Treatment of brain metastases in patients with testicular cancer.

PURPOSE: Despite improved cure rates for patients with metastatic testicular cancer with cisplatin-based combination chemotherapy, patients who develop brain metastases are generally considered to possess a poor prognosis. This report summarizes the long-term results in 44 patients with brain metastases from testicular cancer treated between 1978 and 1995 at Hannover University Medical School. PATIENTS AND METHODS: Histologically, 42 patients (95%) had a nonseminomatous germ cell cancer and two patients (5%) a seminoma. Thirty-nine patients (89%) had lung metastases and 37 (84%) fulfilled the criteria for advanced disease according to the Indiana University classification even without considering the brain metastases. Eighteen patients (41%) presented with brain metastases at primary diagnosis (group 1), four (9%) developed brain metastases at relapse after a previous favorable response to combination chemotherapy (group 2), and 22 (50%) developed brain metastases during or directly after cisplatin-based chemotherapy. Chemotherapy consisted of cisplatin-based combination treatment and radiotherapy was given as whole-brain irradiation of 30 to 40 Gy and in single cases combined with a boost of 10 Gy to single lesions. RESULTS: Overall, 10 patients achieved long-term survival (23%; 95% confidence interval [CI], 10.1% to 35.4%). The prognosis was significantly better for patients in groups 1 and 2, with six of 18 (33%) and three of four (75%) patients alive, compared with only one of 22 (5%) in group 3 (P < .01). Patients treated with either chemotherapy or radiotherapy alone did not achieve long-term survival, while nine of 28 (32%) who received treatment with both modalities with or without surgery achieved sustained long-term survival. During univariate analysis, patients with the diagnosis of brain metastases at first presentation (P < .01), patients with a single brain lesion (P < .02), and patients who received combined chemotherapy and radiotherapy (P < .03) had a significantly improved outcome. CONCLUSIONS: Long-term survival can be achieved in approximately 25% of patients with brain metastases from testicular cancer by combined treatment with brain irradiation and aggressive cisplatin-based chemotherapy. Patients who develop brain metastases during systemic treatment should receive only palliative radiation therapy, since sustained survival will not be reached.

Evaluation of clinical efficacy of new medical treatments in advanced colorectal cancer. Results of a workshop organized by the EORTC GITCCG. European Organization for Research and Treatment of Cancer. Gastrointestinal Tract Cancer Cooperative Group.

During the last few years several factors have contributed to an increasing change in the medical treatment of advanced colorectal cancer. Among them are the more general acceptance of the impact of chemotherapy on quality of life and survival in first as well as in second-line treatment, the introduction of new drugs and the definition of novel endpoints which can roughly be defined as "patient benefit". For this reason the European Organization for Research and Treatment of Cancer (EORTC) Gastrointestinal Tract Cancer Cooperative Group (GITCCG) felt it was appropriate to organize a workshop with experts from different countries and national groups to discuss in depth several aspects concerning the treatment of patients with advanced colorectal cancer.

The relationship of circulating levels of estrogens, corticosterone and calcium to production performance of adult turkey hens under conditions of increasing ambient temperature.

Turkey hens were exposed to stepwise increases in ambient temperature from 21degreesC. to 25degreesC. to 30degreesC. to 35degreesC. at two-week intervals. Dietary calcium levels of 1.54, 2.01 and 2.48% were fed. Production data and circulating levels of estrone, estradiol-17-beta, corticosterone, total calcium, bound calcium, and unbound calcium were studied. The dietary calcium levels had no significant influence on any of the results. The temperature increase caused a significant (P less than .05) decrease in plasma levels of calcium and estrone, egg production, shell thickness and egg weight. The temperature increase caused a significant (P less than .05) fluctuation in plasma corticosterone levels but had no apparent effect on the plasma estradiol levels. With the temperature increase, unbound plasma calcium levels and plasma corticosterone levels showed a significant (R greater than or equal to 0.50, P less than 0. less than .01) positive correlation to egg production.

Blood parameters in Leucocytozoon smithi infected poults fed clopidol.

Poults naturally infected with L. smithi demonstrated a significant (P less than 0.01) decrease in arterial PO2 (mm. Hg) during the second and third weeks after exposure to black fly bites. Poults fed Clopidol (0.0125%) during the exposure period and subsequent experimental periods showed very little parasitemia and no significant reduction in arterial PO2.

Changes in plasma electrolytes, acid-base balance and other physiological parameters of adult female turkeys under conditions of acute hyperthermia.

The effects of acute hyperthermia on certain physiological parameters of turkey hens was studied. It was found that the response of the turkey to hyperthermia is similar to the reported response of the chicken. The birds began panting and the average body temperature increased 0.1 degrees C. as the ambient temperature reached 32 degrees C. The panting or polypnea induced a profound respiratory alkalosis in the turkeys. The acute hyperthermia also caused a significant (P less than 0.05) decrease in plasma levels of sodium, total calcium, magnesium and inorganic phosphorus. The plasma level of potassium was significantly (P less than 0.05) increased.

