We evaluated the effect of norfloxacin, 400 mg given orally every 12 hours, on the prevention of bacterial infections in 68 adult patients who had acute leukemia throughout prolonged courses of granulocytopenia (median, 32 days). Gram-negative infections were documented in 13 of the 33 patients receiving placebo, but only in 4 of the 35 patients receiving norfloxacin; no effect on the frequency of gram-positive or fungal infections was noted. Norfloxacin administration resulted in the suppression of gastrointestinal tract colonization by aerobic bacteria without the development of norfloxacin resistance. Patients receiving norfloxacin developed first infectious fevers later than did those receiving placebo, had more rapid resolution of that fever after systemic antibiotic treatment, and spent less time febrile. Therefore, although no difference was seen in survival duration, we found that the prophylactic administration of oral norfloxacin led to decreases in overall morbidity and gram-negative infections, was well tolerated, and did not predispose to the development of multiply drug-resistant bacteria.

The results of a randomised, prospective trial to investigate the efficacy of prophylactic treatment with ofloxacin during granulocytopenia after cytostatic treatment are presented. 42 patients with metastasised testicular germ-cell tumours entered the study. Cytostatic treatment consisted of at least 4 courses, 2 of which were succeeded by prophylactic treatment with ofloxacin. Three patients undergoing prophylactic treatment developed fever. Fever occurred in 16 patients during control phases (no ofloxacin prophylaxis) of cytostatic treatment. Seven of the 19 infections could be documented microbiologically. No side effects that related to ofloxacin were noted. In conclusion, ofloxacin was highly effective in the prevention of infection and, therefore, should be given prophylactically to patients with granulocytopenia.

We have carried out a randomized, double-blind trial to investigate the relationship between the dose and plasma concentration of metoclopramide and its anti-emetic efficacy and adverse effects in patients receiving cancer chemotherapy. Seventeen patients received four different infusion regimens of high-dose metoclopramide in random order with four consecutive courses of chemotherapy, to achieve an approximately eight-fold range in plasma metoclopramide concentrations. In patients receiving cisplatin the incidence of vomiting decreased with increasing metoclopramide dose, but the overall efficacy was poor. There was no relationship between anti-emetic efficacy and either dose or plasma concentration of metoclopramide in patients receiving cyclophosphamide and doxorubicin. The adverse effects of high-dose metoclopramide included diarrhoea, which increased in incidence with increasing metoclopramide dose, and sedation and extrapyramidal reactions, which were not related to dose or plasma concentration. Although anti-emetic efficacy increases with increasing metoclopramide dose in patients receiving cisplatin, high-dose metoclopramide alone does not adequately control cisplatin-induced nausea and vomiting.

We conducted a randomized crossover study comparing the hemopoietic effect of partially purified human urinary colony-stimulating factor (CSF-HU, an active drug) and human serum albumin (HSA, a control drug) in 24 patients with malignant lymphoma, solid tumors, or multiple myeloma who were receiving two consecutive courses of the same chemotherapeutic regimen. Patients received daily 2-4 X 10(6) units of CSF-HU or an equal amount of protein HSA for five days after the end of the courses of chemotherapy. Assignment to CSF-HU or HSA was determined by the envelope method. The average number of blood granulocytes of 24 cases on day 7 after chemotherapy was 2116 +/- 1649 in CSF-HU-infused courses, which was significantly higher than in HSA-infused courses (1520 +/- 1022) (p less than 0.05). The average time that patients had fewer than 2000 granulocytes/mm3 was 7.6 +/- 4.4 days in CSF-HU-infused courses and 10.3 +/- 5.0 days in HSA-infused courses (p less than 0.02). Fever greater than 38 degrees C was the most frequent side effect, occurring in 32% of the patients receiving CSF-HU infusions. A reduction in the neutropenic interval in CSF-HU-infused courses was observed in patients with fever, as well as in those without fever. Infusions of CSF-HU did not change the number of other hematological parameters, such as erythrocytes, platelets, monocytes, and lymphocytes. These results suggest that CSF-HU infusions may partially protect the patients from granulocytopenia after anticancer chemotherapy.

