Chemotherapy of the ovarian carcinoma (author's transl)]

Ovarian carcinomas are highly sensitive to chemotherapy. The alkylating agents were most extensively investigated. With these drugs remissions can be obtained in about 50% of the patients. Some early results seem to show a higher response rate and a longer duration of remission after combination chemotherapy. In ovarian carcinoma it has to be the aim of the chemotherapy to obtain a complete remission. The indications for chemotherapy are not yet well defined. Treatment is definitely indicated in stage IV (FIGO) or in recurrent disease after radiotherapy. This treatment has to be given as a long-term therapy over a long period of time. In stage III and II b disease a combined treatment plan has to be developed by the radio- and chemotherapist. At the present time no data are available which prove or disprove the value of an adjuvant chemotherapy in the early stages of ovarian carcinoma. Remembering the somewhat promising results of adjuvant chemotherapy in breast cancer, it is conceivable that prophylactic chemotherapy will prove to be indicated in early stages of ovarian carcinoma.     

Population pharmacokinetics/toxicodynamics (PK/TD) relationship of SAM486A in phase I studies in patients with advanced cancers

SAM486A (previously termed CGP 48664), a potent inhibitor of S-adenosylmethionine decarboxylase, is under clinical development for the treatment of advanced refractory malignancies. Hematological toxicity manifested by dose-dependent neutropenia has been observed in phase I studies. Population methods were used to investigate pharmacokinetics (PK) as a prognostic factor for safety end point (hematological toxicity) in patients with advanced cancers. SAM486A plasma concentrations and neutrophil counts were collected from three ascending-dose tolerability and PK studies (study 1: single 5-day continuous intravenous (IV) infusion with doses ranging from 24-700 mg/m2/cycle; study 2: 10-minute to 3-hour IV infusion once weekly with doses ranging from 16-325 mg/m2/week; study 3: 1-hour IV infusion once daily for 5 days with doses ranging from 3.6-202.8 mg/m2/day). The PK of SAM486A were best estimated by a population linear three-compartment model with NONMEM (version 5) using data from 9 patients in studies 1 through 3. The population pharmacokinetic parameters (SD) were CL = 6.2 (0.4) l/h/m2, Q2 = 15.4 (1.5) l/h/m2, Q3 = 33.6 (5.3) l/h/m2, V1 = 9.5 (1.6) l/m2, V2 = 672 (52) l/m2, and V3 = 39.9 (8.3) l/m2, and the corresponding intersubject variability was 45.4%, 74.0%, 85.3%, 80.1%, 37.0%, and 103%, respectively, where CL is total body clearance, Q2 and Q3 are intercompartmental clearances, and V1, V2, and V3 are the volumes of distribution in central and peripheral compartments, respectively. The intrasubject variability was 24.0%. The cumulative AUC before the onset of neutrophil nadir count (AUC) and the duration of exposure over threshold SAM486A concentrations in the range of 0.05 to 0.1 microM based on Bayesian PK parameter estimates significantly correlated with absolute neutrophil count nadir (< 5 x 10(9)/l). AUC showed the best correlation (R2 = 0.72) with absolute neutrophil count nadir by an inhibitory sigmoid Emax model and also correlated with percent decrease in neutrophil count from baseline to nadir by a simple Emax model (R2 = 0.53). Logistic regression analysis indicated that AUC and the duration of exposure over 0.05 to 0.1 microM, but not Cmax, were strong predictors of grade 4 neutropenia (< 0.5 x 10(9)/l). Drug exposure parameters such as AUC derived from population analysis may be used clinically as a useful predictor of drug-induced neutropenia.     

Phase I and pharmacokinetic study of CCI-779, a novel cytostatic cell-cycle inhibitor, in combination with 5-fluorouracil and leucovorin in patients with advanced solid tumors.

BACKGROUND: CCI-779 is a novel ester of the immunosuppressive agent sirolimus that exerts cytostatic effects by the inhibition of the translation of cell-cycle regulatory proteins. We investigated the maximum tolerated dose (MTD) and pharmacokinetics (PK) of CCI-779 in combination with leucovorin (LV) and 5-fluorouracil (5-FU) in patients with advanced solid tumors. PATIENTS AND METHODS: Patients were treated with LV at 200 mg/m(2) as a 1-h i.v. infusion directly followed by continuous 24-h i.v. infusion of 5-FU, in the first patient at 2000 mg/m(2) and in subsequent patients at 2600 mg/m(2). CCI-779 was administered directly prior to LV as a 30-min i.v. infusion at a starting dose of 15 mg/m(2) beginning at day 8 and escalated in subsequent cohorts of patients. One cycle consisted of six weekly administrations followed by 1 week of rest. Blood samples were drawn to assess PK of CCI-779 as well as its effect on steady-state 5-FU exposures. RESULTS: Twenty-eight patients entered the study, the majority having tumor types for which 5-FU is used as a treatment. CCI-779 doses of 15, 25, 45 and 75 mg/m(2) were investigated. Skin toxicity (rash) was prominent at all dose levels examined. Stomatitis was the dose-limiting toxicity (DLT) for 75 mg/m(2) doses of CCI-779. Subsequently the cohort at 45 mg/m(2) was expanded to a total of 15 patients, and at this dose level two treatment-related deaths occurred due to mucositis with bowel perforation. Based on the toxicities observed, it was decided to discontinue the study. Partial responses were observed in three patients with gastrointestinal tumors. No pharmacokinetic interaction between CCI-779 and 5-FU was observed. CONCLUSIONS: The safety profiles of CCI-779 and 5-FU/LV suggest an overlap of drug-related toxicities, and the administration of these drugs at these doses and schedule resulted in unacceptable toxicity and therefore cannot be recommended. If CCI-779 is to be used in combination with 5-FU/LV, other doses or schedules of administration will need to be explored.     

