A double-blind, randomized, crossover study was conducted to compare the efficacy and safety of high-dose dexamethasone (Protocol D) with a combination of dexamethasone, metoclopramide and diphenhydramine (Protocol DMD) in the management of chemotherapy-induced nausea and vomiting in cancer patients. All entered patients had received no prior chemotherapy. During the study chemotherapy was administered on an inpatient basis. The majority of patients (94%) were treated with cytotoxic drugs of significant emetogenic activity and 40% of the study group received cis-platin-containing combinations. Of the 60 evaluable patients, complete antinausea and antivomiting effects of D were observed in 30 (50%) and 34 (57%), respectively and of DMD in 17 (28%) and 26 patients (43%) respectively. The difference was not statistically significant (P = 0.09 and 0.24, respectively). Lack of significant difference between the two regimens was demonstrated irrespective of the administered cytotoxic drugs. The DMD protocol caused more adverse reactions than D. While 27 patients (45%) experienced no side effects from D, only 14 (24%) remained free of complications due to DMD (P = 0.001). Furthermore, DMD produced more sedation, insomnia, headache, diaphoresis, dizziness and diarrhoea than the D regimen. In addition it gave rise to more adverse effects on appetite and activity. Upon direct questioning, 37 patients (62%) expressed a preference for D, 14 (23%) preferred DMD and 9 (15%) found no difference between the two regimens. We conclude that, while the short DMD protocol has an antiemetic activity equivalent in its effectiveness to D, its associated adverse reactions would minimize its usefulness. Therefore, further investigations should be conducted to find a safer and more potent combination of antiemetics suitable for therapy in an outpatient setting.

Thirty-six postmenopausal women were randomized to three groups in a double-blind, prospective study. All were treated for three months with conjugated estrogens (Premarin), 0.625 mg daily, and three different doses of a progestin (Provera), 2.5 mg daily, 5 mg daily or 5 mg during the last 12 days of a 28-day cycle. We found that the endometrium was maintained in an inactive phase in 100% of the women given continuous daily progestin but in only 25% of those given cyclic progestin. Bleeding occurred in 100% of subjects given cyclic progestin and in 50% of those given continuous progestin; however, bleeding episodes diminished with time in those on continuous progestin. A hormonal regimen that leads to reduced or absent bleeding and an inactive endometrium is preferable for postmenopausal women if estrogen therapy is to be used for the long term after menopause.

In a prospective randomized and double-blind cross-over study betamethasone-dixyrazine was compared with metoclopramide as antiemetic treatment in cisplatin and doxorubicin chemotherapy. Sixty-two consecutive patients without prior experience of chemotherapy entered the study and were followed during 1-4 courses of treatment. Effect parameters were recorded on questionnaires using the visual analog scale for quantification. The median number of courses per patient was 3.0 (range 1-4). Full protection against nausea and vomiting was achieved in 74% with betamethasone-dixyrazine and in 45% with metoclopramide regardless of the chemotherapy regimen employed. With doxorubicin regimens betamethasone-dixyrazine gave full protection in 94% and metoclopramide in 45%. In cisplatin regimens full emetic protection was achieved in 40% with betamethasone-dixyrazine and in 29% with metoclopramide. Adverse reactions were a significant problem with metoclopramide: restlessness 48%, akathisia 26%, parkinsonism 13%, and acute dystonia 3%. One case (3.2%) of parkinsonism was noted as the only extrapyramidal reaction in the dixyrazine group. Various degrees of sedation were noted in 84% during dixyrazine treatment compared with 71% during metoclopramide therapy. Diarrhea was encountered in 48% after high-dose metoclopramide compared with 6% after antiemetic treatment with betamethasone-dixyrazine. Betamethasone-dixyrazine appears to be a promising antiemetic combination with regard to both efficacy and side effects, but further refinement of the regimen is probably possible through dose adjustments and alternative routes of administration.

