Bendamustine, vincristine and prednisone (BOP) versus cyclophosphamide, vincristine and prednisone (COP) in advanced indolent non-Hodgkin's lymphoma and mantle cell lymphoma: results of a randomised phase III trial (OSHO# 19).

PURPOSE: The purpose of this study was to compare the efficacy and toxicity of bendamustine, vincristine + prednisone (BOP) with a standard regimen of cyclophosphamide, vincristine + prednisone (COP) in patients with previously untreated advanced indolent non-Hodgkin's lymphoma (NHL) and mantle cell lymphoma. METHODS: A total of 164 patients with follicular lymphoma (grade 1/2), mantle cell lymphoma or lymphoplasmacytic lymphoma (immunocytoma) was randomised to treatment with vincristine 2 mg (day 1) and prednisone 100 mg/m2 (days 1-5) + bendamustine 60 mg/m2 (days 1-5) or + cyclophosphamide 400 mg/m2 (days 1-5) for a total of eight 21-day cycles. RESULTS: The rate of complete remission was 22% with BOP and 20% with COP. The projected 5-year survival rate was 61% with BOP and 46% with COP. The BOP-associated 5-year survival advantage almost reached significance in the subgroup of patients who responded to therapy (74% vs. 56%; P = 0.05), and did reach significance in responders who did not receive interferon maintenance therapy (70% vs. 47%; P = 0.03). Toxicity was acceptable in both treatment groups, although alopecia and leucopenia were more severe with COP. CONCLUSIONS: Bendamustine can efficaciously and safely replace cyclophosphamide, as used in standard COP therapy, for the treatment of patients with indolent NHL and mantle cell lymphoma. Long-term survival data suggest a clinically significant benefit for patients treated with BOP.

A phase I trial of interferon alpha-2b with folinic acid and 5-fluorouracil administered by 4-hour infusion in metastatic colorectal carcinoma.

Preclinical data suggest that both folinic acid and interferon may enhance the efficacy of 5-fluorouracil (5-FU) in colorectal carcinoma. We therefore initiated a phase I trial evaluating the doses, safety, and pharmacokinetics of the combination of recombinant interferon (IFN) alpha-2b with folinic acid (FA) and 5-FU. Seventeen patients with colorectal cancer who failed local chemotherapy received 5-FU as a 4-hour infusion, preceded by a bolus of FA and IFN. The 5-FU dose was escalated over the range of 400 to 650 mg/m2/d for a period of 7 days. Folinic acid was administered as a bolus in a fixed dose of 200 mg/m2/d and IFN as 5 million U/d subcutaneously on days 1 to 7. A total of 89 courses of therapy were completed for the 17 patients, of which there were 10 paired courses with a combination of 5-FU and IFN or 5-FU alone, being performed to analyze the pharmacokinetics and modulation of 5-FU by IFN. The maximum tolerated dose of 5-FU using this combination and a 4-hour schedule was 600 mg/m2/d for 7 days. The dose-limiting toxicity of this regimen was diarrhea. Mucositis and myelosuppression was not a marked problem at dose levels of 400 and 500 mg/m2/d for 7 days. However, at a dose level of 600 to 650 mg/m2/d for 7 days, grade 3 and 4 (WHO) leukopenia occurred in 50% and mucositis occurred in 33%. At a given dose of 5 million U, IFN did not significantly influence 5-FU serum levels. Mean steady-state serum levels of 5-FU at 500 mg/m2 given as a 4-hour infusion were 16.55 +/- 9.34 mumol/L and 18.23 +/- 12.77 mumol/L with and without IFN, respectively. Mean area under the curve (mumol/L x min) was 4,008 +/- 2,133 and 5,114 +/- 2,567 with and without interferon, respectively. Objective responses were seen in one of 17 of these heavily pretreated patients and stable disease was seen in seven of 17 patients. The recommended dose of 5-FU for use of phase II studies is 500 mg/m2/d for 7 days. We conclude that the toxicity of 5-FU plus FA with and without IFN alpha-2b can be reduced by using a 4-hour infusion instead of a bolus.

A phase II trial of interferon alpha-2b with folinic acid and 5-fluorouracil administered by 4-hour infusion in metastatic colorectal carcinoma.

