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  • 1
    Electronic Resource
    Electronic Resource
    Phase I and pharmacologic evaluation of intraperitoneal 5-fluoro-2′-deoxyuridine (1991)
    Springer
    Cancer chemotherapy and pharmacology 28 (1991), S. 241-250 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Intraperitoneal (i.p.) 5-fluoro-2′-deoxyuridine (Floxuridine, FUdR, FdUrd) was evaluated in a phase I study at a starting level of 500 mg given on 1 day in 2 I 1.5% dialysate. Escalations within patients were allowed every other cycle. A total of 23 patients (age, 32–78 years) received 108 treatment courses. Local tolerance at all dose levels was excellent, with no cases of drug-related peritonitis being observed. Nausea and vomiting increased in severity in relation to dose and was universal at 〉3,000 mg ×3 days. One patient each developed grade 1 mucositis as well as diarrhea at a dose of 3,000 mg×3 days and leukopenia and thrombocytopenia at 5,000 mg×3 days. Peritoneal fluid (PF) and plasma (PL) FdUrd profiles were monitored by an HPLC method in 13 subjects, with 7 being studied serially at 2–4 increment doses for up to 6 h. Profiles that exhibited apparent linear pharmacokinetics gave PF drug levels 2–4 logs higher than the PL counterparts, with the latter essentially declining in parallel to the former, indicating that the disposition of FdUrd from the peritoneal compartment is rate-determining. The mean terminal half-life for PF FdUrd was found to be 115 min and mean peritoneal clearance was 25 ml/min. The vast differences in drug levels and AUC found between the PF and the PL profiles suggests a high systemic clearance of FdUrd, which was confirmed in two patients receiving 2 g FdUrd by short i.v. infusion. A disproportionate increase in the plasma FdUrd levels and the corresponding AUC values was found with increasing dose, suggesting a disproportionate increase in the systemic partitioning of FdUrd when doses were escalated within a patient. Substantial levels of peritoneal 5-fluorouracil (FUra) were also detected in most of the subjects. Thus, FdUrd was found to have several desirable properties for i.p. administration: (1) a 2- to 4-log pharmacologic advantage, (2) the absence of local toxicities, and (3) a favorable antitumor spectrum and some evidence of antitumor effects in this phase I and pharmacology study. A 3,000-mg dose given in 2 l 1.5% dialysate for 3 consecutive days exhibited antitumor activity and produced no systemic toxicity except nausea and vomiting, which was controlled by antiemetics. This dose schedule is therefore recommended for phase II trials directed against small-volume disease in the peritoneal cavity, such as may be found in some stages of ovarian and gastrointestinal cancers. In addition, it is suitable for further exploration as a part of regimens including systemic therapy or drugs that modulate the action of fluoropyrimidines.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00685529
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  • 2
    Electronic Resource
    Electronic Resource
    Phase II study of carboplatin in recurrent ovarian cancer: severe hematologic toxicity in previously treated patients (1989)
    Springer
    Cancer chemotherapy and pharmacology 23 (1989), S. 323-328 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Carboplatin (CBDCA) is a second-generation cisplatin analog that has shown activity in early clinical trials. Its spectrum of toxicity is quantitatively and qualitatively different from that of the parent compound. Between November 1984 and September 1986 we conducted a phase II trial of CBDCA in 46 women with epithelial ovarian cancer. All patients had undergone at least one prior chemotherapy regimen; 41 (89%) had previously received cisplatin (mean cumulative dose, 540 mg/m2). The CBDCA dose was based on renal function and was injected i. v. once every 4 weeks. Patients were stratified on the basis of baseline creatinine clearance: those with a baseline creatinine clearance of ≥60 ml/min received 400 mg/m2 CBDCA; those with a creatinine clearance between 30 and 60 ml/min received an initial dose calculated according to a previously published formula [2, 3] that corrected for renal insufficiency and projected nadir platelet counts of 75,000/mm3. Of 41 evaluable patients, 6 (15%) had an objective response [2 complete responses (CRs); 4 partial responses (PRs)]; 5 of the 6 responders had previously responded to cisplatin treatment. No responses were observed in 12 patients who had not responded to prior cisplatin therapy. Significant hematologic toxicity was seen. Of 18 patients with a creatinine clearance of ≥60 ml/min (dose, 400 mg/m2), 6 had nadir platelet counts of 〈25,000/mm3, 4 with symptomatic bleeding. Of the 21 evaluable patients for whom the dose-modification formula was applied, 10 had nadir platelet counts of 〈75,000/mm3; 5 had counts of 〈50,000/mm3. CBDCA has activity even in patients who have previously undergone extensive cisplatin therapy; however, its toxicity is variable and thrombocytopenia is dose-limiting. We did not confirm the ability of the above-mentioned formula to calculate the CBDCA dose and accurately predict the nadir platelet count for all patients. Other factors, such as prior radiotherapy, may also be important in the dosing of CBDCA in pretreated patients.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00292413
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  • 3
    Electronic Resource
    Electronic Resource
    Hexamethylmelamine, adriamycin, and cyclophosphamide (HAC) versus cis-dichlorodiamineplatinum, adriamycin, and cyclophosphamide (PAC) in advanced ovarian cancer: A randomized clinical trial (1985)
