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Biomedical subjects

S M Grunberg

Publications and source records attributed to S M Grunberg.

At least 19 recordsLinked to original sources
PubMed1992

Phase I and other dose-ranging studies of ondansetron.

Phase I studies of intravenous (IV) ondansetron in cancer patients receiving emetogenic chemotherapy were designed to assess the degree of antiemetic protection and pattern of adverse events produced by ondansetron at various doses. In a study of 44 patients receiving various forms of chemotherapy (including cisplatin), ondansetron was administered in three IV doses 2 hours apart beginning 30 minutes prior to chemotherapy. Antiemetic efficacy was seen at all dose levels (0.04 mg/kg to 0.35 mg/kg), with 54% of patients experiencing no vomiting and 76% experiencing two or fewer vomiting episodes within the first 24 hours. Overall, ondansetron was well tolerated, and no dose-limiting toxicity was observed. The most common adverse events were mild sedation, mild headache, and transient elevations of transaminases. In a second phase I study, 45 patients receiving cisplatin (median dose 100 mg/m2) were given ondansetron in three IV doses (range, 0.01 mg/kg to 0.48 mg/kg) 4 hours apart. There was no statistically significant difference in antiemetic efficacy among dose levels from 0.06 mg/kg to 0.48 mg/kg; however, there was a trend toward a decrease in the number of patients with failure of antiemetic protection at the higher exposures. Overall, 44% of patients had no emetic episodes, and 81% of patients had two or fewer emetic episodes within the first 24 hours. The number and intensity of adverse events, of which headache was the most common, appeared to increase at the 0.48 mg/kg dose level. A randomized double-blind study that compared three dose levels of ondansetron indicated that three doses of 0.15 mg/kg was superior in efficacy to three doses of 0.015 mg/kg, and not significantly different from three doses of 0.30 mg/kg. Dystonic reactions or akathisia were not noted in any study.

Antiemetics↗
PubMed1991

Treatment of non-small-cell lung cancer with vinblastine and very high-dose cisplatin. A Southwest Oncology Group study.

Suggestions of a dose-response effect for cisplatin in non-small-cell lung cancer have contributed to the development of very high-dose cisplatin regimens (200 mg/m2 per cycle). We treated 53 eligible patients with metastatic or recurrent non-small-cell lung cancer with a combination of 100 mg/m2 cisplatin and 4 mg/m2 vinblastine, each given on days 1 and 8 of a 28-day cycle. We observed no complete response and 4 partial responses (8%). Median survival was 6 months. Toxicities of grade III or greater included leukopenia (11 cases), nausea/vomiting (6 cases), thrombocytopenia (2 cases), anemia (2 cases), and elevation of transaminase (1 case). Neurotoxicity has been reported to be a major problem in several other very high-dose cisplatin regimens. The low level of neurotoxicity observed in this study may be attributable to the median cumulative cisplatin dose of less than 600 mg/m2. This vinblastine/very high-dose cisplatin regimen showed minor activity against non-small-cell lung cancer. The level of activity did not surpass that of standard-dose (100 mg/m2 per cycle) cisplatin-containing regimens.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

Tolerance of extended (28 day) continuous infusion of 5-fluorouracil in advanced head and neck cancer.

Since continuous exposure increases the cytotoxicity of 5-Fluorouracil, this agent is now commonly administered by 4-5 day continuous infusions. However Phase I studies have suggested that infusion of doses up to 450 mg/m2/day for at least 28 days may be possible. In the present study 12 patients with advanced head and neck cancer were treated with continuous infusion 5-Fluorouracil at starting doses of 400-450 mg/m2/day for 28 days followed by a 14 day rest period. Patients received a median of 2.5 cycles over 10 weeks for a median total 5-Fluorouracil dose of 12,700 mg/m2. One patient achieved Partial Response. Significant stomatitis (Grade II or greater) was seen more frequently than predicted from Phase I studies (8/12 patients) and was the most common cause for dose reduction. Diarrhea, emesis, palmar/plantar syndrome and skin rash were also noted. No significant myelosuppression was seen. Extremely large amounts of 5-Fluorouracil can be delivered to head and neck cancer patients by extended infusion. However due to the high frequency of stomatitis in this population, lower starting doses than those used in this study may be required.

