Paclitaxel combined with carboplatin in the first-line treatment of advanced ovarian cancer: a phase I trial.

Recently, a randomized study conducted by the Gynecologic Oncology Group (GOG 111) demonstrated that, given by a 24-hour infusion, the combination of cisplatin and paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is superior to combination cisplatin/cyclophosphamide in previously untreated patients with advanced ovarian cancer. This combination, however, necessitates hospitalization. Combination paclitaxel/carboplatin would be expected to induce fewer nonhematologic side effects but may be more myelotoxic. Thus, we started a phase I dose-escalation study to determine the maximal tolerated dose of paclitaxel given as a 3-hour infusion in combination with carboplatin, both drugs administered every 21 days. The paclitaxel dose was escalated by increments of 25 mg/m2, starting at 135 mg/m2 (level 1), 160 mg/m2 (level 2), 185 mg/m2 (level 3), and 210 mg/m2 (level 4). Carboplatin was administered to achieve an area under the concentration-time curve of 5, using the Calvert formula For study levels 5 and 6, the carboplatin dose was targeted at area under the concentration-time curves of 6 and 7.5, respectively, and was combined with a fixed paclitaxel dose of 185 mg/m2. Thirty previously untreated patients with stage IIC to IV ovarian cancer were enrolled. Nonhematologic toxicity, including nausea/vomiting and arthralgia/myalgia, was mild. Across all dose levels, a total of 16 patients developed peripheral neurotoxicity (World Health Organization grades 1 and 2). At dose level 5, one patient experienced reversible grade 4 neurotoxicity. Neutropenia was the principal dose-limiting hematologic toxicity. During 33 (31%) of 106 courses, World Health Organization grade 4 neutropenia was observed. Granulocyte colony-stimulating factor was required in only 7.6% of courses. Thrombocytopenia was less than that expected when carboplatin is given alone. Clinical responses were observed in eight of 14 patients, for an overall response rate of 57%. The combination of carboplatin plus paclitaxel was found to be an active regimen. This trial demonstrates that carboplatin dosed by the Calvert equation and 3-hour paclitaxel can be combined safely at full therapeutic doses for six or more courses in patients with advanced epithelial ovarian cancer.

Paclitaxel combined with carboplatin in the first-line treatment of advanced ovarian cancer.

In a phase I study to determine the maximum tolerated dose of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) given as a 3-hour infusion in combination with carboplatin administered every 21 days to women with advanced ovarian cancer, paclitaxel doses were escalated as follows: level 1, 135 mg/m2; level 2, 160 mg/m2; level 3, 185 mg/m2; and level 4,210 mg/m2. The fixed dose of carboplatin at levels 1 through 4 was given to achieve an area under the concentration-time curve (AUC) of 5 using the Calvert formula. In levels 5 and 6 the carboplatin dose was targeted at AUCs of 6 and 7.5, respectively, combined with a fixed paclitaxel dose of 185 mg/m2. To date, 30 previously untreated patients, all with a good performance status (Eastern Cooperative Oncology Group 0 to 2) have been entered into this ongoing study. The dose-limiting toxicity of the combination was myelosuppression (leukopenia, granulocytopenia, and thrombocytopenia). Neurotoxicity was largely moderate. So far, 14 patients are evaluable for response; of these, eight (57%) showed objective (complete or partial) response and disease stabilized in six patients. No patient had disease progression. We conclude that the combination of paclitaxel 185 mg/m2 administered as a 3-hour infusion followed immediately by a 1-hour infusion of carboplatin at an AUC of 6 can be administered safely in a 21-day schedule in the outpatient setting. The recommended dose for phase III studies is paclitaxel 185 mg/m2 and carboplatin AUC 6.

Preliminary results of a phase II study of epirubicin and paclitaxel as first-line treatment in patients with metastatic breast cancer.