Preclinical data suggest that folinic acid as well as interferon alpha-2b may enhance the antitumor activity of 5-fluorouracil (5-FU). In a phase I trial, we recently showed that interferon alpha-2b (IFN), folinic acid and 5-FU can be safely administered with a 4-hour infusion of 5-FU. We therefore initiated a phase II trial evaluating the efficacy and safety of these three drugs. Forty-five evaluable patients with advanced metastatic colorectal cancer, documented progressive disease, and previously unexposed to chemotherapy were treated with sequential IFN 5 MU/d subcutaneously and folinic acid 200 mg/m2/d as bolus on days 1 to 7 followed by 5-FU in a 4-hour infusion at a dose of 500 mg/m2/d, resulting in a total dose of 3,500 mg/m2/course. This schedule was repeated on day 21. A total of 204 courses of therapy were completed. One of 45 patients (2%) achieved a complete response, and 13 of 45 patients (29%) achieved a partial response. An additional 16 patients (36%) had stable disease. The median time to disease progression was seven months (2 to 24 months). Despite the relatively high-dose intensity of 5-FU, toxicity was very mild. Grade 3 or 4 myelosuppression, stomatitis, and nausea/vomiting occurred in only three of 45 patients (7%). Four of 45 patients (9%) suffered from severe (grade 3/4) diarrhea. Neurotoxicity and infections of grade 2 to 4 did not occur. From these data we conclude that modulation of 5-FU with both folinic acid and IFN induces an overall response rate of 31% in disseminated colorectal cancer. Using a 4-hour application schedule of 5-FU, the therapeutic index can be improved even for high-dose intensity and requires further evaluation in combination with other modulators.

Tolerance, safety, and kinetics of the new antineoplastic compound dexniguldipine-HCl after oral administration: a phase I dose-escalation trial.

Dexniguldipine-HCl is a new dihydropyridine compound that exerts selective antiproliferative activity in a variety of tumor models and, in addition, has a high potency in overcoming multidrug resistance. The purpose of this trial was to determine the toxicity and pharmacokinetics of dexniguldipine and to establish a recommended dose for phase II trials. A total of 37 patients with cancer were treated with oral dexniguldipine in increasing doses for up to 7 days. The main parameters evaluated were subjective tolerance and laboratory and cardiovascular parameters (blood pressure and ECG). Blood samples were drawn for analysis of the drug's pharmacokinetics. Dizziness and nausea were the major adverse events observed in seven patients, but episodes were generally mild and not clearly dose-related. Vomiting occurred in one patient. Hypotensive effects and orthostatic dysregulation were observed in some patients but were not considered to be dose-limiting. Therefore, no dose-limiting toxicity was found and the maximally tolerable dose could not be determined. Pharmacokinetic data showed wide interindividual variation and a dose-dependent increase in steady-state serum concentrations at doses of up to 1,000 mg daily, with no clear further increase being observed at higher doses. Consistently high concentrations were achieved with the 2,500-mg dose. Despite the lack of dose-limiting toxicity, higher doses of dexniguldipine do not appear to be useful for clinical evaluation because of the pharmacokinetic properties of the compound: therefore, 2,500 mg/day is recommended as the daily dose for phase II trials.

Bone marrow disturbances of iron utilisation: cytomorphological diagnostic in chronic alcohol abuse.

45 consecutive patients with chronic alcohol abuse up to the day before admission were examined to determine to what extent the investigation of bone marrow smears is suitable for recording the abuse of alcohol and for monitoring the abstinence from alcohol. Using Prussian blue staining, disturbances of iron utilisation subdivided into four degrees of seriousness were detected in 91% (41 out of 45) of subjects, whereas abnormal vacuolisation of red and/or white precursors occurred in only 38% and megaloblastic marrow in 27% of patients, respectively (p less than 0.005). Abstaining from alcohol caused a significant decrease of sideroachrestic signs (p less than 0.005) within a few days.

[Cancerogenic effect of long-term benzene exposure. Occurrence at the same work place of a plasmacytoma and two solid carcinomas ]. / Zur kanzerogenen Wirkung langjähriger Benzenexposition. Aufreten eines Plasmozytoms und zweier solider Malignome an ein und demselben Arbeitsplatz.

A report is given on three different malignomas appearing after high inhalative exposure to benzene for many years at the same working place in a cable plant. The exposure to benzene amounted to 22 years in a 50 year old man with oesophagus carcinoma, 17 years in a 61 year old man with plasmocytoma and 10 years in a 45 year old man with embryonal carcinoma of the testicles. The malignomas appeared 5-7 years after the end of the exposure. The carcinogenity of benzene is discussed on the basis of a survey of medical literature on epidemiological studies, casuistic contributions and experimental investigations in animals. A direct and indirect mechanism of benzene inducing carcinogenity is discussed: Activation of normal cellular oncogenes in DNA molecules by changes directly caused by benzene and; Damage of the lymphatic cell particularly susceptible to benzene followed by a disturbance of immunological monitoring and defence reactions against tumour cells.

[Disturbances in iron utilization in acute leukemia and preleukemia]. / Eisenverwertungsstörungen bei akuter Leukämie und Präleukämie.