Moderate Dose Escalation for Advanced Stage Hodgkin's Disease Using the Bleomycin, Etoposide, Adriamycin, Cyclophosphamide, Vincristine, Procarbazine, and Prednisone Scheme and Adjuvant Radiotherapy: A Study of the German Hodgkin's Lymphoma Study Group

The BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide,vincristine, procarbazine, and prednisone) regimen, a rearranged andaccelerated version of the standard COPP/adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy, has beenshown to be effective and safe in a previous pilot study for advanced stage Hodgkin's disease (HD). The present study aimed to determine amaximum practicable dose of three drugs, ie, etoposide, adriamycin, andcyclophosphamide, for which acute toxicities were acceptable and toassess the feasibility of the escalated scheme. Sixty untreated patients with advanced stage HD were enrolled in this study.Radiotherapy was given in 44 patients (73%) after chemotherapy toinitial bulk lesions and residual disease. Granulocyte-colonystimulating factor (G-CSF) was given from day 8 to prevent prolongedneutrocytopenia and severe infections. The intended doses ofadriamycin, etoposide, and cyclophosphamide in the BEACOPP schedulecould be substantially escalated: adriamycin from 25 to 35, cyclophosphamide from 650 to 1,200, and etoposide from 100 to 200 mg/m². The major toxicities were leukocytopenia andthrombocytopenia with considerable heterogeneity between individualpatients. Of 60 patients, 56 (93%) achieved a complete remission (CR).At a median observation of 32 months, the rates of survival and freedom from treatment failure (FFTF) were estimated to be 91% (95%confidence interval 83% to 99%) and 90% (82% to 98%). Theseresults show that a moderate dose escalation of adriamycin,cyclophosphamide, and etoposide of the baseline BEACOPP regimen isfeasible. The escalated BEACOPP regimen shows very encouraging resultsin advanced stage HD and is now being compared in a randomized phaseIII study with BEACOPP at baseline dose level.     

T and B lymphocytes in Hodgkin's disease

Summary Phytohemagglutinin stimulation of peripheral lymphocytes from 54 patients with Hodgkin's disease and 40 normal blood donors was studied as a parameter for T-cell function. Lymphocytes carrying immunoglobulin determinants (B-cells) in peripheral blood from 67 patients with H. D. and normal blood donors were quantitated by membrane immunofluorescence. PHA stimulation was severely depressed in 48 patients with H. D. as compared to the controls. There was no correlation to clinical stage or histological type. Distribution of B-cells in the normal blood donors was 33% (S. D. ± 4) the mean value in all patients with H. D. was 27% (S. D. ± 12). No specific pattern of distribution of B-cells could be found when the data were analysed for clinical stage (stage I 36.50%±14.47, stage II 26.21%±9.63, stage III 25.77%±12.18, stage IV 25.59%±13.18), histological subtype (lymphocytic predominance 25.84%±13.88, nodular sclerosis 25.58%±11.53, mixed cellularity 29.80%±11.35, lymphocytic depletion 28.00%±13.06) or age. Since no change in the relative distribution of B- and T-cells could be found it is concluded that the disturbance in cellular immunity in these patients is caused by a functional defect of the T-cells rather than a decrease in their number.

