Intraperitoneal therapy in ovarian cancer: time's not up.
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Cisplatin↗
Biomedical subjects
F M Muggia
Publications and source records attributed to F M Muggia.
Selection of cancer chemotherapy for a patient by an in vitro assay versus a clinician.
One hundred thirty-three patients with advanced metastatic cancer were randomized to receive single-agent chemotherapy selected by either a medical oncologist or an in vitro capillary cloning system. Thirty-six of the 65 patients (55%) who were randomly assigned to selection of a drug by the clinician actually received a drug; these patients were able to be evaluated for clinical response. Of these 36 patients, one had a partial tumor response (3%). Only 19 of the 68 patients (28%) who were randomly assigned to selection of a drug by the capillary system actually received a drug; these patients were able to be evaluated for clinical response. Of these 19 patients, four (21%) had partial tumor responses. In the assessable patients (36 in the clinician's choice group, 19 in the capillary cloning group), the partial response rate was superior for drug selection by the capillary cloning system (P = .04). For all patients randomly assigned to a group (65 in the clinician's choice group, 68 in the capillary cloning group), the response rate was not significantly different (1.5% and 5.9%, respectively; P = .37). When overall survival rates for patients in the two groups were compared, there was no difference. We conclude that drug sensitivity testing in capillary tubes can improve the response rate for patients with advanced malignancies. This improved response rate, however, does not translate into improved survival times for these patients.
Antineoplastic Agents↗
Phase II study of esorubicin (4'deoxydoxorubicin) in anthracycline naive patients with ovarian cancer.
Sixteen patients with metastatic ovarian cancer who had not previously been treated with anthracyclines were treated with 4'deoxydoxorubicin at a dose of 30 mg/m2 intravenously every 3 weeks. There were no clinical responses in this group of patients. Toxicities were infrequent with neutropenia and thrombocytopenia being dose limiting. Nausea and vomiting occurred in only 4 patients. We conclude that 4'deoxydoxorubicin is an inactive drug in this patient population and does not warrant further investigation in this disease.
Adult↗
Plasma carcinoembryonic antigen as an indicator of cerebral metastases.
Four patients in whom the plasma CEA reflected the clinical course of intracranial disease are presented. We conclude that a search to explain an elevated CEA should include the central nervous system. In addition, in selected patients with brain metastases the plasma CEA is a helpful indicator of tumor control and of its response to radiation and chemotherapy.
Adenocarcinoma↗
Evidence of the selective alteration of anthracycline activity due to modulation by ICRF-187 (ADR-529).
Anthracyclines are powerful anticancer drugs whose use is limited by the development of chronic cardiotoxicity. The bisdioxopiperazine compound ICRF-187 (ADR-529) specifically abrogates this toxicity both in preclinical animal models and in humans. It does this without effecting either the acute toxicities or the anticancer activity. Therefore, with a specific antagonist, the mechanism of activity of the anthracyclines can be explored. This review discusses recent clinical trials and animal models addressing this issue and concludes by hypothesizing a mechanism of action.
Animals↗
Intraperitoneal carboplatin: favorable results in women with minimal residual ovarian cancer after cisplatin therapy.
From August 1985 to November 1989 we conducted a trial of intraperitoneal (IP) carboplatin including a dose-escalation design in 25 women with advanced gynecologic malignancies. All had extensive prior therapy with cisplatin (median cumulative dose, 525 mg/m2). Carboplatin was administered IP in 2 L of 1.5% dextrose with a 4-hour dwell time every 4 weeks for six cycles at a starting dose of 200 mg/m2. Patients with reduced creatinine clearance (30 to 60 cc/min) were escalated more slowly than those with high (greater than 60 cc/min) clearance. Thrombocytopenia was dose-limiting and often more severe in patients with compromised renal function; there was no local drug toxicity. The median time of follow-up is 25 months. Complete responses (CRs) were documented in six of 23 assessable patients (26%) by repeat laparotomy, and an additional 11 patients (48%) had no disease evident by noninvasive restaging. Five of the CRs and six of the patients with no clinically evident disease have relapsed from 3 to 40 months after therapy. Six patients (26%) are alive and free of disease 8 to 47 (median, 20) months after therapy. IP carboplatin is effective against relapsed ovarian cancer, even after prior cisplatin therapy.
Adenocarcinoma↗
Monoclonal antibody therapy in intra-abdominal malignancies.
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Abdominal Neoplasms↗
Overview of cancer-related hypercalcemia: epidemiology and etiology.
