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Biomedical subjects

M Valdivieso

Publications and source records attributed to M Valdivieso.

At least 19 recordsLinked to original sources
PubMed1992

Difluorodeoxycytidine (dFdC)--gemcitabine: a phase I study.

Difluorodeoxycytidine (dFdC) demonstrated broad spectrum activity in preclinical models. A phase 1 study utilizing twice weekly injections was conducted in 50 eligible and evaluable patients. Twenty-nine patients received drug by 30 minute infusion at doses of 5-90 mg/m2 and 22, by 5 minute bolus at 30-150 mg/m2. The primary dose limiting toxicities were marrow suppression and flu-like symptomatology. Thrombocytopenia was dose limiting at 75 mg/m2 on the infusion schedule and 150 mg/m2 on the 5 minute schedule. Flu-like symptoms with fever, rigors and malaise occurred the day of injection in many patients. One patient with renal cell carcinoma attained a partial response. Evaluation of the drug's efficacy and schedule dependency continue.

Adult↗
PubMed1992

Effect of calcium replacement on the hemodynamic changes associated with high dose interleukin-2 therapy.

Administration of high-dose IL-2 results in hemodynamic changes that are similar to those seen in septic shock. These include a decrease in systemic vascular resistance (SVR) with a resultant drop in mean arterial pressure (MAP). Hypocalcemia is seen in septic shock and with IL-2 administration. Calcium replacement in septic shock has been reported to result in hemodynamic improvement; we therefore administered calcium to patients receiving high dose IL-2 to correct ionized hypocalcemia. Five consecutive patients underwent invasive hemodynamic monitoring before and during IL-2 administration. Calcium chloride was administered to correct ionized hypocalcemia, and hemodynamic parameters were monitored before and after calcium administration. Ionized hypocalcemia was associated with an elevation in parathyroid hormone levels. There was no toxicity related to the administration of calcium. An improvement in the MAP and SVR was seen early and late (after a dose of IL-2 was held) in the IL-2 treatment cycle; there were minimal effects at other points. Because of the potential hemodynamic benefit of calcium replacement, we recommend that ionized hypocalcemia be corrected in patients receiving high-dose IL-2.

Adult↗
PubMed1992

Phase I trial of recombinant macrophage colony-stimulating factor by rapid intravenous infusion in patients with cancer.

Fourteen patients were entered into a phase I dose-escalation trial of macrophage colony-stimulating factor (M-CSF). M-CSF was administered to inpatients by rapid 15 min i.v. infusion every 8 h x 5 days, repeated after a 9-day rest. Dose levels evaluated were 20, 40, 80, 330, and 1,100 micrograms/m2. Monitoring of patients every 4 h included vital signs, daily complete blood count (CBC), and serum chemistries (SGOT, creatinine, and bilirubin) while receiving M-CSF. No clinical or laboratory evidence of toxicity was seen. The average serum t1/2 varied with dose level. At 330 and 1,100 micrograms/m2, the serum t1/2 was 25 and 84 min, respectively, implying a saturable mechanism of clearance. After 5 days of treatment, the t1/2 decreased by twofold, consistent with enhancement of the saturable mechanism. Monocyte cytotoxicity against the A375 melanoma cell line was evaluated pretreatment and day 5 of each cycle. No consistent enhancement of monocyte cytotoxicity was seen. No effect on peripheral blood monocyte number was seen until the 1,100 micrograms/m2 dose level. At this dose level, the mean monocyte number on day 5 was increased compared to baseline (1,300 mm3 vs. 300/mm3). Clinical activity was seen in two patients with previously progressive leiomyosarcoma metastatic to the liver. A partial response (PR) lasting 7 months occurred at the 330 micrograms/m2 dose level while a patient treated at 1,100 micrograms/m2 has had stable disease for 20+ months. The maximum tolerated dose (MTD) of M-CSF was not determined. Based on clinical responses, a phase II trial is warranted in patients with metastatic soft tissue sarcoma.

Antineoplastic Agents↗
PubMed1991

5-Fluorouracil, etoposide, and cisplatin in the management of metastatic non-small cell lung cancer.