Methylprednisolone sodium succinate and metoclopramide were compared for their efficacy, tolerance, and safety in the prevention of nausea and vomiting induced by moderately emetogenic chemotherapy in patients with cancer. Previously untreated patients about to receive at least 2 cycles of identical chemotherapy were entered into a study using a randomized, double-blind, crossover design. Patients were given either 250 mg of methylprednisolone or 10 mg of metoclopramide intravenously before the first cycle of chemotherapy and were then crossed over to receive the alternate medication before the second cycle of chemotherapy. Prochlorperazine was prescribed in both cycles for postchemotherapy nausea and vomiting. After each treatment cycle patients recorded the degree of nausea, drowsiness and anxiety, the number of episodes of vomiting experienced, and the amount of prochlorperazine taken. After the second treatment cycle patients recorded their preference for either the first or the second antiemetic medication with respect to nausea, vomiting, and overall effectiveness. Of 157 patients entered into the study, 115 were fully appraisable. Methylprednisolone was superior to metoclopramide in preventing nausea and vomiting and in decreasing anxiety and the amount of prochlorperazine used. A majority of the patients expressing a preference preferred methylprednisolone to metoclopramide for control of nausea (p = 0.003), control of vomiting (p = 0.0006), and overall effectiveness (p = 0.00004). There were few side-effects. We conclude that methylprednisolone may have some utility as an antiemetic in patients receiving moderately emetogenic chemotherapy, and who are treated as outpatients.

One hundred sixty-six patients with germ-cell tumors (GCT) of the testis, retroperitoneum, and mediastinum were treated with cyclophosphamide, vinblastine, bleomycin, dactinomycin, and cisplatin (VAB-6), with and without maintenance chemotherapy. The overall complete response (CR) rate was 78%, 67% to chemotherapy alone, and 11% after chemotherapy and resection of viable residual cancer. The CR rate in all patients with seminoma was uniformly high, while the CR rate of patients with testicular nonseminomatous germ-cell tumors (79%) was superior to that of similar tumors of extragonadal origin (60%). The overall relapse rate was 12%, and was greater in tumors of extragonadal origin (21%) than in those of testicular origin (11%). Three relapses occurred after 2 years. Maintenance chemotherapy did not prolong either relapse-free or total survival. Toxicity was tolerable, and there were no treatment deaths. No Raynaud's phenomena have occurred, with a minimum duration since start of therapy of 36 months. VAB-6 is an effective chemotherapy regimen in patients with GCT with no treatment-related deaths and a majority of patients requiring only 3 months of treatment.

Fifty-four marijuana-naive cancer patients undergoing chemotherapy and about to use THC (delta-9-tetrahydrocannabinol) as an antiemetic for the first time were randomly assigned to one of two conditions: stress inoculation or placebo/information training. It was hypothesized that subjects exposed to stress inoculation training would experience fewer adverse subjective effects of THC, experience less stressful nausea and vomiting, and be less likely to voluntarily withdraw from subsequent THC trials. None of the hypotheses was confirmed.

The results of a prospective randomized study of 46 patients with breast carcinoma are presented. Twenty six patients were treated with AM3 (biological response modifier) associated with adjuvant radiotherapy and chemotherapy. Bone marrow hypoplasia was observed in 26.9% of the patients treated with AM3 compared with a 65% incidence in the control group (P less than 0.05). All patients showed leukopenia in peripheral blood count; however, the nadir of leukocytes was 4,000 leu/mm3 in the test group, compared with 1,900 leu/mm3 in the control group. None of the patients in the AM3 group showed thrombocytopenia, whereas 55% in the control group did. In none of the AM-3-treated cases was it necessary to modify the therapeutic schedule of adjuvant treatment.

