The safety and efficacy of intravenous granisetron were compared with combinations of conventional antiemetics in two single-blind, parallel-group studies which have been reported previously. In this review updated data from both studies is presented. In both studies granisetron (40 micrograms/kg) was given as a single 5-min infusion before chemotherapy with two additional doses allowed to control subsequent nausea and vomiting. All patients were naive to chemotherapy. Patients due to receive cisplatin (greater than 49 mg/m2) were randomly assigned to receive either granisetron alone or metoclopramide (3 mg/kg) plus dexamethasone (12 mg) given prophylactically followed by an 8-h infusion of metoclopramide (4 mg/kg). In the 24 h after the start of chemotherapy 70% of granisetron-treated patients and 67% of comparator group were complete responders. In patients due to receive moderately emetogenic chemotherapy, granisetron was compared with chlorpromazine (up to 200 mg/24 h) plus dexamethasone (12 mg). Twenty-four hour efficacy was significantly higher in the granisetron group with complete response in 68% of patients compared to 47% in the comparator group (P less than 0.001). A subset of 40 patients in this study were crossed over to receive the alternative antiemetic on their next cycle of chemotherapy. A significant majority of patients (32/34; 94%) preferred granisetron (P less than 0.001). Around 80% of the granisetron-treated patients in both groups required only a single prophylactic dose of granisetron. Following the first additional dose of granisetron, around 87% of patients reported symptoms to be improved or resolved. Adverse experience reporting was higher in the comparator groups with somnolence and extrapyramidal reactions representing the most common events. Headache was the most commonly reported adverse experience in granisetron-treated patients. Granisetron has proved safe and effective in controlling chemotherapy-induced emesis and is more convenient to administer than conventional antiemetics.

200 cancer patients who were due to receive fractionated chemotherapy (cisplatin greater than or equal to 15, ifosfamide greater than or equal to 1.2 or etoposide greater than or equal to 120, all mg/m2 per day) for 5 days, entered a multicentre study. Patients were randomised single-blind to receive either prophylactic intravenous granisetron (40 micrograms/kg) or alizapride (4 mg/kg followed by 4 mg/kg at 4 and 8 h post-treatment) plus dexamethasone 8 mg. Granistron was superior to the combination in preventing nausea and vomiting (54% vs. 43% complete responders). The differences were in the cisplatin-treated group. The time to first episode of moderate to severe nausea was significantly longer in the granisetron group (P = 0.03). Dosing with granisetron was more simple, with over 85% of patients requiring only a single prophylactic dose. Fewer patients receiving granisetron experienced adverse events (48% vs. 62%, P = 0.047). The frequency of constipation was, as expected, significantly higher in the granisetron group. Extrapyramidal effects, which were not noted by any granisetron patient, occurred in 5.3% of comparator patients.

Medroxyprogesterone acetate (MPA) is widely used in the hormonal therapy of breast cancer. So far, oral formulations of MPA commercially available present a very low bioavailability, with a less than 10% extent of oral absorption. A new oral preparation of MPA has been recently developed. Based on a pilot study, an open, randomized, crossover trial has been performed on 22 breast and endometrial cancer patients to evaluate the relative bioavailability of this new oral formulation (200-mg sachet, twice daily) as compared with a standard formulation (Farlutal, 500-mg tablet, twice daily). The bioavailability evaluation was mainly based on the area under the curve measured between two administrations at steady state, after 15 days of continuous therapy. Wide interpatient variability of MPA plasma levels after oral MPA administration was confirmed. The MPA plasma levels were higher in patients treated with the new formulation than in patients treated with Farlutal. The relative bioavailability of the new preparation was 3.5 times higher than that of the standard. This new formulation represents a great improvement in the extent of oral absorption of MPA and could lead to better management of hormone-responsive tumors by hormonal therapy.