Hypercalcemia is one of the most serious metabolic disorders associated with cancer. The incidence and clinical circumstances associated with hypercalcemia vary in different types of cancer. Hypercalcemia is the most frequent metabolic complication of breast cancer and is usually related to widespread osteolytic metastases; however, local and systemic humoral factors mediating bone resorption have been described. In some patients with breast cancer, hypercalcemia results from treatment with estrogens, antiestrogens, androgens, or progestins. Coexisting primary hyperparathyroidism rarely confounds the diagnosis. In patients with lung cancer, the incidence of hypercalcemia varies with histology and is often unrelated to bone metastases. Hypercalcemia may occur either late or early in the disease but is seldom a presenting symptom. In patients with cancers of the head and neck region, hypercalcemia is most often associated with advanced recurrent and terminal disease, presumably humorally mediated. In renal cell carcinoma, hypercalcemia is also an adverse prognostic indicator, commonly mediated by humoral factors. On the other hand, almost all patients with multiple myeloma have extensive osteolytic bone destruction and hypercalcemia is frequently a presenting symptom. Hypercalcemia is uncommon in most lymphomas; however, it is usually a prominent feature of adult T-cell lymphomas and also occurs in some large cell, diffuse B-cell lymphomas. Awareness of the setting in which hypercalcemia of malignancy occurs will lead to its prompt diagnosis and institution of appropriate therapy.
Humans↗
Noninvasive monitoring of drug biodistribution and metabolism: studies with intraarterial Pt-195m-cisplatin in humans.
We have performed a comparative evaluation of systemic (i.v.) and intraarterial (i.a.) cisplatin by using a trace dose of the radiolabeled form of this drug [( 195mPt]cisplatin) to monitor the drug's biodistribution by dynamic scintigraphic imaging. We have analyzed the drug's metabolism using a compartmental model both following i.a. and i.v. administration in patients with gliomas. Significantly larger amounts of radioactivity (up to 10 times higher than in the uninvolved brain) were measured in tumors following i.a. administration, whereas the differential localization following i.v. drug administration was, at best, only twofold that of the uninvolved brain. On the other hand, no significant differences could be detected in the pharmacokinetics of either free cisplatin or platinated proteins in blood. The washout slope in tumors following i.a. administration may be an indicator of the higher local concentration of free cisplatin; no such washout could be observed in tumors following i.v. administration. The present noninvasive methods may help document the amount and the rate of (active) drug deposition at the desired target site. They may also assist in monitoring, prospectively and/or, on line, the probable effect of chemotherapy in an individual patient. In turn it may lead to novel methods for optimizing chemotherapeutic effectiveness at specific tumor-bearing sites and in defined treatment protocols.
Cisplatin↗
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↗
The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: a prospective randomized phase III trial. Gastrointestinal Tumor Study Group.
A total of 343 patients with previously untreated metastatic measurable colorectal carcinoma were studied to evaluate the impact on toxicity, response, and survival of leucovorin-modulated fluorouracil (5-FU). A maximally tolerated intravenous bolus loading course regimen of 5-FU alone (500 mg/m2 x 5 days every 4 weeks with 25 mg/m2 escalation) was compared with a high-dose leucovorin regimen (600 mg/m2 of 5-FU with 500 mg/m2 of leucovorin weekly for 6 weeks with a 2-week rest) and with a similar low-dose leucovorin regimen (600 mg/m2 of 5-FU with 25 mg/m2 of leucovorin weekly for 6 weeks with a 2-week rest). The dose-limiting toxicity for the two 5-FU and leucovorin regimens was gastrointestinal, specifically diarrhea; severe diarrhea was seen frequently, and treatment-related toxicity was implicated in the demise of 11 of the patients (5%). Significant improvements in response rates were observed with a response rate of 33 of 109 (30.3%) on the high-dose leucovorin regimen (P less than .01 v control); 13 of 107 (12.1%) on the 5-FU control; and 21 of 112 (18.8%) on the low-dose leucovorin regimen. A trend toward longer survival in the 5-FU plus high-dose leucovorin regimen was observed. In this study, leucovorin was shown to significantly enhance the therapeutic effect of 5-FU in metastatic colorectal carcinoma.
Aged↗
Phase I/II trial of thymostimulin in opportunistic infections of the acquired immune deficiency syndrome.
