and from the bone marrow of a patient with blast crisis of CML showed TdT activity of 1.52 and 2.72 U/mg, respectively. Two other patients with blast crisis were negative. Not TdT activity was found in leukemic plasma cells. Our results show that lyophilized cells can be used for determinations of TdT activity. This greatly facilitates multi-parameter studies including cytological, cell surface marker and biochemical analyses.

62, chemotherapeutisch nicht vorbehandelte Patienten mit metastasierten Weichteilsarkomen wurden mit dem Cyvadic-Schema behandelt. Komplette Remissionen wurden bei 10 %, komplette plus partielle Remissionen bei 20 % der Patienten erreicht. Die mittlere Dauer der kompletten Remission betrug 25, der partiellen Remission 2,5 Monate. Die mittlere Uberlebenszeit der Patienten, die auf die Therapie ansprachen, lag bei 28 Monaten, bei den nicht-ansprechenden Patienten bei 14 Monaten. Die Chemotherapie mit Ifosfamid plus Cisplatin fuhrte bei 50 % der Patienten mit primarer oder sekundarer Cyvadic-Resistenz zu Remissionen.

Es wird erstmals uber die prospektive kontrollierte deutsche Studie zur Therapie der chronisch myeloischen Leukamie (CML) berichtet. Nach einer Laufzeit von 3 Jahren wurden bisher 188 von 300 vorgeseh

A patient with chronic myelocytic leukaemia positive for the Philadelphia (Ph-1) chromosome underwent splenectomy in the "terminal phase" of his disease. Chromosomal analysis of a marrow aspirate obtained during the operation showed nothing abnormal. Material from the spleen, however, showed the absence of a C chromosome and the presence of a "marker" chromosome in all metaphases examined. The patient did well for almost three years after splenectomy, and serial cytogenetic studies of marrow specimens showed the Ph-1 chromosome to be the only significant abnormality. Six months before death from recurrent blastic transformation aneuploidy was found in a marrow specimen. Subsequently additional abnormalities, including cells with two Ph-1 chromosomes, were detected. The karyotypic abnormalities found in the splenic specimen, however, never recurred.

Die randomisierte, multizentrische bundesdeutsche Studie 1982 zeigt nach TAD9-Induktion und Konsolidierung einen klaren, signifikanten Vorteil der Remissionsdauer und weniger ausgepragt auch des Uberl

In this article the three different manifestations of pulmonary aspergillosis are compared with each other: bronchopulmonary aspergillosis, aspergilloma and invasive pulmonary aspergillosis, and their different clinical and radiological manifestations. In particular, invasive pulmonary aspergillosis--being a severe complication in immunosuppressed patients whose defenses are weak--often presents diagnostic problems due to its initially mostly unspecific clinical and radiological signs. The late signs of a pulmonary aspergillus infection, such as formation of a cavern or the manifestation of the "air crescent" sign, however, are seen only when the patient is just beginning to convalesce.

Twenty-six bone marrow transplantations were performed at the West Germany Tumour Centre at Essen between December 1975 and December 1981. Three patients had aplastic anaemia, 23 acute leukaemia. Of the leukaemia patients 13 had a recurrence and ten were in full remission at the time of the transplantation. Two of the patients with a recurrence received deep-frozen autologous marrow from the remission phase. One patient with aplastic anaemia had an identical twin as donour, while all other patients received allogeneic marrow from histocompatible family members. Eleven patients are still alive, all three of those with aplastic anaemia, one of those with leukaemia in a recurrence, and seven of those with acute leukaemia in full remission. Two of the survivors have a chronic graft-host reaction, but the others are symptom-free, after an observation period of up to four years. Main causes of death were leukemic recurrence (6), infection (5), and graft-host reaction (2). It would seem that at present bone marrow transplantation offers the best chance of a cure for severe aplastic anaemic and acute leukaemia in adults, but only if transplantation is undertaken early and not in the end-stage of the disease.

The idea that earlier diagnosis leads to better prognosis is appealingly simple. This chapter concerns the extension of that idea to the routine periodic screening of large populations of persons without symptoms. To convert this idea into an effective large-scale programme is a complex organisational undertaking, for which the expected benefit should be reasonably clearly known before it is embarked upon.

We report on 32 patients with testicular tumor who--after earlier retroperitoneal lymph node dissection--underwent a second-look operation. Whereas in 16 patients vital tumor tissue was found in the retroperitoneum 9 patients had only degenerative changes with fibrosis and necrosis. In 7 patients the retroperitoneum showed no evidence of disease. It is our conclusion that an extensive pre-operative diagnostic workup, including tumor-markers, ultrasound and CT in patients treated with chemo- and radiotherapy cannot determine whether viable tumor tissue is present in the retroperitoneum. In 13 patients with non-seminomatous germinal cell tumors where viable tumor tissue was found at second-look operation 61,5% had normal tumor-markers. Those patients in whom at second-look operation no viable tumor tissue was found benefit from that approach because of the possibility of terminating aggressive chemotherapy. On the other hand patients with vital tumor tissue had a poor prognosis.

The current status of the prospective German multicenter study on the therapy of chronic myelogenous leukemia (CML) is reported. After three years 188 of the projected 300 patients have been randomized. The duration of the study will be 8 years. The clinical characteristics of the randomized patients correspond well to those reported in the literature. Risk factors are distributed equally in both arms. One problem is the relatively high drop-out rate of about 12% thus far. Survival curves for the two treatment arms will be presented, although at present the number of patients having reached the end of the chronic phase is too small to allow definitive evaluation.