Because the results of our published trial [R. Ramphal, B. S. Kramer, K. H. Rand, R. S. Weiner, and J. W. Shands, Jr., J. Antimicrob. Chemother. 12(Suppl. A):81-88, 1983] of ceftazidime versus cephalothin, gentamicin, and carbenicillin (KGC) revealed a preponderance of gram-positive superinfections, including those caused by clostridia, in patients treated with ceftazidime, we added vancomycin to the ceftazidime regimen at study entry 49 and continued with a 2:1 randomized comparison of ceftazidime-vancomycin (CV) versus KGC. Criteria for study entry were fever (temperature, greater than or equal to 38.5 degrees C on one occasion or greater than or equal to 38 degrees C on two occasions 6 h apart) and granulocytopenia (less than 500/mm3 or a falling count anticipated to be less than 500/mm3). Ninety-five entries (79 patients) were evaluable. The numbers of initial clinical responses for ceftazidime-, KGC-, and CV-treated patients were 9 of 21 (43%), 21 of 37 (57%), and 21 of 37 (57%), respectively; differences were not significant. The death rate was lower with CV (2 of 37 patients) than with KGC (10 of 37 patients) (P less than 0.05 by two-tailed analysis) or with ceftazidime alone (7 of 21 patients) (P less than 0.025). Death from presumed infections occurred in 9 of 37 KGC-treated patients versus 1 of 37 CV-treated patients (P less than 0.025). Superinfections occurred in five ceftazidime-treated patients (24%) versus 7 KGC-treated patients (19%) but not in CV-treated patients (CV versus KGC, P less than 0.05; CV versus ceftazidime, P less than 0.01). CV appears to be superior to KGC or ceftazidime alone in the management of febrile granulocytopenic cancer patients.

This is the first prospective randomized study comparing commonly used antiemetics in children receiving cancer chemotherapy. We compared metoclopramide (MCP) with chlorpromazine (CLP), both administered in conventional doses, in 50 cancer patients aged 6 to 18 years who were receiving emetic chemotherapy. CLP proved significantly better than MCP in reducing both the frequency of vomiting (P less than .05) and the duration of nausea and vomiting (P less than .025). Extrapyramidal reactions (EPRs) were more common in MCP-treated patients. We conclude that, in the standard doses used, CLP is a better overall antiemetic than MCP for children receiving intensive chemotherapy. However, further prospective pediatric studies of antiemetic combinations are needed.

A randomized double-blind cross-over study was performed to evaluate the possible anti-emetic effect of the partial opiate antagonist buprenorphine in comparison to domperidone in chemotherapy-induced nausea and vomiting. Emesis was of significantly shorter duration on domperidone treatment. Most patients preferred domperidone, mainly due to adverse side-effects of buprenorphine. Nevertheless, emesis in buprenorphine treatment was less disabling. Therefore, it might be useful to search for new alternatives in this group of drugs or to use them in a combination regimen of anti-emetic agents.

Ninety patients with breast cancer refractory to cyclophosphamide/fluorouracil/methotrexate (CMF) have been randomized in their treatment, receiving either doxorubicin or mitoxantrone. Seventy-nine have received two full courses of therapy. Twelve of the 40 (30%) who initially received doxorubicin responded, whereas eight of the 47 (17%) who received mitoxantrone responded. These rates are not statistically different. The degree of myelosuppression was equivalent. Patients who received mitoxantrone had less nausea, vomiting, alopecia, and fatigue. Controllable clinical congestive heart failure developed in seven patients, and four others had a deterioration of noninvasive measures of cardiac function without clinical failure. One patient with clinical heart failure developing received only doxorubicin and one, only mitoxantrone, whereas the others received both agents. The duration of remission and time lapsed before disease progression were almost identical for the two regimens. This study included a crossover design. Two of 22 (10%) patients receiving doxorubicin and five of 24 (21%) receiving mitoxantrone as secondary therapy responded. This suggests that there is not absolute cross-resistance between these agents. We conclude that the efficacy of these two drugs is comparable in patients refractory to CMF, though the nonhematologic side effects of mitoxantrone are less.