A phase I multicenter evaluation of a novel antiestrogen, toremifene, was undertaken in postmenopausal women with various advanced difficult-to-treat malignancies. One hundred and seven women were treated at one of six dosage levels (10, 20, 40, 60, 200, or 400 mg/d orally) for at least 8 weeks. Weekly evaluations for toxicity were conducted. The most common side effects were nausea (31%), vomiting (12%), and hot flashes (29%). Five patients were removed from the study for possible adverse reactions: three patients experienced hypercalcemia; one experienced tremulousness, fatigue, and inability to think clearly; and one had vaginal bleeding. Twelve patients died while on study, 11 with disease progression and one with a pulmonary embolus. Sex hormone-binding globulin (SHBG) levels increased and there was a modest decline in serum antithrombin III levels. Four of 48 assessable patients had partial responses: three with breast cancer and one with endometrial cancer. Toremifene was generally well tolerated at the doses tested.

Both aciclovir and brivudin are effective in the treatment of immunocompromised children with varicella-zoster virus infection. To determine which drug is preferable, a prospective randomized trial aciclovir vs. brivudin was conducted. Forty-three immunocompromised children were randomly assigned to receive aciclovir intravenously at a dose of 1,500 mg/m2/d and brivudin orally at a dose of 15 mg/kg/d, respectively. Twenty-two patients were treated with aciclovir and 21 with brivudin. In all children the general status improved within two days. The eruption of new lesions stopped within one to five days, fever stopped within one to nine days, complete remission occurred within five to six days after introduction of the virustatic therapy. There was no difference in therapeutic efficacy between aciclovir and brivudin. Two children in each group did not respond to the medication. No myelo-, hepato- and nephrotoxic side effects due to aciclovir or brivudin were observed. All obviously immunocompromised children with varicella or zoster may be treated with aciclovir or brivudin.

Several agents in a new class of antiemetic compounds, 5-hydroxytryptamine (5-HT3) antagonists, have shown promise as effective antiemetics with fewer side effects than metoclopramide. One of these agents, batanopride, produced no severe toxicity at doses that prevented emesis due to chemotherapy in early Phase I trials. We conducted a randomized, double-blinded, 7 arm clinical trial to: (1) identify the presence of a dose-response for complete protection from emesis, and (2) compare batanopride with a standard antiemetic, methylprednisolone if a dose-response was found not to exist. Prior to chemotherapy, six patient groups each received a single intravenous dose of batanopride ranging from 0.2 to 6.0 mg/kg whereas a seventh group received methylprednisolone 250 mg intravenously. Chemotherapy-naïve cancer patients scheduled to receive moderately emetogenic chemotherapy were eligible. Primary treatment outcomes that were recorded and analyzed included the number of episodes of emesis, the time to the first episode of emesis as well as the frequency and severity of nausea. Two hundred and eight patients accrued between April 1989 and February 1990 were evaluable for response. A significant dose-response effect for complete protection from emesis was not seen over the first 24 hours after chemotherapy (p = 0.102). However, a linear dose-response effect for time to first emesis was evident in a multivariate analysis (p = 0.029). While the highest batanopride dose group was associated with a higher complete protection rate (CPR) than the control group, this group also exhibited a higher incidence of diarrhea (p = 0.013), hypotension, and electrocardiographic abnormalities.(ABSTRACT TRUNCATED AT 250 WORDS)

Four hundred eleven women with metastatic breast cancer were randomly assigned to receive either 60 mg/m2 doxorubicin (130 patients), 320 mg/m2 bisantrene (146 patients), or 14 mg/m2 mitoxantrone (135 patients). The doses were given intravenously every 3 weeks with a cross-over design to determine their relative efficacy and toxicity. To be eligible, patients must have had one previous chemotherapy regimen, and patients who were estrogen receptor positive must have failed endocrine therapy. There were 365 patients assessable for response and 399 assessable for toxic effects. The median age was 57 years; 18% were premenopausal or perimenopausal. Visceral dominant disease was present in 66% of the patients. Ninety-seven percent of the patients had a disease-free interval from diagnosis to first recurrence of less than 1 year. The response rate was 28% with doxorubicin, 13% with bisantrene, and 14% with mitoxantrone (P = .004). Median time to treatment failure was 133 days with doxorubicin, 66 days with bisantrene, and 68 days with mitoxantrone (logrank P = .06). The median survival was 315 days for doxorubicin, 290 days for bisantrene, and 177 days for mitoxantrone (logrank P = .04), although survival at 2 years was similar for all three agents. There were five responses in the 66 patients crossed over to doxorubicin and one response each for patients crossed over to bisantrene (39 patients) or mitoxantrone (63 patients). Toxicity leading to discontinuance of therapy was more common with doxorubicin, and discontinuance of therapy was due primarily to patient's request or cardiotoxicity. The major dose-limiting toxic effect for all three agents was leukopenia. Nausea and vomiting, mucositis, and alopecia were more severe with doxorubicin. Congestive heart failure developed in nine patients treated with doxorubicin, zero patients treated with bisantrene, and two patients treated with mitoxantrone. A decrease in the left ventricular ejection fraction, as defined by moderate to severe Alexander grade changes, was more common in patients treated with doxorubicin (doxorubicin-treated patients = 20%, bisantrene-treated patients = 5%, and mitoxantrone-treated patients = 10%). This study demonstrates that bisantrene and mitoxantrone have only modest activity in metastatic breast carcinoma. The activity of doxorubicin is greater than that of the other two agents, but at a cost of increased toxicity.