Fifteen patients with acquired immune deficiency syndrome (AIDS) and opportunistic infection, were randomized to receive treatment with either thymostimulin (TP-1) at 1 mg/kg for 14 days then weekly for 12 weeks or placebo. The objectives of this study were to evaluate the toxicity of TP-1 in this patient population and to make observations on clinical response as measured by time to second opportunistic infection (OI) and changes in laboratory parameters of immune function. The study demonstrates that TP-1 can be administered safely. There were no differences, however, in time to second OI or overall survival between patient groups. In addition, no change in the immune function could be detected in patients receiving thymostimulin.
Acquired Immunodeficiency Syndrome↗
Epipodophyllotoxins: new laboratory and clinical findings.
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Drug Administration Schedule↗
Overview of carboplatin: replacing, complementing, and extending the therapeutic horizons of cisplatin.
Carboplatin is the one platinum analogue that has received widespread clinical testing both in cancers that are normally targets for cisplatin and in others. It was introduced in 1981 because of its lesser toxicity and equivalent biochemical selectivity and antitumor spectrum relative to cisplatin in preclinical systems. Clinical studies have generally confirmed these expectations and given rise to interesting prospects in current cancer therapeutics. Carboplatin is as effective as cisplatin in ovarian cancer and considerably less toxic. Replacement of cisplatin by carboplatin seems likely in a number of other diseases where cisplatin has played a major role, especially if ongoing phase III studies confirm the regimens are equivalent. Carboplatin may also complement cisplatin's role by its innovative integration into treatment strategies, and by use of it as additional treatment when cisplatin's nonhematologic toxicities are prohibitive. Finally, although it is not likely to possess a different therapeutic spectrum than cisplatin, carboplatin appears to be extending the indications for platinum compounds to new areas such as acute leukemia, endometrial cancer, and breast cancer. In the latter, use of autologous bone marrow reconstitution permits the dose intensity needed for promising therapeutic results. Carboplatin has become the experimental platinum analogue of choice in a wide range of new clinical situations and in combinations with other modalities.
Antineoplastic Agents↗
Future of cancer chemotherapy with cisplatin.
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Antineoplastic Combined Chemotherapy Protocols↗
Toxicity comparisons between two chemotherapy regimens as adjuvant or salvage treatment in nonseminomatous testicular cancer.
The Testicular Cancer Intergroup Study was initiated to evaluate the efficacy of adjuvant chemotherapy in Stage II and salvage therapy in Stage I nonseminomatous testicular carcinoma. Chemotherapy regimens of cisplatin, vinblastine, and bleomycin (PVB) or the same drugs plus cyclophosphamide and dactinomycin (VAB) were used at institution or cooperative group preference. A comparison of the toxicities of these two regimens shows that VAB caused significantly more mucosal, dermatologic, and otologic toxicity than PVB, and PVB caused more leucopenia. Both regimens were equally effective in controlling cancer. Either regimen could be used as chemotherapy in testicular cancer, and the decision about which one to use could be based on their differences in toxicity and degree of patient convenience.
Antineoplastic Combined Chemotherapy Protocols↗
Phase I trial of escalating dose doxorubicin administered concurrently with alpha 2-interferon.
The clinical use of alpha 2-interferon and doxorubicin is based on in vitro and preclinical in vivo observations of synergistic antitumor efficacy. To test this combination a Phase I clinical and pharmacokinetic study of the concurrent use of alpha 2-interferon and doxorubicin was initiated in patients with malignant solid tumors. Each 5-wk treatment cycle consisted of 3 wk of drug administration and 2 wk of rest. The alpha 2-interferon was administered s.c. at a constant dose of 10 million IU/m2 on Mondays, Wednesdays, and Fridays in all patients while the doxorubicin was administered weekly beginning with a dose of 5 mg/m2 and escalated to the maximum tolerated dose of 25 mg/m2. At least three evaluable patients were entered at each dose level, and no dose escalations were allowed within patients. The dose-limiting toxicities were granulocytopenia and thrombocytopenia. Hepatic enzyme elevations and systemic symptoms due to interferon occurred at all dose levels. None was severe or dose limiting, and all were reversible. These toxicity data suggest that the hepatotoxic effects of interferon do not enhance doxorubicin toxicity when given by this dose and schedule. Doxorubicin plasma levels were measured at each dose level. The recommended dose of doxorubicin is 25 mg/m2 per wk when administered with 10 million IU/m2 of interferon in this schedule. This schedule allows for the administration of a greater total dose of doxorubicin than has been achieved when given every 3 wk with the same dose and schedule of alpha 2-interferon in a parallel study.
Adult↗