Adult↗
PubMed1991

Chemotherapy of metastatic Merkel cell carcinoma: case report and review of the literature.

Merkel cell carcinoma is a skin cancer that bears histologic, ultrastructural, and immunohistochemical resemblance to small cell lung cancer. Although this tumor is often localized and may be treated with wide excision, metastatic Merkel cell carcinoma does appear in 18%-28% of patients and may be aggressive and lethal. We report a case of metastatic Merkel cell carcinoma who responded to treatment with cisplatin/etoposide. Review of the literature reveals that doxorubicin/cyclophosphamide-based regimens and cisplatin-based regimens have been most commonly studied. Complete and partial responses are often achieved although the duration of response tends to be short. Further investigation of chemotherapeutic regimens similar to those used in small cell lung cancer should be undertaken.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

Treatment of unresectable meningiomas with the antiprogesterone agent mifepristone.

The possibility that meningioma growth may be related to female sex hormone levels is suggested by several lines of evidence. Meningiomas are twice as common in women as in men, have been observed to wax and wane with pregnancy, and are positively associated with breast cancer. A physiological explanation for these phenomena is provided by the finding of steroid hormone receptors in meningiomas. However, unlike breast cancer, meningiomas are much more commonly positive for progesterone receptors than for estrogen receptors. The authors initiated a study on long-term oral therapy of unresectable meningiomas with the antiprogesterone mifepristone (RU486). Fourteen patients received mifepristone in daily doses of 200 mg for periods ranging from 2 to 31+ months (greater than or equal to 6 months in 12 patients). Five patients have shown signs of objective response (reduced tumor measurement on computerized tomography scan or magnetic resonance image, or improved visual field examination). Three have also experienced subjective improvement (improved extraocular muscle function or relief from headache). The side effects of long-term mifepristone therapy have been mild. Fatigue was noted in 11 of the 14 patients. Other side effects included hot flashes in five patients, gynecomastia in three, partial alopecia in two, and cessation of menses in two. Long-term therapy with mifepristone is a new therapeutic option that may have efficacy in cases of unresectable benign meningioma.

Adult↗
PubMed1990

Phase I trial of a 5-day course of carbetimer.

Carbetimer (carboxyimamidate) is a low molecular weight derivative of ethylene/maleic anhydride polymer. This compound has demonstrated antitumor activity against several animal models with a daily x 5 schedule appearing most effective. A phase I clinical study of the daily x 5 schedule repeated every 28 days was therefore performed. Forty-one evaluable patients received 66 evaluable cycles of Carbetimer at daily doses ranging from 100-11,000 mg/m2. Hypercalcemia was the dose limiting toxicity with both patients at the 11,000 mg/m2 daily dose level and one patient who received 6 cycles of drug at the 4200 mg/m2 dose level developing severe hypercalcemia not explained by the underlying malignancy. Mild nausea, concentration and rate dependent arm pain at the site of infusion, proteinuria, and coagulopathy were also seen. Calcium balance studies revealed hypercalciuria, suggesting increased mobilization of calcium rather than renal retention. In vitro coagulation studies revealed concentration dependent prolongation of the partial thromboplastin time and thrombin time. No complete or partial responses were seen. However mixed response or biochemical response (reduction in serum lactic dehydrogenase) were seen in 5 patients with melanoma or renal cancer. Due to unacceptable toxicity at the 11,000 mg/m2 daily dose level, Carbetimer 8500 mg/m2 is the recommended dose for a 5-day treatment schedule every 28 days. Special attention should be directed toward possible activity against melanoma and renal cancer.

Adult↗
PubMed1990

Lack of efficacy of megestrol acetate in the treatment of unresectable meningioma.