The purpose of this quasi-experimental pilot study was to compare the effect of patient-controlled (PCAE) and nurse administered (NCAE) antiemetic therapy for controlling chemotherapy-induced nausea and vomiting in patients receiving moderate emetogenic chemotherapy. Twenty subjects were randomly assigned to either the PCAE group who received IV antiemetic medication via a patient-controlled pump or the NCAE group who received antiemetic medication via nurse administered minibags. Nausea, vomiting, sedation, and drug consumption were measured. There was no difference in nausea scores between the two groups. Subjects in the PCAE group consumed significantly less medication than subjects in the NCAE group.

Dronabinol (Marinol, Roxane Laboratories, Columbus, OH) and prochlorperazine were tested alone and in combination in a randomized, double-blind, parallel group, multicenter study. Patients were randomized to receive either 1) dronabinol 10 mg every 6 hr plus placebo; 2) placebo plus prochlorperazine 10 mg every 6 hr; or 3) dronabinol and prochlorperazine, each 10 mg every 6 hr. Antiemetic treatment was begun 24 hr prior to and continued for 24 hr after the last dose of chemotherapy; all was given orally. Only 29% of patients in group 3 versus 47% in group 1 and 60% in group 2 experienced nausea after chemotherapy. In addition, the median duration per episode and severity of nausea were significantly less with combination therapy. Vomiting occurred after chemotherapy in 41%, 55%, and 35% of patients in groups 1, 2, and 3, respectively. The median duration per episode of vomiting was 1 min in group 3 versus two in group 1 and four in group 2. Side effects, primarily CNS, were more common in group 1 than in group 2; addition of prochlorperazine to dronabinol appeared to decrease the frequency of dysphoric effects seen with the latter agent. The combination was significantly more effective than was either single agent in controlling chemotherapy-induced nausea and vomiting.

Acivicin (AT-125) is a glutamine antagonist with dose-limiting, schedule-dependent CNS toxicity and predictable CSF penetration after intravenous administration. Because of these properties, a trial in CNS malignancies was initiated. Thirty-two patients with recurrent or residual malignant astrocytomas were treated with AT-125. The majority of patients had glioblastoma multiforme (24) and had received prior nitrosoureas (21). The median age was 50 years, and Southwest Oncology Group (SWOG) performance status was 2. The major determinant of response was based upon radiologic criteria using computed tomographic (CT) scanning and/or magnetic resonance imaging (MRI) scans. The tumor mass was measured in two perpendicular planes, which yielded the largest cross-sectional area. Standard solid tumor criteria for response were used. All responding patients also had a stable or tapered dose of corticosteroids with stable or improved performance status and neurologic examination. There were four objective responses (12%): one complete remission (3 1/2+ years) and three partial remissions (57, 86, and 322 days). Two patients had improvement in disease that did not meet requirements for a partial remission. Toxicity was mild and primarily consisted of nausea, vomiting, and lethargy. Two patients were removed from study due to neurotoxicity (depression and hallucinations). The strict response criteria used in this trial were not those that have been used in testing other active agents such as carmustine (BCNU). We conclude that AT-125 has objective antitumor activity in malignant astrocytomas and warrants further study.