With Prussian blue reaction nonhaemoglobin iron in the erythroblasts is demonstrable. Three pathological sideroblast types are recorded separately: abnormal intermediate type I and II sideroblasts and ring sideroblasts, representing increasing levels of sideroachrestic disturbance. This permits the classification of sideroachrestic disturbances into four degrees of seriousness. The frequency of a sideroachrestic disturbance in 47 untreated patients with acute myeloid leukaemia was 87%. Among 11 patients with preleukaemic condition, 8 had a disturbance of iron utilisation. In both preleukaemia and leukaemia mainly intermediate sideroblasts were present. All patients with preleukaemia developed leukaemia within 1-20 months. In the course of preleukaemic condition a slight increase of iron misutilisation was obvious when terminating in overt leukaemia. This could be of prognostic importance. After treatment, pathological sideroblasts disappeared only in 2 out of 15 patients with complete remission. There was no correlation between effect of therapy and course of iron misutilisation.

[Cytomorphologic diagnosis of iron utilization disturbance in chronic alcohol abuse]. / Zytomorphologische Diagnostik der Eisenverwertungsstörung bei chronischem Alkoholmissbrauch.

45 consecutive patients with chronic alcohol abuse up to the day before admission were examined to determine to what extent the bone marrow smear can be used to detect alcohol abuse and to monitor abstinence. Bone marrow aspiration was performed within the first three days of admission and repeated an average of two weeks later in 35 patients. Using Prussian Blue staining, disturbances of iron utilization presented the most striking hematologic finding and were detected in 91% (41/45) of subjects. By contrast, both abnormal vacuolization of red and/or white cell precursors (in 38%) and megaloblastic marrow (in 27%) of patients respectively occurred significantly less often (p less than 0.005). However, if iron stores were fully depleted no sideroblasts were detectable. Obviously, iron deficiency limited the development both of normal and pathological sideroblasts. Sideroachrestic disturbances were divided into four degrees of severity according to frequency and types of sideroblasts. 3 pathological types of sideroblasts were differentiated: two forms of abnormal intermediate sideroblasts and ring sideroblasts, representing an increasing degree of sideroachrestic disturbance. The intermediate types were much more common than the ringed forms and therefore claim full attention. Abstinence from alcohol caused a highly significant decrease in sideroachrestic signs, as shown by the sideroblast score (p less than 0.005), which largely returned to normal in the period of examination. On the other hand, no significant decrease in the control value of the sideroblast score was observed in the patients which did not abstain from alcohol.

[Hemorrhagic diathesis as a rare lead symptom in Addison-Biermer's anemia]. / Hämorrhagische Diathese als seltenes Leitsymptom beim Morbus Addison-Biermer.

It is reported on a patient with Addison-Biermer's disease who was admitted to hospital under the diagnosis of a bleeding ventricle ulcer and in whom was detected a thrombocytopenic haemorrhagic diathesis. By means of injections of vitamin B12 a complete haematologic remission was achieved. The absence of a clear increase of reticulocytes as a sequel of the blood transfusions performed before the specific therapy is discussed.

[Influence of the reticulocyte crisis in the healing phase of megaloblastic anemias following transfusion]. / Beeinflussung der Retikulozytenkrise in der Heilungsphase megaloblastärer Anämien nach vorausgegangener Auftransfundierung.

The numerical behaviour of the leucocytes, thrombocytes and reticulocytes of 12 patients with megaloblastic anaemia before and after additional transfusion as well as after following parenteral therapy with vitamin B12 was investigated. Transfusions alone had no influence on the numbers of leukocytes thrombocytes and reticulocytes. After 4--5 days vitamin B12 led to a very inhibited crisis of reticulocytes in 9 of the 12 patients, in the others an increase did not take place. Thrombocytes and leukocytes appeared partly in form of a crisis in all patients after 6 to 9 days with normalisation of the values, latest after 14 days. The very reduced or lacking crisis of reticulocytes after treatment with vitamin B12 due to previous additional transfusion was discussed.

[Detection of alcohol abuse and monitoring of alcoholic abstinence using sideroblastic index and gamma-glutamyltransferase]. / Erfassung von Alkoholmissbrauch und Monitoring der Alkoholabstinenz mittels Sideroblastenindex und Gamma-Glutamyltransferase.