The detection of hormone receptors on meningiomas raises the possibility of hormonal manipulation as a form of therapy. Since progesterone receptors are found on meningiomas more frequently and in greater amounts than estrogen receptors, manipulation of progesterone levels would be most promising. A trial of the oral progesterone agonist megestrol acetate for the treatment of unresectable meningioma was therefore performed. Megestrol acetate was administered at a dose of 40 mg four times daily which could be escalated to 80 mg four times daily. Nine patients (six meningothelial, two fibrous, and one anaplastic meningiomas) were treated for 1 to 12 months. No tumor responses were seen. However three patients required discontinuation of therapy due to deteriorating vision within 2 1/2 months. The major systemic toxicity of megestrol acetate was weight gain with a median weight gain of 14 kg for patients treated for at least 6 months. Due to the lack of efficacy and the significant toxicity noted, megestrol acetate is not recommended for the treatment of meningioma. However clinical trials of progesterone antagonists would still be of interest.

Adult↗
PubMed1990

Correlation of anti-emetic efficacy and plasma levels of ondansetron.

Intravenous ondansetron was administered at doses from 0.01 to 0.48 mg/kg every 4 h for three doses to patients receiving cisplatin 60-120 mg/m2 for the first time. Plasma samples were collected from 28 patients at baseline and at suitable times post-dose for pharmacokinetic analysis, and were assayed for ondansetron by high-pressure liquid chromatography. Plasma trough level was defined as the level before the third dose and 4 h area-under-the-curve (AUC4) was calculated with the linear trapezoidal method. Despite wide inter-patient variation, a correlation was seen between both trough level (r = 0.737, P less than 0.0001) and AUC4 (r = 0.903, P less than 0.001) related to dose. Trough level was also predictive of AUC4 (r = 0.824, P less than 0.0001). Frequency of complete protection (no emetic episodes) was equivalent throughout the AUC4 range, suggesting anti-emetic activity even at low AUC4. However, a trend toward better protection against failure (5 or more episodes) was seen when higher values of AUC4 were achieved, suggesting more consistent anti-emetic activity at moderate to high AUC4.

Adult↗
PubMed1990

Phase II evaluation of recombinant interferon-beta (IFN-beta ser) in patients with diffuse mesothelioma: a Southwest Oncology Group study.

Fourteen evaluable patients with diffuse malignant mesothelioma were treated with a once-a-day for 5 days out of 7 for 6 weeks regimen of recombinant interferon-beta (IFN-beta ser). No responses were noted. The major toxicities included fever, chills, nausea, vomiting, and anorexia. IFN-beta ser at this dose and schedule does not appear to be an active single agent for patients with refractory malignant mesothelioma.

Drug Evaluation↗
PubMed1989

Progressive paresthesias after cessation of therapy with very high-dose cisplatin.

Control of cisplatin-induced nephrotoxicity and nausea/vomiting has enabled the development of very high-dose cisplatin regimens (monthly total dose, 200 mg/m2). Neurotoxicity is now recognized to be the dose-limiting toxicity of these regimens. However, during a pilot study involving 5 mg/m2 vinblastine and 100 mg/m2 cisplatin given every 28 days on days 1 and 8 for the treatment of advanced non-small-cell lung cancer, we noted a high incidence of progressive peripheral neuropathy, which continued for several months after the discontinuation of cisplatin chemotherapy. Of the six patients treated, four received at least three cycles of therapy (median total cisplatin dose, 685 mg/m2; range, 500-725 mg/m2). All four patients developed a progressive peripheral neuropathy, with a worsening of toxicity by 1-3 grades over the 2-3 months after cisplatin discontinuation. One patient progressed from grade I (mild paresthesia) to grade IV (inability to ambulate) over a period of 3 months after the discontinuation of therapy. Stricter rules for early dose de-escalation and discontinuation may be required for very high-dose cisplatin regimens. Delayed progressive neuropathy should be recognized as a possible late complication of this form of therapy.

Adult↗
PubMed1989

Advances in the management of nausea and vomiting induced by non-cisplatin containing chemotherapeutic regimens.