    Springer
    Cancer chemotherapy and pharmacology 14 (1985), S. 222-228 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary After stratification according to diameter of the largest residual tumor, 120 previously untreated ovarian cancer patients were randomized to receive adriamycin and cyclophosphamide in combination with hexamethylmelamine (HAC) or cis-dichlorodiamineplatinum (PAC). The surgical response rates were 66% to HAC and 70% to PAC, with median times to progression of 14 and 22 months and median survival times of 23 and 24 months, respectively. In patients with residual tumor 〉2 cm the surgical response rates to HAC and PAC were 56% and 63%, with complete response rates of 13% and 21%, respectively. In two of five complete responders to HAC there has still been no progression at 38 and 48 months, with a median response duration of 25 months. Only one of the nine complete responders to PAC has relapsed, at 33 months, while in the eight others response is maintained at follow-up times of 35–64 months. Myelosuppression was generally mild and similar in the two arms. No significant nonhematological toxicity was reported. It is concluded that at a median follow-up time of 36 months HAC is as effective as PAC in terms of response, duration of remission, and survival in previously untreated advanced ovarian cancer.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00258120
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  • 4
    Electronic Resource
    Electronic Resource
    The disposition of carboplatin in ovarian cancer patients (1988)
    Springer
    Cancer chemotherapy and pharmacology 22 (1988), S. 263-270 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Carboplatin was given as a 30-min infusion to 11 ovarian cancer patients at doses of 170–500 mg/m2. The ages, weights, and creatinine clearances (Clcr) ranged from 44 to 75 years, from 44 to 74 kg, and from 32 to 101 ml/min, respectively. Plasma, plasma ultrafiltrate (PU), and urine samples were obtained at appropriate times for 96 h and were analyzed for platinum. The PU and urine were also analyzed for the parent compound by HPLC. In patients with a Clcr of about 60 ml/min or greater, carboplatin decayed biexponentially with a mean t1/2α of 1.6 h and a t1/2β of 3.0 h. The mean (±SD) residence time, total body clearance, and apparent volume of distribution were 3.5±0.4 h, 4.4±0.85 l/h, and 16±31l, respectively. Cmax and AUCinf values increased linearly with dose, and the latter values correlated better with the dose in mg than in mg/m2. No significant quantities of free, ultrafilterable, platinum-containing species other than the parent compound were found in plasma, but platinum from carboplatin became protein-bound and was slowly eliminated with a minimal t1/2 of 5 days. The major route of elimination was excretion via the kidneys. Patients with a Clcr of 60 ml/min or greater excreted 70% of the dose as the parent compound in the urine, with most of this occurring within 12–16 h. All of the platinum in 24-h urine was carboplatin, and only 2%–3% of the dosed platinum was excreted from 48 to 96 h. Patients with a Clcr of less than about 60 ml/min exhibited dose-disproportional increases in AUCinf and MRT values. The latter were inversely related to Clcr (r=-0.98). Over a dose range of 300–500 mg/m2, carboplatin exhibited linear, dose-independent pharmaco-kinetics in patients with a Clcr of about 60 ml/min or greater, but dose reductions are necessary for patients with mild renal failure.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00273422
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  • 5
    Electronic Resource
    Electronic Resource
    DR antigen expression on ovarian carcinoma cells does not correlate with their capacity to elicit an autologous proliferative response (1988)
    Springer
    Cancer immunology immunotherapy 27 (1988), S. 63-68 
    Details
    ISSN: 1432-0851
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Expression of HLA-DR antigens by purified preparations of human ovarian carcinoma cells freshly isolated from surgical specimens was examined in parallel with the capacity of tumor cells to elicit a blastogenic response from autologous lymphocytes in mixed lymphocyte-tumor culture (MLTC) assay. Of 21 tumor preparations, 11 (52%) reacted with monoclonal antibodies 279 and/or 949 specific for a monomorphic determinant of HLA-DR antigens, with heterogeneous positivity, ranging between 30% and 95%. In this series of patients positive MLTC occurred in 8/21 individual experiments. The HLA-DR expression was proportionally similar in tumors giving positive MLTC (4/8=50%) and negative MLTC (7/13=53%). The lack of correlation between DR expression on tumor cells and stimulatory activity in autologous MLTC and the fact that DR-negative tumors could induce lymphocyte stimulation, support the hypothesis that blastogenesis occurs upon recognition of tumor-associated antigens, different from DR molecules, possibly tumor-specific antigens.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00205760
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  • 6
    Electronic Resource
    Electronic Resource
    Phase II study of esorubicin (4 ′ deoxydoxorubicin) in anthracycline naive patients with ovarian cancer (1990)
    Springer
    Investigational new drugs 8 (1990), S. 333-336 
    Details
    ISSN: 1573-0646
    Keywords: anthracycline ; esorubicin ; 4′ deoxydoxorubicin ; ovarian cancer ; clinical trial
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary 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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00171850
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