Acid-base balance, plasma electrolytes and production performance of adult turkey hens under conditions of increasing ambient temperature.

Turkey hens were exposed to stepwise increases in ambient temperature from 21 degrees C. to 25 degrees C. to 30 degrees C. to 35 degrees C. at two-week intervals. Dietary calcium levels to 1.54, 2.01 and 2.48 percent were fed. Acid-base balance, plasma electrolytes and production performance were studied. The temperature increase caused a significant (P less than 0.05) decrease in plasma sodium, calcium, and magnesium, and in egg production, shell thickness and egg weight and a significant (P less than 0.05) increase in plasma potassium. There was no significant change in the acid-base balance of the blood as measured by blood PO2, PCO2 and pH. Egg production was not significantly correlated to blood gas activitelated to plasma calcium and magnesium levels. Dietary calcium levels had no influence on the parameters measured.

Drug input rate from the GI-tract. Michaelis-Menten kinetics and the bioavailability of slow release verapamil and nifedipine.

We present evidence, from studies with slow release verapamil and nifedipine, for Michaelis-Menten metabolism during first pass through the liver. Drug input rate from the GI-tract after an oral dose appears to be a determinant of bioavailability. Highest oral bioavailabilities are observed with standard release formulations at high dosage. The bioavailability of slow release formulations with a zero order release kinetic is lower than standard release formulations and related to the dissolution rate in vitro. In addition, (a) the presence of non-linear absorption kinetics offers a further explanation for the considerable inter-patient variability in AUC since the ability of drug to cross the liver is a function of the concentrations attained in portal blood which will be dependent on dissolution conditions prevailing in the GI-tract, (b) depending on the choice of the dose and dosage interval of the conventional release formulation used for comparison and as a consequence of Michaelis-Menten first pass metabolism it is possible to obtain relative bioavailability data showing superiority, equivalence or bioavailability loss with the slow release form. This may explain the discrepancies in bioavailability data for slow release drugs reported in the literature, (c) 'true' estimates of relative bioavailability of a slow release formulation can only be achieved if steady state conditions are present, and the dose and dosage interval of the slow and conventional release formulation are the same, (d) since a slower dissolution rate is 'ipso facto' associated with a lower bioavailability, slow release formulations of verapamil and nifedipine cannot be classified as being 'inferior' or of poorer quality on the basis of bioavailability alone.

Hematopoietic growth factors and treatment of testicular cancer: biological interactions, routine use and dose-intensive chemotherapy.

With the use of aggressive cis-platinum-based combination chemotherapy the majority of patients with metastatic testicular cancer will be cured. Hematopoietic growth factors (HGFs), particularly G- and GM-CSF, have been investigated for the treatment of testicular cancer in order to (a) ameliorate chemotherapy-induced myelosuppression, (b) increase the dose intensity of treatment, or (c) generate peripheral blood stem cells (PBSC) as hematopoietic support for mega-dose chemotherapy. Results from in vitro and animal models have excluded a significant influence of both factors, G-CSF and GM-CSF, on tumor growth and response to cytotoxic treatment. For the group of 'good-risk' patients with metastatic testicular cancer, 85-90% of whom will reach long-term survival, the incidence of granulocytopenic infections after standard chemotherapy regimens appears to be lower than 20%. The prophylactic use of HGFs for these patients is not routinely recommended but may be considered in case of an increased risk for infections. For 'poor risk' patients, who will achieve 50% survival following standard chemotherapy, different attempts of treatment intensification have been investigated. The use of aggressive multidrug regimens is associated with granulocytopenic infections in 20-70% of patients. A randomized trial has demonstrated that the prophylactic use of G-CSF significantly reduces granulocytopenia, the number of septic infections, and the infection-related death rate. For 'poor risk' patients the prophylactic use of HGFs, particularly G-CSF due to its favorable side effect profile, is recommended. The availability of G- and GM-CSF has made it possible to develop dose-intensified chemotherapy regimens. Demonstrated particularly for GM-CSF, a 1.5 fold dose increase can be achieved by the use of a myeloid growth factor alone, and thrombocytopenia and other organ toxicity will become dose limiting. Mobilization of PBSC, either after stimulation with HGFs alone or with HGFs, following chemotherapy has been successfully used in patients with testicular cancer. For the treatment of patients with relapsed disease PBSC support followed by HGFs has allowed the use of mega-dose therapy in multiple phase-II studies. This has prompted the investigation of high-dose therapy as first-line treatment for 'poor-risk' patients. In these patients sequential high-dose treatment with cis-platinum, etoposide, and ifosfamide for four consecutive cycles, each supported by G- or GM-CSF and PBSC, is currently being investigated by the German Testicular Cancer Study Group. HGFs have substantially reduced treatment-associated morbidity and mortality in patients receiving chemotherapy for testicular cancer. They make it possible for the first time to clinically explore the true value of dose-intensified chemotherapy regimens in testis cancer, serving as a model of a highly chemotherapy sensitive disease. Enrollment of patients in prospective clinical trials evaluating the role of high-dose therapy is strongly recommended.