A prospective randomised double blind crossover trial was conducted comparing the new synthetic cannabinoid nabilone with oral domperidone in a group of children receiving repeated identical courses of emetogenic chemotherapy for a variety of malignant diseases. Eighteen of 23 consecutive eligible children, aged 10 months to 17 years, completed the trial. When taking nabilone they experienced significantly fewer vomiting episodes and less nausea, and two thirds expressed a preference for the drug. The most common side effects of treatment with nabilone were somnolence and dizziness, with one patient being disturbed by hallucinations. The results indicate that nabilone is an effective antiemetic for children having chemotherapy, even for young children. It seems to be superior in this respect to domperidone, and although it has a higher incidence of side effects, these are mostly acceptable to patients. It can be recommended as an alternative to conventional antiemetic treatment throughout childhood.

A multicenter, randomized, controlled trial was conducted comparing active treatment with placebo in 227 patients with breast, colorectal, lung and other solid forms of cancer. Combination therapy, (CT) conventionally employed for the various types of tumor involved, was associated with MPA (117 patients) or placebo (110 patients). MPA was given orally as tablets, as a dose of 500 mg b.i.d. for 6 months. The results were, briefly, as follows: The incidence of leukopenia was significantly lower in the groups receiving MPA in patients with breast and colorectal cancer (P less than 0.02). Tumors of the lung and other solid forms showed no such difference. The incidence of thrombocytopenia was the same in all disease groups. Objective responses (CR + PR) were observed in 23/46 (50%) of breast cancer patients treated with CT + MPA, and in 13/47 (28%) of those given CT + placebo. The difference was significant (P less than 0.02). Subjective parameters also showed more improvement in the MPA group than in the patients given CT alone. No significant differences were found for the other types of tumor, but the numbers in this population were very limited. In a group of 45 patients, antithrombin III a (%), antithrombin III R: Ag (%), plasminogen (mg/dl), alpha-2 macroglobulin (%), factor VIII C (%), factor VIII R: Ag (%) and factor IX C (%) were determined. The most interesting post-treatment findings were an increase in anti-thrombin III (activity and antigen level) and in plasminogen. This suggests that MPA does not increase the risk of thrombosis, and might even, to some extent, impede tumor-induced thrombophilia.(ABSTRACT TRUNCATED AT 250 WORDS)

A double-blind, randomized, crossover study was conducted to compare the efficacy and safety of high-dose dexamethasone and high-dose metoclopramide in the treatment of chemotherapy-induced nausea and vomiting. All entered patients had no prior chemotherapy and all received inpatient emetogenic chemotherapy mainly without cisplatin. Of the 40 evaluable patients, 23 (58%) had no vomiting with dexamethasone compared with only 11 (28%) receiving metoclopramide (P less than 0.025). Dexamethasone was found to have less adverse effect than metoclopramide on patient's appetite and activity (P less than 0.025 and P less than 0.01, respectively). Twenty-one patients (53%) developed mild to severe somnolence with metoclopramide compared to only seven (18%) who experienced this adverse effect with dexamethasone (P less than 0.01). Six patients (15%) developed extrapyramidal manifestations with metoclopramide, but none with dexamethasone. Furthermore, during dexamethasone therapy, patients developed less diaphoresis, insomnia, headache and dizziness. Upon questioning patients about their preference to future use of the antiemetic drug therapy, 28 patients (70%) preferred dexamethasone, two (5%) preferred metoclopramide and 10 (25%) found no difference. We conclude that high-dose dexamethasone has a greater antiemetic activity and is more safe than high-dose metoclopramide in patients receiving emetogenic chemotherapy mainly without cisplatin.