Preliminary results of this ongoing phase II study of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) plus epirubicin administered as first-line treatment to women with metastatic breast cancer indicate encouraging response rates and no severe toxicity. Among the 57 patients admitted to this study, 52% had received prior adjuvant chemotherapy (85% with cyclophosphamide/methotrexate/5-fluorouracil), 46% had received radiotherapy, and 30% had received both forms of therapy; 63% of patients were postmenopausal, mainly with poorly differentiated tumors, and 80% presented with > or = 2 metastatic sites. Epirubicin 60 mg/m2 was administered intravenously as a 1-hour infusion followed by paclitaxel 175 mg/m2 infused over 3 hours. Standard premedication was given. Granulocyte colony-stimulating factor support was not used. Neutropenia was evident in 72% of cycles but was not severe. Instances of anemia and thrombocytopenia were rare. Alopecia was universal. All nonhematologic toxicity observed was mild or moderate (peripheral neuropathy, myalgia, nausea, vomiting World Health Organization toxicity grade < 2). At this time, 41 patients are currently evaluable for response, complete and partial remission are evident in seven and 21 patients, respectively. The overall response rate so far is 68%. An additional 12 patients show evidence of stable disease, and one has shown disease progression. Paclitaxel is considered a promising new drug in the adjuvant treatment of patients with metastatic breast cancer. Combining it with epirubicin allows safe administration with no evidence of severe cardiotoxicity. The incidence of adverse cardiac events was much lower than that observed with combinations of paclitaxel and doxorubicin.

Interim Analysis of a Phase II study of epirubicin and paclitaxel as first-line therapy in patients with metastatic breast cancer.

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), the first taxane to be used routinely in clinical practice, has aroused considerable interest for its high single-agent activity in breast cancer and its novel mechanism of action. The 4' epimer of doxorubicin, epirubicin is an agent with high activity against breast cancer but a lower rate of toxic side effects, especially cardiotoxic events, than its parent compound. Although the paclitaxel/doxorubicin combination has yielded response rates between 63% and 94% in phase I/II studies, some severe cardiotoxic events were reported. The rationale for our study was to evaluate the paclitaxel/epirubicin combination, focusing mainly on cardiotoxicity. In all, 57 patients with metastatic breast cancer entered the study, 28% of whom had primary metastatic breast cancer with large tumors at the primary site. Half of the patients had received adjuvant chemotherapy. Study medication consisted of 60 mg/m2 epirubicin given intravenously over 1 hour, followed by paclitaxel 175 mg/m2 administered as a 3-hour intravenous infusion after premedication with steroids, antihistamines, and H2 antagonists. The main toxicity was neutropenia (World Health Organization toxicity index grade 3/4, 72%). Other hematologic side effects were rare and no febrile neutropenia was reported. Peripheral neuropathy, arthralgia, and myalgia were mild (only World Health Organization grade 1 and 2). All patients had alopecia. The paclitaxel dose was escalated to 200 mg/m2 in eight patients, four of whom received a further escalation to 225 mg/m2. Severe neutropenia necessitated dose reductions in eight patients. No cardiac adverse events were reported. Of 41 patients evaluable for response, seven had complete remissions and 21 had partial remissions (68%). An additional 12 patients (29%) had stable disease. The combination of paclitaxel 175 mg/m2 and epirubicin 60 mg/m2 can be administered safely to patients with metastatic breast cancer. Although response was not the primary end point of this trial, the response data are nonetheless encouraging and suggest that further evaluation of the role of this combination in the first-line treatment of metastatic breast cancer is warranted.

Synthesis and hypoglycemic activity of N-alkylated hydrazonopropionic acids.

A series of N-alkylated 2-hydrazonopropionic acids have been synthesized and evaluated for their hypoglycemic activity. Most of the compounds exhibit a remarkable blood glucose lowering activity in fasted guinea pigs. Some of the structural variables studied were the effects of branching, unsaturation, or substitution on the alkyl side chain and the effect of nuclear substitution on the aralkyl analogues. From these compounds, 2-[[(E)-2-methyl-3-phenyl-2-propenyl]hydrazono]propionic acid (BM 42.304; 42) was selected for further investigation.

Chronic and acute effects of thiazolidinediones BM13.1258 and BM15.2054 on rat skeletal muscle glucose metabolism.