To evaluate the role of endogenous opiates in chemo-therapy-induced nausea and vomiting, the narcotic-antagonist naloxone was administered to six pediatric patients receiving cancer chemotherapy. Naloxone was administered by continuous intravenous (i.v.) infusion after randomized, double-blind controlled assignment at a dose of 0, 10 or 40 micrograms/kg/h for 12 h. Each patient was studied for four consecutive and identical courses of chemotherapy (eight courses for each naloxone dose or 24 courses in all). A dose-related increase in nausea (nausea score 2.5 +/- 2.24, 3.83 +/- 2.73, and 5.75 +/- 2.86/12 h, p = 0.003), vomiting (emetic events 6.0 +/- 7.50, 8.08 +/- 6.71, and 10.3 +/- 8.91/12 h, p = 0.035), and patient aversion (course preference rank 1.5 +/- 0.45, 2.83 +/- 1.17, and 3.25 +/- 0.42/4 courses, p = 0.014) was observed. The infusion of naloxone in the absence of chemotherapy was without effect. These results support a role for endogenous opiates in regulating chemotherapy-induced nausea and vomiting, and further suggest that narcotic agents may be effective antiemetics in this setting.

A new water-soluble nitrosourea derivative, methyl 6-[3-(2-chloroethyl)-3-nitrosoureido]-6-deoxy-alpha-D-glucopyranoside (MCNU), was found to be useful for the treatment of chronic myelogenous leukemia (CML) in the chronic phase. To compare the efficacy of MCNU with that of busulfan, patients were randomized. In the 40 patients administered MCNU, the median time to the achievement of a complete remission (CR) was 50 days. This value was shorter than that observed in 37 patients administered busulfan (126 days, p less than 0.05). There were no differences in the rate of CR achieved, mortality, median time to the onset of blast crisis (BC), BC rate, or survival rate during the observation period. The overall incidence of side effects was higher for MCNU (31%) than for busulfan (15%), but the symptoms were mild, transient and tolerable for most patients. These results suggest that MCNU is a safe and valuable addition to the therapeutic repertoire for the control of CML.

One hundred thirteen patients were randomized for the study. There was no significant difference between the groups for response or survival. The incidence of side effects related to the reduction of testosterone was similar in both groups. Disease "flare" was seen in three patients treated with long-acting D-Trp-6 LH-RH. All symptoms resolved by the end of 8 weeks. There was less psychological morbidity in the D-Trp-6 LH-RH group but the difference did not reach statistical significance. Our results indicate that long-acting D-Trp-6 LH-RH offers a safe and effective alternative to surgical orchidectomy.

Patients with inoperable non-small cell lung cancer, limited disease, were randomized to either chemotherapy (cisplatin and etoposide) or radiotherapy of the thorax. A set of questionnaires, covering 4 areas: psychosocial well-being, medical side effects, physical function, and everyday activity was filled out by 101 patients. The correlations between psychosocial well-being (dependent variable) on the one hand, and medical side effects, physical function, and everyday activity (independent variables) on the other were subjected to multiple regression analysis. No significant correlation was found between psychosocial well-being and chemotherapy- or radiotherapy-related subjective side effects. The disease-related symptoms correlated highly with psychosocial well-being during the observation period. Psychosocial well-being and the independent variables tended to be more strongly correlated during the follow-up period (14-52 weeks) than during the treatment period.

A randomized prospective clinical trial was conducted to evaluate the potential utility of adding transdermal scopolamine to a standard regimen of metoclopramide and dexamethasone for the prevention of cisplatin-induced emesis. Thirty-one patients who were about to receive their first cycle of chemotherapy, using a combination regimen including cisplatin at a dose greater than or equal to 60 mg/m2 were randomized to receive an antiemetic regimen of either metoclopramide and dexamethasone alone, or these two drugs plus transdermal scopolamine patches. The mean number of episodes of emesis was .63 +/- 1.31 in the 16 scopolamine-treated patients, and 2.27 +/- 2.66 in the 15 patients who did not receive scopolamine (P less than .01). The scopolamine appeared to inhibit extrapyramidal reactions to the metoclopramide, but the number of cases was too small for statistical significance. We conclude that the addition of transdermal scopolamine to a standard metoclopramide and dexamethasone antiemetic regimen provides additive benefit in the control of cisplatin-induced emesis.