The purpose of this study was to evaluate efficacy and safety parameters in women with leiomyomata uteri treated with the GnRH agonist leuprolide acetate depot, 3.75 mg intramuscularly every 4 weeks for 24 weeks. One hundred twenty-eight patients were enrolled in a randomized, double-blind, placebo-controlled multicenter study involving 13 investigative centers. Mean uterine volume decreased by 36% at 12 weeks and 45% at 24 weeks of leuprolide therapy. Patients treated with placebo had increased in mean uterine volume of 16% at 12 weeks and 5% at 24 weeks. Seventy-seven percent of leuprolide-treated patients had a more than 25% reduction in uterine volume, compared with 9% of placebo-treated controls. Mean uterine volume returned to pre-treatment size 24 weeks after cessation of leuprolide treatment. The majority of patients had resolution or improvement of their fibroid-related symptoms after 24 weeks of leuprolide treatment. Of 38 leuprolide-treated patients presenting with menorrhagia, 37 (97%) had resolution of this symptom at the time of the final visit. Although 95% of women treated with leuprolide acetate experienced some side effects related to hypoestrogenism, only five patients (8%) terminated treatment prematurely. We conclude that leuprolide acetate depot treatment of leiomyomata uteri is safe and causes significant but temporary reductions in uterine size and fibroid-related symptoms.

Experimental models have demonstrated the Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH)-potentiating activity of lonidamine. Phase II clinical trials on advanced breast cancer have shown that this drug induced a 16% objective response rate. Present multicentric randomized trial was conducted to verify whether lonidamine can potentiate the antineoplastic effects of conventional fluorouacil, Adriamycin, cyclophosphamide (FAC) chemotherapy in advanced breast cancer. From January 1987 to December 1989, 265 patients were enrolled in this study, and 231 are evaluable for response. After stratification according to institution and ECOG performance status (PS), the patients were randomly allocated to receive either standard FAC therapy (group A) or FAC plus lonidamine (600 mg orally daily three times a day) (group B). After three FAC courses, the patients with no progressive disease were further randomized to either receive continuous treatment up to the time of tumor progression (maximum: 10 courses) or to discontinue therapy when a response "plateau" was reached. In this latter group, the same therapy was restarted at relapse or disease progression. Objective response (complete response plus partial response) was significantly higher in group B (66.3%) compared to group A (42.3%). The actuarial median times to disease progression was also significantly longer (P less than 0.0001) in group B (median 9 months) than in group A (median 6 months). Other than myalgia and gastric pain, no increased toxicity was observed in the lonidamine. The analysis of second randomization are yet available because of the longer follow-up time required. Present findings suggest an interesting additive effect of lonidamine when combined with FAC chemotherapy and warrant further investigation in other therapeutic regimens and in other neoplastic diseases.

Sixty patients with metastatic renal cell carcinoma were entered into an ongoing randomized phase II study with lonidamine, 350 mg/m2 orally daily (arm A) and high dose tamoxifen, 150 mg/m2 orally daily for 6 months, afterwards 50 mg/m2 (arm B), until tumor progression. All patients had measurable disease and documented tumor progression prior to treatment. There were 1 complete and 1 partial remission among 19 evaluable patients in arm A (10.5%) and 2 complete and 1 partial remission among 25 evaluable patients (12%) in arm B. Objective responses were observed in pulmonary, nodal, and cutaneous metastases. In addition, in 63% and 64% tumor progression could be stopped in arm A and B, respectively. Median response duration was 100 days (range, 20-361) in arm A and 150 days (range, 28-355) in arm B. One year survival rate was 37.5% with lonidamine and 35% with tamoxifen. In arm A patients with tumor progression within 12 weeks after diagnosis of metastatic disease survived significantly shorter than patients with a longer interval (P less than 0.05). Nephrectomy or number and localization of metastatic sites failed to significantly influence probability of remission or survival. Toxicity was mostly mild to moderate. Four patients in the lonidamine arm had to discontinue treatment because of intolerable myalgias, which were immediately reversible. These data suggest that lonidamine and high-dose tamoxifen are moderately effective in widespread renal cell carcinoma where treatment intention is palliative.