1 New thiazolidinediones BM13.1258 and BM15.2054 were studied with regard to their PPARgamma-agonistic activities and to their acute and chronic effects on glucose metabolism in soleus muscle strips from lean and genetically obese rats. 2 Both BM13.1258 and BM15.2054 revealed to be potent PPARgamma-activators in transient transfection assays in vitro. 3 In insulin-resistant obese rats, but not in lean rats, 10 days of oral treatment with either compound increased the stimulatory effect of insulin on muscle glycogen synthesis to a similar extent (insulin-induced increment in micromol glucose incorporated into glycogen g-1 h-1: control, +1.19+/-0.28; BM13.1258, +2.50+/-0.20; BM15.2054, +2.55+/-0.46; P<0.05 vs control each). 4 In parallel to insulin sensitization, mean glucose oxidation increased insulin-independently in response to BM13.1258 (to 191 and 183% of control in the absence and presence of insulin, respectively; P<0.01 each), which was hardly seen in response to BM15.2054 (to 137 and 124% of control, respectively; ns). 5 Comparable effects on PPARgamma activation and on amelioration of insulin resistance by BM13.1258 and BM15.2054 were therefore opposed by different effects on glucose oxidation. 6 In contrast to chronic oral treatment, acute exposure of muscles to BM13.1258 or BM15.2054 in vitro elicited a distinct catabolic response of glucose metabolism in specimens from both lean and obese rats. 7 The results provide evidence that BM13.1258 and BM15.2054 can affect muscle glucose metabolism via more than one mechanism of action. 8 Further efforts are required to clarify, to what extent other mechanisms besides insulin sensitization via the activation of PPARgamma are involved in the antidiabetic actions of thiazolidinediones.

In vivo and in vitro effects of a new hypoglycemic agent, 2-(3-methylcinnamylhydrazono)-propionate (BM 42.304) on glucose metabolism in guinea pigs.

A new compound, 2-(3- methylcinnamylhydrazono )-propionate (BM 42.304), showed a dose dependent hypoglycemic effect in starved guinea pigs after both oral and intraperitoneal administration. In contrast to biguanides (phenformin and metformin) the new compound produced only a moderate increase in blood lactate concentration and did not alter the content of adenine nucleotides in the freeze-clamped liver in vivo. Gluconeogenesis from a variety of precursors in the perfused guinea-pig liver was also inhibited by BM 42.304. These properties suggest that the compound deserves further investigation in connection with its potential usefulness for the treatment of diabetes.

Blood-glucose-lowering activity of 2-(3-phenylpropoxyimido)-butyrate (BM 13.677).

A single oral or intraperitoneal application of 2-(3-phenylpropoxyimido)-butyrate (BM 13.677) resulted in a dose-dependent blood-glucose-lowering effect in fasted guinea-pigs. The threshold dose and the EC50 were estimated as 25 mg/kg and 63 mg/kg, respectively, which is between that of the biguanides phenformin and metformin. A rise in blood lactate concentrations was observed only at high doses of BM 13.677, but was not related to an irreversible metabolic inhibition. Among several rodent species studied the potency of the drug decreased in the order guinea-pig much greater than mouse greater than rat = rabbit. Inhibition of hepatic gluconeogenesis by the drug was demonstrated in the perfused liver or hepatocytes of guinea-pigs. Inhibition of glucose production by the perfused liver in the presence of 0.1 mM BM 13.677 was dependent on the substrate and decreased in the order: lactate greater than pyruvate greater than alanine much greater than propionate greater than glycerol = fructose. This suggests a specific interaction of the drug with a mitochondrial key reaction of gluconeogenesis. Stimulation of glucose oxidation in rat diaphragm by the compound (EC50 = 0.85 mM) suggests that besides inhibition of gluconeogenesis also extrahepatic effects contribute to the blood-glucose-lowering effects of the drug.

Studies on the mechanism of action of the hypoglycemic agent, 2-(3-methylcinnamylhydrazono)-propionate (BM 42.304).

A new hypoglycemic agent, 2-(3-methylcinnamylhydrazono)-propionate MCHP (BM 42.304) was shown to be an inhibitor of the transfer of long-chain fatty acids across the mitochondrial inner membrane. The following data support this conclusion: the drug, at already 5 microM, inhibited ketogenesis from oleate but not from octanoate in the perfused guinea-pig liver; likewise, ketogenesis from L-(-)-palmitoylcarnitine and palmitoyl-CoA + L-(-)-carnitine, but not from octanoate, was depressed in isolated guinea-pig liver mitochondria. Oxigraphic measurements of the oxygen uptake by isolated mitochondria showed that the drug impaired oxygen uptake with the long-chain fatty acid derivatives but not with octanoate. Finally, in vivo effects of the drug such as hypoketonemia and an increased concentration of free fatty acids in blood are in agreement with the above formulated mechanism of action. A comment is given on the relationships between fatty acid oxidation and gluconeogenesis in the guinea-pig liver.

BM 17.0744: a structurally new antidiabetic compound with insulin-sensitizing and lipid-lowering activity.