One hundred and twenty-four patients with advanced breast cancer were randomly allocated to treatment with either low dose (300 mg/day) or high dose (1000 mg/day) oral medroxyprogesterone acetate. The objective response rate was 24% for both treatment groups. For premenopausal patients, responses were achieved in two out of four on low dose and three out of six on high dose therapy (overall 5 out of 10 responders). No significant differences in response were seen in relation to previous endocrine therapy or site of disease. Both treatments were associated with a high incidence of bone pain relief (43 and 52%) but a low objective response rate (13%) in bone. Median response duration (10 vs. 11 months) and survival (13 vs. 11 months) were not significantly different for the two treatments. Both treatments were in general well tolerated, but toxicity was greater with the high dose treatment. Low dose oral medroxyprogesterone acetate is as effective as high dose therapy in the treatment of advanced breast cancer, and is cheaper and less toxic.

To further define optimal combinations of antiemetics, high-dose metoclopramide and lorazepam (M+L) were compared with prochlorperazine and lorazepam (P+L) in a randomized, double-blind, cross-over study. Both patient and observer assessments were documented in 66 patients receiving cisplatin and noncisplatin chemotherapy. M+L significantly reduced the severity of vomiting (P = 0.01), duration of vomiting (P = 0.05), and number of vomiting episodes (P = 0.003). Comparing the severity or duration of nausea, M+L and P+L were not significantly different. M+L significantly reduced severity of vomiting (P = 0.005) and number of vomiting episodes (P = 0.03) in the cisplatin subset. The number of vomiting episodes was also reduced in the noncisplatin subset (P = 0.03). When asked to nominate a preferred regimen, 41% of patients preferred P+L, 35% preferred M+L, and 24% rated them equally. M+L was associated with significantly more anxiety and less sedation than P+L. Patient assessments produced similar results to observer assessments but gave a broader understanding of our patients' tolerance to chemotherapy. M+L is a superior regimen in controlling vomiting induced by chemotherapy.

In a randomized, double-blind, crossover trial, nabilone was compared to prochlorperazine for control of cancer chemotherapy-induced emesis in 30 children 3.5 to 17.8 years of age. All subjects received two consecutive identical cycles of chemotherapy with the trial antiemetics given in accordance to a body weight-based dosage schedule beginning eight to 12 hours before treatment. The overall rate of improvement of retching and emesis was 70% during the nabilone and 30% during the prochlorperazine treatment cycles (P = .003, chi 2 test). On completion of the trial, 66% of the children stated that they preferred nabilone, 17% preferred prochlorperazine, and 17% had no preference (P = .015, chi 2 test). Major side effects (dizziness, drowsiness, and mood alteration) were more common (11% v 3%) during the nabilone treatment cycles. CNS side effects appeared to be dose related and were most likely to occur when the nabilone dosage exceeded 60 micrograms/kg/d, but individual tolerance to nabilone varied considerably. Lower dosages of nabilone were associated with equivalent efficacy and no major side effects. Nabilone appears to be a safe, effective, and well-tolerated antiemetic drug for children receiving cancer chemotherapy. Although major side effects may occur at higher dosages, nabilone is preferable to prochlorperazine because of improved efficacy.

The effects on anterior pituitary function of FCE 21336 (1-ethyl-3-(3'-dimethylaminopropyl)-3-(6'-allylergoline-8'-beta-ca rbonyl)-urea- diphosphate), a synthetic ergoline derivative with selective dopamine agonistic properties, were studied. Circulating PRL, GH, TSH, cortisol and LH levels were determined up to 96 h after single oral doses of 50, 100, 200 and 300 micrograms of the compound to eight healthy males, and up to 168 h after single oral doses of 400 and 600 micrograms to six healthy males, according to double-blind, within subjects, experimental designs vs placebo. Vital signs, ECG, laboratory tests and the appearance of newly observed signs and symptoms were monitored. A dose-related decrease of serum PRL in comparison with both basal and post-placebo levels was observed after 200 micrograms and greater doses of the compound, with inhibition of spontaneous circadian rhythm. Maximal inhibition (PRL less than 2 ng ml-1) was observed in one out of five subjects after 200, three out of seven subjects after 300, four out of six after 400 and five out of six subjects after 600 micrograms. The effect was of rapid onset and long duration; the maximum or nearly maximum decrease was observed within 3 h after dosing as well as up to 96 h (200 and 300 micrograms) and up to 168 h (400 and 600 micrograms). No modifications of GH, TSH, LH and cortisol as well as of vital signs, ECG and laboratory tests were apparent.(ABSTRACT TRUNCATED AT 250 WORDS)