In a randomized trial of 58 cancer patients receiving strongly emetogenic cytostatic drugs (cisplatin or comparable cytostatic agents, alone or in combination), the anti-emetic action of oral metoclopramide was tested, alone or combined with prednisone. Patients of group A (33 during 46 treatment cycles) received three times 50 mg metoclopramide and three times 25 mg prednisone. Those of group B (25 patients during 35 cycles) received three times 50 mg metoclopramide. The drug was given two hours before as well as two hours and six hours after administration of the cytostatic drugs. Good or satisfactory prophylaxis of nausea and vomiting (no or at most three vomits) was achieved during 37 cycles (80.5%) of group A patients and 30 (85.7%) of group B patients. Complete absence of vomiting was obtained in 52% of cycles in group A, 46% of cycles in group B; complete absence of nausea in 39% and 32%, respectively. There was no statistically significant difference between the two treatments in their preventive action. Three times 50 mg metoclopramide (with or without prednisone) four hours apart during one cytostatic-drug cycle was well tolerated by patients in both groups and can be recommended as a simple, practical prophylaxis of nausea and vomiting in the course of strongly emetogenic treatment of cancer.

The efficacy of trioxifene mesylate, a new antiestrogen, in the management of advanced breast cancer was evaluated in 69 patients. Fifty-two patients were randomly allocated to dose schedules of 5 mg, 10 mg, and 20 mg orally twice daily. There were five complete responders (10%), 22 partial responders (42%), and 9 patients (17%) with no change in disease. The median time to progression was 12 months (range, 4-27+). Positive estrogen receptor status, long disease-free interval, and low tumor burden (with fewer sites of disease) correlated with higher response rates. Higher doses did not result in better responses. Another group of 17 patients who responded to prior tamoxifen administration, upon failure, were treated with trioxifene. Two (12%) had partial remission with time to progression of 3 and 10 months, respectively. Side effects were mild and generally well-tolerated, with hot flashes being most common (20%). These results suggest that trioxifene mesylate is an active agent, and has similar therapeutic efficacy and toxicity compared with those reported for tamoxifen. In a small fraction of patients treated after tamoxifen therapy was received, objective response was also observed. This observation requires further evaluation.

Schedule dependency of bisantrene was evaluated in refractory metastatic breast cancer. Patients were randomly assigned to receive either a single (S) bolus injection of 300 mg/m2 (37 patients) or an injection of 80 mg/m2 daily for 5 days (D x 5) (35 patients) every 3-4 weeks after stratification by performance status, dominant disease site, and response to prior doxorubicin therapy. All but one patient had received prior doxorubicin. Partial remission (PR) was achieved by 5 of 35 patients (14%) in the S arm and 7 of 35 patients (20%) in the D X 5 arm (P = NS). There were 4 patients who had primary refractoriness to doxorubicin but responded to bisantrene. The median number of courses was two for both arms. The median time to progression was 5 months for the responders in each arm and 3 and 4 months, respectively, for patients who showed no change in the S and D X 5 arms. Myelo-suppression was dose-limiting and greater for the D X 5 arm. Drug fever (34% versus 21% of courses; P = 0.02) and myalgia (22% versus 10% of courses; P = 0.02) were reported more often in the D X 5 arm; malaise was greater in the S arm. Grade 2-3 nausea and vomiting occurred more often in the S arm (40% versus 10% of courses; P less than 0.01). Significant hypotension that was not symptomatic occurred in 1 patient in the D X 5 arm. Phlebitis occurred in 3 patients without a central line. One patient who had previously received doxorubicin and mitomycin C developed heart failure, which was controlled with medication. Bisantrene is an effective drug for metastatic breast cancer that has incomplete cross resistance to doxorubicin, and there was no schedule dependency in this study.

The oral bioavailability of high-dose metoclopramide was studied in 12 patients, who received oral or intravenous (i.v.) metoclopramide in random order with each of 2 consecutive courses of cytotoxic chemotherapy. The terminal half-life of metoclopramide was 7.1 +/- 0.4 h (mean +/- SEM) and was not affected by the route of drug administration. Mean bioavailability was 86.6 +/- 4.7% and the range (65-118%) was less than that reported for standard doses. Neither half-life nor bioavailability was significantly correlated with age. Adverse effects were mild and were similar for both oral and iv metoclopramide. Oral high-dose metoclopramide, given in the same doses as for i.v. administration, should therefore be as effective as the i.v. regimen and may be easier to administer.