BM 17.0744 (2,2-dichloro-12-(p-chlorophenyl)-dodecanoic acid) is a substance from a group of omega-substituted alkyl carboxylic acids with the general formula, ring-spacer-carboxylic acid. With BM 17.0744-a compound structurally unrelated to thiazolidinediones--antihyperglycemic and antihyperinsulinemic potency has been demonstrated in various animal models of type II diabetes. The antidiabetic effect is independent of the genetic background of the disease, gender, and animal species. The 24-hour blood glucose profile was dose- and time-dependently improved in ob/ob mice after a single and fourth oral administration of 0.3, 1, and 3 mg/kg/d. A dose-dependent reduction of hyperglycemia (10%, 15%, 28%, and 66%) was found in db/db mice after the fifth oral administration of 3, 10, 30, and 100 mg/kg/d. Hyperinsulinemia was reduced dose-dependently in yellow KK mice by 1%, 24%, 34%, and 66% after the fifth oral administration of 0.3, 1, 3, and 10 mg/kg/d. Overall glucose metabolism was predominantly higher in euglycemic-hyperinsulinemic clamp studies in obese fa/fa rats pretreated for 14 days with 10 mg/kg/d BM 17.0744. The data in diabetic and insulin-resistant animals suggest an improvement of insulin action that is supported by enhancement of insulin effects in vitro. There is no evidence of a risk for hypoglycemia in diabetic and metabolically healthy animals. Triglyceride (TG) and cholesterol were reduced in the serum of metabolically healthy rats, as well as serum lipids in db/db mice, which suggests this effect is independent of amelioration of the diabetic status. Lipid-lowering effects in diabetic and healthy animals show an additional property of BM 17.0744. Because of its antidiabetic and lipid-lowering potency, the substance is of great interest in treating the metabolic syndrome. Lipid decreases in rats are associated with a dose-dependent increase in carnitine acetyltransferase activity in the liver to about 100-fold (12.5 mg/kg/d). This together with hepatomegaly in small rodents may indicate peroxisomal proliferation, a phenomenon considered species-specific. Its relevance for humans is well documented for other classes of compounds including fibrates. Specific side effects of insulin sensitizers of the thiazolidinedione type, such as an increase in body weight and heart weight, could not be observed after 4-week oral application of BM 17.0744 in rats. In general, BM 17.0744 was well tolerated in the pharmacological dose range in all species tested.

(-)-BM 13.0913: a new oral antidiabetic agent that improves insulin sensitivity in animal models of type II (non-insulin-dependent) diabetes mellitus.

Insulin resistance is one of the key features of non-insulin-dependent diabetes mellitus (NIDDM). Therefore, a drug that causes an improvement in insulin sensitivity would be of great interest for the treatment of NIDDM. In addition to the insulin-sensitizing thiazolidinediones, we have found another class of insulin-sensitizing agents: the alpha-activated carbonic acids. (-)-BM 13.0913, a member of this class, was effective in improving insulin resistance in hyperinsulinemic and hypoinsulinemic insulin-resistant animal models of NIDDM. The 50% effective dose (ED50) for the glucose-lowering action was 4, 2.4, and 8 mg/kg in ob/ob, yellow KK, and db/db mice, respectively. The ED50 for the insulin-lowering action was 14.5, 5, and 26 mg/kg. This rightward shift of the dose-response curve for insulin indicates that improving glucose homeostasis is the primary effect of the drug, followed by an insulin-decreasing action. This effect on glucose homeostasis may be brought about by sensitizing peripheral target tissues to the effects of insulin. An increase in deoxyglucose uptake and glucose oxidation measured in adipocytes from rats that had been treated for 14 days with (-)-BM 13.0913 supports this conclusion. Glucose uptake and oxidation was increased at all insulin concentrations tested, suggesting an improved responsiveness. Insulin sensitivity in adipocytes was not influenced by the drug. Studies in the moderately hypoinsulinemic, low-dose streptozotocin (STZ) diabetic rat with a residual insulin concentration showed a decrease in blood glucose concentrations, as well as a decrease in urinary glucose.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of the new oral antidiabetic agent (-)-BM 13.0913.Na on insulin resistance in lean and obese Zucker rats.