Nausea and vomiting are the most feared toxicities of chemotherapy. Afferent impulses from the chemoreceptor trigger zone, peripheral sites, the cerebral cortex, or the vestibular center can initiate the emetic reflex. Antiemetic protection therefore requires interruption of appropriate emetogenic pathways. Since the chemoreceptor trigger zone contains numerous dopaminergic neurons, antidopaminergic agents including phenothiazines and metoclopramide have gained importance as antiemetics. However standard dose phenothiazines have limited efficacy while high dose metoclopramide may have excessive toxicity in the non-cisplatin setting. Recent advances have therefore centered on development of new classes of antiemetics. Corticosteroids have excellent activity alone or in combination with other antiemetic agents. Cannabinoids have recently been introduced into commercial use as antiemetics with particular activity against non-cisplatin chemotherapy. Benzodiazepines are active against anticipatory nausea and vomiting and are also used in combination antiemetic regimens. Although the vestibular center seems to have a lesser influence on chemotherapy-induced nausea and vomiting, vestibular blocking agents such as scopolamine may have a potential role as adjunctive antiemetics. Finally, appreciation of the role of serotonin (5-HT3) receptors in both peripheral and central emetic pathways may lead to a new class of antiserotonergic antiemetic agents.

Adrenal Cortex Hormones↗
PubMed1989

Dose ranging phase I study of the serotonin antagonist GR38032F for prevention of cisplatin-induced nausea and vomiting.

GR38032F is a specific 5-HT3 (serotonin) receptor antagonist with antiemetic activity in animal and early human studies. We performed a dose-ranging phase I study of GR38032F in 43 evaluable patients receiving cisplatin 60 120 mg/m2 for the first time (38 of these patients were chemotherapy-naive). Intravenous GR38032F was administered over a dose range from 0.01 to 0.48 mg/kg given three times at four-hour intervals beginning one half hour before cisplatin, and patients were observed for 24 hours. An additional five patients were treated with 0.18 mg/kg given three times at six-hour intervals. Excellent antiemetic efficacy was noted, with 44% of patients experiencing no vomiting and 26% no nausea. Major protection from vomiting (less than or equal to 2 episodes) and from nausea (less than or equal to 2 hours) was experienced by 81% and 44%, respectively. Mild to moderate headache (40%), lightheadedness (21%), and elevated transaminase (19%) were the most common adverse events reported. One patient experienced an apparent hypersensitivity reaction that responded to conventional medications. No extrapyramidal reactions or akathisia were seen. GR38032F was effective through most of the dose range. However, efficacy decreased at the 0.01 mg/kg level and number and intensity of adverse events increased at the 0.48 mg/kg level. Analysis of those patients receiving high-dose cisplatin (100 to 120 mg/m2) revealed a positive association of GR38032F dose and antiemetic activity (Fisher's exact test, two-sided; P less than .05). The 5-HT3 receptor antagonists may provide antiemetic efficacy similar to high-dose metoclopramide without antidopaminergic toxicity. The maximum recommended dose on this schedule of GR38032F is 0.36 mg/kg.

Adult↗
PubMed1988

Oral metoclopramide with or without diphenhydramine: potential for prevention of late nausea and vomiting induced by cisplatin.

Late nausea and vomiting lasting 2-7 days occurs in 20%-68% of patients receiving cisplatin. We therefore studied the effects of oral metoclopramide given at doses of 20, 50, or 100 mg four times a day for 25 doses (7 days) beginning after cisplatin to determine the maximum tolerated dose (MTD) for prophylactic oral antiemetic regimens. Patients were stratified into younger (less than or equal to 30 yr old) and older (greater than 30 yr old) groups. Dose escalation was performed without or with concomitant oral diphenhydramine. For the younger group, the MTD for metoclopramide without diphenhydramine was less than 20 mg, and the MTD with diphenhydramine was 20 mg. For the older group, the MTD without diphenhydramine was 20 mg, and the MTD with diphenhydramine was 50 mg. Extrapyramidal reactions in the younger group and agitated depression in the older group were the major dose-terminating toxic effects. Patient acceptance of these regimens was excellent.

Adolescent↗