Copovithane (BAY i 7433), a copolymer of 1,3-bis(methylaminocarboxyl)-2-methylenepropanecarbamate and N-vinyl pyrrolidone, has antitumor activity in vitro and in vivo. The mechanism of this polymer is unknown. Thirty patients with advanced colorectal carcinoma with measurable tumors were treated in an open randomized study with two schedules of copovithane (schedule A: 6 g/m2 i.v. over 30 min daily for 5 consecutive days and repeated every 3 weeks; schedule B: 10 g/m2 i.v. over 30 min once a week until progression, unacceptable toxicity, or up to 18 months). Fifteen patients received copovithane on a weekly schedule, and 15 patients received it on an intermittent schedule. None of the patients on either schedule achieved a complete or partial remission. Copovithane was ineffective against colorectal carcinoma by both schedules selected in this study.

Eighty-four cancer patients at risk of infection because of neutropenia were randomized to receive nalidixic acid as an alternative to trimethoprim-sulfamethoxazole (TMP-SMX) for infection prophylaxis. Infections were documented significantly earlier and more often among patients who entered the trial with neutrophil counts of less than 0.1 X 10(9)/liter. TMP-SMX recipients experienced fewer microbiologically documented infections and bacteremias and were free of infection for a higher proportion of days with severe neutropenia (less than 0.1 X 10(9)/liter) than nalidixic acid recipients. Gram-negative bacillary and Staphylococcus aureus infections accounted for the major differences. Although the majority of aerobic gram-negative bacilli were eliminated from the feces after 1 week of prophylaxis with either agent, TMP-SMX was proved superior to nalidixic acid in this regard and was associated with acquired drug resistance by gram-negative bacilli less frequently. Both agents selected for colonization and subsequent infection by gram-positive cocci. Our data suggest that prophylaxis is most likely to be effective if administered to patients for at least 1 week before they become severely neutropenic. Nalidixic acid used as a single agent in doses of 4 g daily, however, cannot be recommended as an alternative to TMP-SMX for infection prophylaxis in neutropenic cancer patients.

A prospective, double-blind, placebo-controlled study was designed to evaluate the clinical efficacy and tolerance of danazol and high-dose medroxyprogesterone acetate (MPA) in the treatment of mild-moderate endometriosis. After laparoscopical confirmation of endometriosis, 59 patients were randomized to receive danazol (200 mg 3 times daily), MPA (100 mg daily) or placebo for 6 months. Clinical examinations were done before and 1, 3, 6 and 12 months after the beginning of the study, and a 2nd laparoscopy 6 months after termination of the medication. Eighteen patients in the danazol group, 16 in the MPA group and 17 in the placebo group completed the trial. Total or partial resolution of peritoneal implants was observed in 60% of the patients receiving danazol and in 63% of the patients receiving MPA. In the placebo group, resolution was observed in 18%, while the size of the implants was estimated to be increased in 23% of the patients. In relation to placebo, danazol and MPA significantly alleviated endometriosis-associated pelvic pain, lower back pain and defecation pain, but they did not differ from each other in these actions. The appearance of acne, muscle cramps, edema, weight gain and spotting bleeding complicated MPA treatment. The present results indicate that because of good efficacy and tolerance, high-dose MPA is a useful alternative in the hormonal treatment of endometriosis.

A prospective randomised study was conducted comparing the efficacy and toxicity of the antibiotics ticarcillin and cefamandole (TC) with or without tobramycin (TCT) in 100 febrile neutropenic patients with solid tumours undergoing conventional chemotherapy. In this study, neutropenia less than 100/microliter was noted in 31% of 106 evaluable infectious episodes and neutrophil counts less than 1,000/microliter persisted for a median 4 days. Infection was microbiologically documented in 42% of episodes (bacteremia 24%) with gram-negative organisms responsible for 63% of bacterial isolates. Overall, 65% of episodes responded to TC and 76% to TCT (p greater than 0.05). Patients with initial shock bacteremia, pulmonary infection, or gram-negative sepsis responded relatively poorly. Neutrophil nadir and pathogen susceptibility did not influence outcome. Antibiotic toxicity was minimal with no tobramycin-related nephrotoxicity. These results are broadly comparable to those observed with leukemic patients, but the relatively short duration of neutropenia in the solid-tumour patients appears to minimize the need for additional antibiotics provided there is adequate antimicrobial coverage with the initial choice of antibiotics.