The new antidiabetic agent (-)-BM 13.0913.Na (BM) was administered to 12-week-old lean and obese Zucker rats, an animal model of insulin resistance, at a daily dose of 50 mg/kg for 14 days. Hyperinsulinemic-euglycemic clamps were performed on treated and untreated lean and obese Zucker rats. Basal hepatic glucose production (HGP) rates were similar in lean and obese untreated animals. Insulin-induced suppression of HGP was significantly less effective in obese animals. In addition, these animals exhibited the characteristic impaired glucose utilization. In obese animals, drug treatment improved insulin suppression of HGP and total glucose utilization (GU) during clamp studies. Furthermore, drug treatment decreased insulin levels during clamp studies, suggesting an acceleration of insulin clearance. Drug treatment also decreased basal plasma insulin levels and serum and liver concentrations of cholesterol in both fasted lean and obese rats. Additionally, blood glucose, plasma nonesterified fatty acids (NEFA), and serum triglyceride levels were reduced in fasted obese rats, but only minor changes in liver triglycerides were observed in lean and obese rats. On the basis of these results, we suggest that BM is an effective antidiabetic agent that may reduce abnormalities of glucose and lipid metabolism.

Phase II study of carboplatin/ifosfamide in untreated advanced cervical cancer.

A total of 32 patients with advanced squamous-cell carcinoma of the cervix were treated with 300 mg/m2 i.v. carboplatin and 5 g/m2 ifosfamide as a 24-h i.v. infusion, both given on day 1 every 4 weeks. In all, 3 (9%) complete responses (CRs) and 19 (59%) objective responses (CR + PR) were achieved in 32 patients. Myelosuppression with leukopenia and/or thrombocytopenia of WHO grade 4 in 28% and 13% of patients, respectively, was the main toxicity. The results of our study suggest that carboplatin/ifosfamide is active as neoadjuvant treatment in advanced cervical cancer.

A new inhibitor of the long-chain fatty acid transfer across the mitochondrial membrane: 2-(3-methylcinnamylhydrazono)-propionate (BM 42.304).

Using two different assay systems to distinguish between overt and inner forms of carnitine palmitoyl transferase (CPT, EC 2.3.1.21) of intact guinea-pig liver mitochondria, we have shown that the hypoglycemic agent 2-(3-methylcinnamylhydrazono)-propionate (BM 42.304) inhibits the activity of carnitine-acylcarnitine translocase of liver mitochondria. The results offer an explanation for the inhibitory effect of the compound on ketogenesis with oleate but not with octanoate in the perfused guinea-pig liver, previously reported by us (Biochem. Pharmacol. 32, 3405-3412, 1983).

UFT/oral calcium folinate plus weekly paclitaxel for metastatic breast cancer.

Paclitaxel (Taxol) is one of the most active drugs in the treatment of ovarian and breast cancers. Combination therapy with paclitaxel and 5-fluorouracil (5-FU) exhibits high activity in anthracycline-pretreated breast cancer, yielding response rates of 54% to 69% in recent studies. Weekly dosing of paclitaxel produces notable activity, while maintaining relatively low toxicity in heavily pretreated metastatic breast cancer patients. Uracil and tegafur (UFT) plus oral calcium folinate constitute an orally administered compound known as Orzel. This agent provides activity comparable to that of intravenously administered 5-FU plus calcium folinate, with the additional attributes of ease of administration and a more favorable side-effect profile. We initiated a phase I dose-finding trial to determine the maximum tolerated dose and dose-limiting toxicities of the combination of weekly paclitaxel by 1-hour infusion plus UFT/oral calcium folinate administered to patients with anthracycline-resistant metastatic breast cancer.

A phase I study. UFT/leucovorin combined with paclitaxel for anthracycline-pretreated advanced breast cancer.

Taxanes are the most active drugs in the treatment of metastatic breast and ovarian cancer. Weekly therapy with paclitaxel produces notable activity, with remarkably low toxicity. Moreover, combination therapy with paclitaxel and fluorouracil (5-FU) exhibits high activity in anthracycline-pretreated breast cancer patients: recent studies report response rates of 54% to 69%. UFT plus oral leucovorin constitutes an orally administered compound that provides activity comparable to that of intravenously administered 5-FU plus leucovorin. An open-label phase I study was initiated to determine the maximum tolerated dose and dose-limiting toxicities of the combination of weekly paclitaxel and UFT plus leucovorin administered to patients with anthracycline-resistant metastatic breast cancer.