45 hospitalised patients with chronic alcohol abuse observed immediately until that time preceding hospitalisation were examined with the aim of finding out whether examinations of the bone-marrow and gamma-glutamyltransferase (GGT) i.s. may be used for recording the consumption of alcohol and for monitoring the abstinence from alcohol. Bone-marrow puncture was made within 3 days after hospitalisation and was repeated at n = 35 after two weeks on an average. Simultaneously, GGT was determined. Disturbances of iron utilization, which were divided according to frequency and kind of sideroblasts into 4 degrees of seriousness, represented by far the most constant hematological findings. An sideroblastic+ index (SI) was counted, which, in addition to the count of sideroblasts, takes into account even qualitative disturbances. The sideroblastic+ index was increased in 91% (41/45) of patients irrespective of the presence or extent of an anemia so far as iron stores had not been completely depleted because of bleedings. In 71% (32/45) of the patients, gamma-glutamyltransferase (GGT) remained within the pathological range, thus lying significantly (p less than 0.05) below the sensitivity of the sideroblastic index (SI). By taking the increase of SI or GGT as a basis, the rate of recording alcoholics could be improved to 98% (44/45). Abstaining from alcohol caused a highly significant decrease of SI and GGT (p less than 0.005). Thereby, the sideroblasts index predominantly normalised in the period of examination, whereas gamma-glutamyltransferase fell below the pathological range only by way of exception. No significant decrease in the control value of SI and GGT was observed in those patients who did not abstain from alcohol. In comparing the differences of average values between abstaining and non-abstaining persons only SI revealed significant differences (p less than 0.005). SI and GGT complement each other in the control function of drinking behaviour. Under the given circumstances a simultaneous examination enables alcohol abuse to be recorded with nearly 100% of probability. SI is more sensitive and is able to differentiate more clearly between abstaining and non-abstaining. Due to its slower response GGT can indicate former alcohol abuse over a longer period. Concerning doubtful or potentially hepatotoxic+ substances at places of work, the sideroblastic+ index could provide an essential aid in deciding whether alcohol is a disturbing factor.

[Treatment of non-seminomatous testicular tumors in combination with vinblastine/bleomycin and adriamycin/cisplatin]. / Behandlung nichtseminomatöser Hodentumoren mit einer Kombination von Vinblastin/Bleomycin und Adriamycin/Cisplatin.

Following orchiectomy and retroperitoneal lymph node dissection (RND) 11 patients with non-seminomatous testicular cancer were treated alternately with combination chemotherapy consisting of vinblastine/bleomycin and adriamycin/cis-dichlorodiammineplatinum (II) (DDP). A total of 39 course of vinblastine/bleomycin and 36 course of adriamycin/DDP were administered. The two patients with disseminated testicular cancer came into complete and partial remission respectively. 1 patient with stage N3 and minor residual disease after RND, 7 patients with stages N1-2 and complete RND and 1 patient with stage N0, but chorio-carcinomatous portions in the testicular tumour show not sign of recidivation at present. The period of observation after orchiectomy ranges from 4 to 21 months, the median being 13 months. The side effects of chemotherapy are discussed in detail and both combinations are judged to be aggressive. The avoidance of DDP-nephrotoxicity by forced diuresis and the distinct and rapidly beginning intensification of the effect of phenprocoumon due to both regimens are stressed.

Epidemiological study on the hepatotoxicity of occupational toluene exposure.

In a cross-sectional study of 181 male workers of a rotogravure printing plant, most of whom were exposed to toluene levels well above the GDR threshold limit values, 55 subjects revealed pathological liver screening values (activities of serum aspartate aminotransferase, alanine aminotransferase, gamma glutamyltransferase; liver size). The differential diagnostic examination showed in 51 out of these 55 subjects an association with competing factors such as alcohol abuse (78%) and overweight (40%), to a slight extent disorders of fat and carbohydrate metabolism and of the gallbladder. Drug intake did not play any role. The variance and regression analyses of the biochemical data have shown that alcohol significantly and considerably increases the activities of all three enzymes tested. Bodyweight had a similar, but less pronounced, significant effect. On the other hand, in subjects with a higher alcohol intake the activities of liver enzymes in highly toluene exposed subgroups were significantly and clearly lower than among slightly toluene exposed workers.

[Tumor marker diagnosis in non-seminomatous testicular tumors using human chorionic gonadotropin (HCG) and alpha fetoprotein (AFP)]. / Tumormarkerdiagnostik bei nicht-seminomatösen Hodentumoren mittels Humanchoriongonadotropin (HCG) und Alpha-Fetoprotein (AFP).

In 28 patients with non-seminomatous testicle tumour the tumour markers human chorionic gonadotropin (HCG) and alpha-fetoprotein (AFP) were determined radioimmunologically and enzymeimmunologically, respectively. While tumours with chorionic carcinoma (n = 8) always were marker-positive, in the embryonic carcinoma in 2 out of 10 cases falsely negative findings appeared. On 5 patients the biochemical monitoring of the course of the testicle tumour disease is demonstrated in detail by means of HCG and AFP and estimated as very helpful method. Advantages and problems of the marker diagnostics are shown and discussed. The positive marker findings were absolutely evident for a metastasation. On the other hand, marker negativation was not always to be equated with absence of a tumour and demanded a further control of the patient by means of all other available methods of diagnostics up to the second-look-operation.