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Zusammenfassung Bei 54 Patienten mit Morbus Hodgkin und 40 normalen Blutspendern wurde die Phytohämagglutininstimulierbarkeit peripherer Lymphocyten als Parameter für die T-Zellfunktion untersucht. Bei 67 Patienten mit Morbus Hodgkin und den normalen Blutspendern wurden die Immunglobulindetenninanten auf der Oberfläche peripherer Lymphocyten mit Hilfe der Membranimmunfluorescenz (B-Zellparameter) bestimmt. Bei 48 Patienten mit Morbus Hodgkin war die PHA-Stimulierbarkeit im Vergleich zu den Kontrollpersonen stark erniedrigt. Eine Korrelation zu klinischem Stadium oder histologischem Untertyp konnte nicht gefunden werden. Der Anteil von B-Zellen bei den normalen Blutspendern betrug 33% (S. D. ± 4), der Mittelwert bei allen Patienten mit Morbus Hodgkin 27% (S. D. ± 12). Es konnte kein spezifisches Verteilungsmuster für B-Zellen gefunden werden, wenn man die Ergebnisse nach klinischem Stadium (Stadium I 36,50%±14,47, Stadium II 26,21%±9,63, Stadium III 25,77%±12,18, Stadium IV 25,59%±13,18), dem histologischen Untertyp (lymphocytäre Prädominanz 25,84%±13,88, Noduläre Sklerose 25,58%±11,53, Mischzellform 29,80%±11,35, lymphocytäre Depletion 28,00%±13,06) oder nach Alter aufgliedert. Signifikante Veränderungen in der relativen Verteilung von B- und T-Zellen im peripheren Blut bei Patienten mit Morbus Hodgkin konnten nicht gefunden werden. Der Schluß liegt nahe, daß die bekannten Störungen der cellulären Immunität bei Patienten mit Morbus Hodgkin durch einen funktioneilen Defekt der T-Zellen und nicht durch eine T-Zellverarmung verursacht werden.

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Mit Unterstützung des Landesamtes für Forschung, NRW und der Deutschen Forschungsgemeinschaft.     

Epirubicin in colorectal cancer

Summary Epirubicin, a stereoisomer of doxorubicin with suggested lower potential for cardiotoxicity in experimental animal tumor systems, was studied in a disease-oriented phase II trial in patients with advanced colorectal cancer. The drug was given as a direct iv injection of 90 mg/m² q 3 weeks. No objective response was observed in 52 evaluable patients with colon (n = 34) and rectal (n = 18) carcinoma. Fourteen patients (27%) had stable disease for a median of four treatment courses. Leukopenia (88%), nausea and vomiting (71%) and alopecia (54%) were the most common toxic effects.We conclude that epirubicin at the present dose and schedule is an ineffective agent in patients with metastatic colorectal cancer.     

New cytostatic drugs. Status: 1986

In oncology phase-II studies are planned for testing antitumor activity in a series of malignant tumors. Most important is the development of drugs from entirely new classes of chemicals, fermentation products etc. Clinical research with analogues of known cytotoxic drugs aims at broader spectra of activity and at decreased toxicity in an attempt to avoid, for example, the cardiac toxicity of the anthracyclines or the renal and gastrointestinal toxicities of cis-platinum.     

Phase-I study of mafosfamide-cyclohexylamine (ASTA-Z-7557, NSC 345 842) and limited phase-I data on mafosfamide-lysine

Summary Mafosfamide-cyclohexylamine is a new oxazaphosphorine derivative. It was chosen for phase-I clinical testing because of an expected higher therapeutic index and lack of complete cross resistance in animal tumors compared to cyclophosphamide. The schedule consisted of a single iv dose repeated every three weeks. The compound was found to cause as it's dose limiting toxicity severe pain along the injected vein and acute irritation of mucous membranes. The maximal tolerated dose was around 1000 mg/m² given as a slow infusion over 2–3 hours. Hematological toxicity was mild. A limited phase-I study with the lysine salt of mafosfamide showed an identical type of toxicity. Mafosfamide given iv in a high-dose intermittent schedule is of little interest for further clinical trials.It is probable, that the severe venous pain and the mucosal irritation are caused by the high local concentration of 4-hydroxy-cyclophosphamide or by a metabolite. An oxazaphosphorine derivative undergoing slower hydrolysis therefore leading to lower active drug concentrations within the injected vein may be more promising.     

Chemotherapy in bronchogenic carcinoma (author's transl)]

Therapy results in bronchogenic carcinoma remain unchanged since the establishment of thoracic surgery. Prognosis depends on the two main factors: histological type and extension of disease at the time of diagnosis. Both factors are mutually dependent. Small cell carcinoma of the bronchus represents a special entity with its early hematogenous spread and the poorest prognosis of all bronchogenic carcinomas. The tumor is highly sensitive to radioor chemotherapy. A marked prolongatoion of medium survival time can be obtained by combination chemotherapy. This is usually accompained by an obvious improvement in the patient's general condition. In certain cases results can be further improved by irradiation of the primary tumor and the mediastinum. Prophylactic cranial irradiation is often indicated because of the frequent cerebral metastases. Results of chemotherapy are much less impressive in adenoor squamous-cell carcinomas of the bronchus. Such therapy can only be recommended for the exceptional case. Pilliative radiotherapy should be used freely. Till now, adjuvant chemotherapy after surgery has only proven its value in small cell bronchogenic carcinoma.