Determination of glomerular filtration rate (GFR) on two consecutive days using inulin in a single-sample plasma clearance method.

Reliable estimation of the GFR is essential in nephrological practice for the early recognition and follow-up of latent or residual renal disturbance. The GFR of ten healthy volunteers on two consecutive days and of 40 patients with different renal diseases were investigated by means of a plasma slope clearance technique. After injection of 5 g/50 ml inulin solution, eight plasma samples were taken at 10, 20, 30, 40, 120, 180, 240, 300 min p.i. and analyzed with the aid of a fully enzymatic method. The results were correlated on the basis of 1- and 2-compartment models (1 CM, 2 CM) and the one-sample method (1 S), using only the plasma inulin concentration of the 240 min p.i. sample. The accuracy of the GFR data of volunteers estimated in these models was checked by comparison with the standardized agewise normal values, while for the patient group we found in terms of equations of correlation: 1. GFR (2 CM) = 4.46 + 0.763*GFR (1 S), n = 31, r = 0.985 2. GFR (2 CM) = 1.27*GFR (1 CM)0.9, n = 40, r = 0.996 3. GFR (1 CM) = 0.568*(GFR[1 S] + 5.85)1.11, derived The single-sample method using inulin is closely correlated to multi-sample methods but much more suitable for patients and staff. Therefore, it is recommended for clinical use.

Objective demonstration of cervical softening with a prostaglandin F2 alpha gel during first trimester abortion.

In a prospective study the cervix softening and dilating effects of intracervically applied prostaglandin F2 alpha gel were investigated in 100 patients during induced abortion in the 7-12th week of pregnancy. A specially designed tonometer was used to measure the resistance of the cervical canal before as well as 6-8 h, 4 days and 5-6 weeks after gel application. The cervix of 99 patients proved to be freely passable without use of undue force for at least Hegar 8 after treatment. Measurements in 96 patients 5-6 weeks after the operation showed good general agreement with those values obtained before gel application. No spontaneous or operation-induced lesions of the cervix occurred. Intracervical prostaglandin gel application proved itself to be a safe, practicable and gentle method for avoiding dilation-induced complications during first trimester abortions.

Pharmacokinetics of ceftizoxime in patients undergoing hemodialysis.

Serum pharmacokinetics of 1 g ceftizoxime were studied in eight patients undergoing chronic haemodialysis. Arterial blood samples were collected at 3, 60, 120, 180 and 240 minutes and before the next dialysis 2-3 days after injection of ceftizoxime. Three minutes after injection the serum levels were 122 +/- 8.4 microgram/ml and 19.4 +/- 1.7 microgram/ml at the end of the dialysis. Mean elimination half-life under haemodialysis was 2.1 hours. Serum concentrations ranged from 4.9 to 13 microgram/ml two to three days after the haemodialysis.

Cyclophosphamide, methotrexate, 5-fluorouracil, and folinic acid (CMFF) as first line chemotherapy for treatment of advanced breast cancer. A pilot study.

In order to evaluate the maximum tolerable dose of a combination chemotherapy consisting of cyclophosphamide, methotrexate, 5-fluorouracil, and folinate (CMFF), 30 female patients with histopathologically confirmed, previously untreated advanced breast cancer were entered into this pilot study. Chemotherapy consisted of fixed doses for methotrexate (40 mg/m2 i.v. on day 1), 5-fluorouracil (500 mg/m2 i.v. on day 2 to 4) and folinic acid (2 x 200 mg/m2 i.v., 0 + 2 h on day 2 to 4). The dose of cyclophosphamide was escalated stepwise, starting with 200 mg/m2 i.v. on day 2 to 4, to 240 mg/m2, 290 mg/m2, 360 mg/m2 and 400 mg/m2, respectively, for each subsequent five patients. Treatment was repeated every four weeks. A total of 92 treatment cycles was given. Myelosuppression was the dose-limiting toxicity: leukopenia WHO grade III or IV was observed after a total of 28 cycles and anemia of equal intensity after 1 cycle. No thrombocytopenia WHO grade III or IV was recorded. Myelotoxicity increased with higher doses of cyclophosphamide. Among non-hematologic toxicities, alopecia was reported in two-thirds of the patients. Nausea and vomiting was noted in 25% of treatment cycles, but in one cycle only WHO grade III was recorded. No other toxicities exceeding WHO grade II occurred.(ABSTRACT TRUNCATED AT 250 WORDS)