The beneficial effects of transcutaneous electrical stimulation of the P6 antiemetic point (Neiguan) as an adjuvant to standard antiemetics was studied in over 100 patients in whom chemotherapy-induced sickness was not adequately controlled by antiemetics alone. Although the results were not quite as good as with invasive acupuncture, more than 75% patients achieved considerable benefit from what was a non-toxic procedure. The use of large diffuse low impedence electrodes simplifies the technique. The 2 hourly application of Sea Bands prolongs the antiemetic action. Best results were obtained from the 2 hourly self-administration of 5 min of transcutaneous electrical stimulation of P6 using a simple battery-operated TENS machine (15 Hz) to activate a large, easy-to-place surface electrode and increasing current until Qi is elicited.

One hundred eighty four patients with advanced inoperable non-small cell lung cancer were treated with either lonidamine (A), mitomycin-C/vindesine (B), or mitomycin-C/vindesine plus lonidamine (C) in a prospective randomized trial. The response rates for each treatment arm were 3.4% (A), 22.4% (B) and 25.9% (C), respectively. This difference is statistically significant (P less than 0.01). The median survival time for patients treated with mitomycin-C/vindesine and mitomycin-C/vindesine plus lonidamine was 194 days and 221 days, respectively. In comparison with 145 days for lonidamine alone there is a statistically significant difference in survival between the chemotherapy groups (P less than 0.01). When combined with mitomycin-C/vindesine, lonidamine induces an increase in the response rate and there is a higher proportion of patients living after 12 months of treatment (32% v 20%) in comparison to mitomycin-C/vindesine alone. The subjective tolerance of all treatment groups was very good, toxicity was only mild without major differences between the treatment arms. Combination chemotherapy with mitomycin-C/vindesine plus or minus lonidamine could prolong survival in advanced inoperable nonsmall cell lung cancer significantly without severe toxicity.

Seventy consecutive patients were entered in a two-arm randomized trial after surgical resection for locally advanced gastric cancer. In the first arm, 37 patients were included as a control group, receiving no further treatment after surgery. In the second arm, 33 patients were treated with adjuvant chemotherapy consisting of mitomycin C (MMC), 20 mg/m2 administered intravenously once every 6 weeks for four consecutive cycles. All patients in both arms were followed in the same way for 5 years. At 5 years 23 of 37 patients in the control arm and 7 of 33 patients in the treatment arm were dead because of relapse. Actuarial survival curve was statistically significant in favor of patients given adjuvant MMC (p less than 0.001). After 10 years follow-up, 31 of 37 patients in the control arm and 16 out of 33 patients in the treatment arm were dead because of relapse, the statistical differences continuing in the actuarial survival curve in favor of treated patients (p less than 0.01). The best advantages of adjuvant treatment were observed in the T3N0M0 stage. The most frequent relapse site was the peritoneal cavity and the relapse pattern shows special decrease in liver metastases in treated patients. Toxicity was acute and mild. No delayed toxicity or second malignancies were observed. These data suggest that adjuvant MMC after resected surgery of gastric cancer is a successful treatment and its effects are still evident after 10 years of follow-up.

In phase I studies of KRN 8601, single administration and six-day consecutive administration studies were conducted in healthy male adults using intravenous drip infusion and subcutaneous administration. Safety and tolerance to KRN 8601 were confirmed and a dose-related increase of neutrophil counts by KRN 8601 was observed. In an early phase II study, the safety and tolerance to KRN 8601 in cases of neutropenia following cancer chemotherapy were shown at doses of 25-800 micrograms/m2 and an improvement of neutropenia was seen at doses of more than 50 micrograms/m2. In a phase II study, the optimal dose was investigated for subcutaneous administration and intravenous drip infusion in cases of neutropenia induced by chemotherapy for malignant lymphomas. The optimal dose was 75 micrograms/body (about 50 micrograms/m2) for subcutaneous administration and 100-200 micrograms/m2 for intravenous drip infusion. In a phase III study, a double-blind prospective randomized trial comparing KRN 8601 with an inactive placebo against malignant lymphomas was performed and the inhibitory, improvement and recovery-promoting effects of KRN 8601 (75 micrograms/body, sc) on neutropenia were demonstrated.