K. H. Pflüger

Alternating versus sequential chemotherapy in small cell lung cancer. A randomized german multicenter trial

A total of 306 patients with small cell lung cancer (SCLC) were randomized to receive chemotherapy in a sequential or alternating mode. Sequential chemotherapy consisted of eight cycles of cyclophosphamide, Adriamycin (doxorubicin), and vincristine (CAV) and alternating chemotherapy consisted of three cycles (1, 3, 5) of etoposide, vindesine, and ifosfamide (EVI); three cycles (2, 4, 6) of cisplatin, Adriamycin, and vincristine (PAV); and two cycles (7, 8) of cyclophosphamide, methotrexate, and CCNU (CMC). Responsive patients received prophylactic cranial irradiation after three cycles and chest irradiation after eight cycles of chemotherapy. No maintenance therapy was applied to patients achieving complete remission. Minimum follow‐up was 2 years. Of the 302 patients evaluable, overall response rate was 59% in the sequential arm and 70% in the alternating arm. Patients treated with CAV had a complete response rate of 21% in contrast to 36% for those receiving alternating therapy. The median survival for all patients was 9.8 versus 11.3 months, for limited disease 11.1 versus 13.4 months, and for extensive disease 8.9 versus 9.9 months, all in favor of the alternating treatment. Two‐year survival rate for all patients was 6% versus 9%, for limited disease 11% versus 14%, and for extensive disease 3% versus 6%, all preferring the alternating treatment mode. Progression‐free survival demonstrated a strong correlation to the extent of response irrespective of the treatment regimen applied. Toxicity included 11 lethal and 8 life‐threatening complications with a higher frequency in the alternating treatment arm. These results suggest that alternating treatment of SCLC with different drug combinations is more effective than sequential application of CAV. Cancer 59:1072‐1082, 1987.

Pharmacokinetics of etoposide: correlation of pharmacokinetic parameters with clinical conditions

SummaryThe pharmacokinetic parameters of etoposide were established in 35 patients receiving the drug parenterally within the framework of different polychemotherapy protocols. A total of 62 data for 24-h kinetics were analysed. After sample extraction and high-performance liquid chromatography (HPLC) or thin-layer cromatographic (TLC) separation, etoposide was measured by means of [252Cf]-plasma desorption mass spectrometry (PDMS). This highly specific detection system proved to be very practicable and reproducible. The present study comprised two parts that were absolutely comparable in terms of clinical and pharmacokinetic parameters. In part II of the study, sensitivity was improved by modifying the analytical technique. After the exclusion of patients who had previously been given cisplatin or who exhibited renal impairment and of one patient who showed extremely high levels of alkaline phosphatase, γ-GT and SGPT, the mean values calculated for the pharmacokinetic parameters evaluated were: beta-elimination half-life (t1/2β), 4.9±1.2 h; mean residence time (MRT), 6.7±1.4 h; area under the concentration-time curve (AUC), 5.43±1.74 mg min ml−1; volume of distribution at steady state (Vdss), 6.8±2.7 l/m2; and clearance (Cl), 18.8±5.3 ml min−1 m−2. The pharmacokinetic parameters were correlated with 12 different demographic or biochemical conditions. Impaired renal function, previous application of cisplatin and the age of patients were found to influence etoposide disposition to a statistically significant extent. We suggest that the dose of etoposide should be reduced in elderly patients and/or in individuals with impaired renal function, especially in those exhibiting general risk factors such as reduced liver function with regard to the polychemotherapy.

Pharmacokinetics of high-dose etoposide after short-term infusion

SummaryThe pharmacokinetics of high-dose etoposide (total dose, 2100 mg/m2 divided into three doses given as 30-min infusions on 3 consecutive days) were studied in ten patients receiving high-dose combination chemotherapy followed by autologous bone marrow transplantation. In addition to etoposide, all subjects received 2×60 mg/kg cyclophosphamide and either 6×1,000 mg/m2 cytosine arabinoside (ara-C), 300 mg/m2 carmustine (BCNU), or 1,200 mg/m2 carboplatin. Plasma etoposide concentrations were determined by252Cf plasma desorption mass spectrometry. In all, 27 measurements of kinetics in 10 patients were analyzed. According to graphic analysis, the plasma concentration versus time data for all postinfusion plasma ctoposide values were fitted to a biexponential equation. The mean values for the calculated pharmacokinetic parameters were:t1/2β, 256±38 min; mean residence time (MRT), 346±47 min; AUC, 4,972±629μg min ml−1 (normalized to a dose of 100 mg/m2); volume of distribution at steady state (Vdss), 6.6±1.2l/m2; and clearance (CL), 20.4±2.4 ml min−1 m−2. A comparison of these values with standard-dose etoposide pharmacokinetics revealed that the distribution and elimination processes were not influenced by the dose over the range tested (70–700 mg/m2). Also, the coadministration of carboplatin did not lead to significant pharmacokinetic alterations. Although plasma etoposide concentrations at the time of bone marrow reinfusion (generally at 30 h after the last etoposide infusion) ranged between 0.57 and 2.39 μg/ml, all patients exhibited undelayed hematopoietic reconstitution.

Altered expression of the human retinoblastoma gene in monocytic leukaemias

Summary. Inactivation of the retinoblastoma growth suppressor gene (RB) is responsible for the development of retinoblastomas and occurs frequently in osteosarcomas and small cell lung carcinoma. Knowledge about the involvement of RB in the pathogenesis of myeloid leukaemias is still scarce. In this study we looked at the expression of the retinoblastoma gene product (p105) in 20 primary myelomonocytic and monoblastic leukaemias by Western blotting and immunocytochemistry using the anti‐p105‐monoclonal antibody PMG3‐245. We found absence of or barely detectable levels of p105 in 11 patients (55%). Absence of or low levels of p105 were correlated with a higher leucocyte count at presentation (133 × 109/l v 83 × 109/l) and with the occurrence of extramedullary leukaemia (8/10 v 2/10). We conclude that abnormal expression of RB with absence of p105 or strongly reduced p105 levels occurs frequently in myelomonocytic and monoblastic leukaemias and that this may be correlated with a more malignant course of the disease.

Drug monitoring of etoposide (VP16-213)

SummaryDrug monitoring is performed by means of sample extraction, sample purification by high-performance liquid chromatography (HPLC), and sample detection by time-of-flight mass spectrometry. This mass spectrometry utilizing 252Cf fission fragment-induced ionization and desorption of nonvolatile compounds is suitable as a universal, nondestructive detector in HPLC. Liquid chromatography and mass spectrometry are combined, so that mass analysis can be operated online and offline to the fractional sampling of the effluent and the samples can still be recovered.As an alternative to HPLC separation, samples can be purified by thin-layer chromatography (TLC), resulting an offline TLC + MS combination. Preliminary pharmacokinetic data for etoposide (VP16-213) together with calibration data are presented, and are discussed with reference to the sensitivity and detection limit of the new experimental methods.

Hematopoietic reconstitution after high-dose chemotherapy and autologous nonfrozen bone marrow rescue

SummaryThe kinetics of marrow engraftment were analyzed in 50 patient with acute leukemia (21), malignant lymphoma (15), and solid tumors (14) after high-dose multiagent chemotherapy followed by autologous bone marrow transplantation (ABMT) with nonfrozen bone marrow. Unseparated heparinized whole bone marrow was stored in 10% CPDA1 at 4°C for 72 h, then filtered and reinfused. The median number of nucleated cells reinfused was 1.6×108/kg (range 0.5–3.8×108/kg). All patients had a full hematopoietic reconstitution. Median time to achieve a neutrophil count > 500/μl was 20 days (range 12–39) and median time to achieve an unsupported platelet count > 20.000/μl was 20 days (range 10–55). The main factor associated with delayed engraftment was the number of prior chemotherapy cycles. We conclude that high-dose chemotherapy with nonfrozen ABMT is a safe procedure, without the requirement for costly cryopreservation facilities.

Successful treatment of neutropenia in T-LGL leukemia (Tγ-lymphocytosis) with granulocyte colony-stimulating factor

SummarySevere neutropenia is a common feature in patients with T-large granular lymphocytic (LGL) leukemia. Neutropenia often causes severe infections and septicemia, thus representing a major cause of morbidity and mortality in this disease. We have treated two outpatients with T-LGL leukemia who had severe neutropenia (neutrophils <0.2×109/l) successfully with G-CSF (5μg/kg daily, s.c). After 10 days of treatment the neutrophil count was within the normal range and a severe oral infection healed rapidly. We conclude that G-CSF therapy is able to normalize the neutrophil count in T-LGL leukemia within a few days and that it can be used to treat severe infections in these patients even on an outpatient basis.

Myeloperoxidase deficiency: An epidemiological study and flow-cytometric detection of other granular enzymes in myeloperoxidase-deficient subjects

SummaryMPO deficiency, as first studied in the 1960s, has been recorded with increasing frequency, following the introduction of the automated cytochemical count into clinical routine. However, with regard to the diseases correlated to MPO deficiency, no exact data on the frequency of co-existance have been recorded. Moreover, the question remains whether or not a further deficiency of other granular enzymes co-exists, especially with regard to acquired MPO deficiency. In order to answer these questions, an epidemiological study of more than 70000 unselected patients was performed; the resulting prevalence of MPO deficiency was 0.15%. Within this patient group the intercellular content of elastase-like protease (ELP) and lactoferrin was measured semiquantitatively in a flow cytometer by means of indirect immunofluorescence staining. The frequency of coinciding diseases did not differ from the frequency of diaseases in the hospital patients in general. The flow-cytometric studies revealed a normal content of ELP and lactoferrin in one group and a reduced content in another, suggesting the inherited form in the former and acquired MPO deficiencies in the latter group and thus indicating that differing mechanisms characterize the two forms of MPO deficiency. Nevertheless, we do not suggest distinguishing between acquired and inherited deficiencies solely with this technique. Instead, molecular-biologic and/or genetic methods should be referred to.

GM-CSF Versus G-CSF in the treatment of infectious complication in Felty's syndrome — a case report

Feltys syndrome, consisting of the triad of rheumatoid arthritis, splenomegaly, and neutropenia, is a rare complication of rheumatoid disease that predisposes individuals to recurrent bacterial infections [2]. As treatment strategy is not yet conclusively standardized [1], we treated a patient with an infectious complication of Feltys syndrome with human recombinant GM-CSF and ! year later, because of another severe infection, with human recombinant G-CSF. The 66-year-old male farmer with known Feltys syndrome presented with cervical abscess formation. After conservative treatment of the abscesses in the Ear, Nose and Throat department parenteral antibiotic treatment (Cefuroxim, Imipenem) was started but failed to show clinical effect. After 13 days of therapy recombinant GM-CSF (6.85 pg/kg per day s.c.) was administered. During treatment with GM-CSF the patient recovered,

Multiple myeloma of the bladder and vagina

A case is described of multiple myeloma with involvement of the urinary bladder and vagina. The patient was admitted with hematuria and postrenal obstruction. She was treated successfully with local radiotherapy and combination chemotherapy with vincristine, Adriamycin (doxorubicin), and dexamethasone (VAD).