Encouraging response rates have been reported in Stage III non-small cell lung cancer when 5-fluorouracil (5-FU), etoposide (VP-16), and cisplatin (FED) have been combined with radiation therapy (RT) or RT and surgery. The current study evaluated the effectiveness of FED chemotherapy in 32 patients with metastatic non-small cell lung cancer. Treatment consisted of 5-FU (800 mg/m2/d) on days 1 to 4 by continuous infusion, intravenous (IV) VP-16 (60 mg/m2) over 1 hour on days 1 to 4, and IV cisplatin (60 mg/m2) over 1 hour on day 1. Treatment cycles were repeated every 28 days as toxicity permitted. Partial responses occurred in 7 of 32 patients (22%; 95% confidence limit [CL] 0.09, 0.40), including 6 of 19 patients (32%) with performance status of 0 or 1, and 1 of 13 patients (8%) with performance status of 2 or 3. The median response duration was 5.0 months. Although toxicity was modest and consisted of primarily hematologic and gastrointestinal side effects, this combination does not appear to provide an advantage over other cisplatin combinations in Stage IV non-small cell lung cancer.

Adult↗
PubMed1990

Antitumor efficacy of interleukin-2 alone and in combination with adriamycin and dacarbazine in murine solid tumor systems.

Recombinant interleukin-2 (IL-2)/chemotherapy combinations have recently entered clinical trial. The rationale for sequencing has primarily been empiric or based on in vitro data. To establish in vivo models for chemoimmunotherapy trials, we investigated IL-2 alone and in combination with dacarbazine (DTIC) and adriamycin. IL-2 (as a single agent given i.v. at 1-3 x 10(5) Cetus units once daily for 5 days, repeated 7-10 days later), was highly active against an immunogenic line of colon adenocarcinoma no. 11/A [tumor growth inhibition (T/C) = 0% with cures]. It was modestly active against colon adenocarcinoma no. 38 (T/C = 39%), mammary adenocarcinoma no. 16/C (T/C = 18%), and B16 melanoma (T/C = 21%). IL-2 was inactive against colon adenocarcinoma no. 7/A (T/C = 83%). Combination trials were done using DTIC and IL-2 against colon no. 7/A and upstaged colon no. 11/A. The combination of adriamycin and IL-2 was tested against mammary adenocarcinoma no. 16/C. In the DTIC/IL-2 combination trials, the combination was superior over either agent used alone. In the IL-2/adriamycin trials, the combination was no better than adriamycin alone at optimum dosages.

Adenocarcinoma↗
PubMed1990

A phase I-II study of dacarbazine in combination with outpatient interleukin-2 in metastatic malignant melanoma.

Because of encouraging response rates published with recombinant interleukin-2 (rIL-2) alone in metastatic malignant melanoma (MMM), dacarbazine (DTIC) and rIL-2 were sequentially combined to evaluate efficacy, toxicity, pharmacokinetics, and immunologic interaction. Thirty-two patients aged 18 to 67 years have received 127 courses of treatment. The dose of DTIC was 1.0 g/m2 as a 24-hour infusion every 28 days on day 1. Recombinant interleukin-2 (2.0, 3.0, 4.0, or 5.0 x 10(6) Cetus units/m2) was administered as a 30-minute infusion on days 15 through 19 and 22 through 26 of each 28-day cycle. Seven of 32 patients (22%) who received therapy had a remission, one complete and six partial. The complete response was in a lung mass. Partial responses were seen in lymph nodes, liver, and lung. The median duration of response was 4.7 months. One patient is in persistent partial remission of the liver for greater than 2 years. One patient had residual mediastinal disease resected after partial response and remains without evidence of disease for 18+ months. This regimen was generally well tolerated, did not create overlapping toxicity, and produced encouraging responses in visceral sites. This provides a framework for future combinations of chemotherapy with rIL-2 alone or in combination with other biologic response modifiers in an outpatient setting.

Adolescent↗
PubMed1990

Alteration of dacarbazine pharmacokinetics after interleukin-2 administration in melanoma patients.

In an effort to improve the treatment of metastatic malignant melanoma, we evaluated the sequential administration of the chemotherapeutic agent dacarbazine (DTIC) and the biological response modifier interleukin-2 (rIL-2) in a phase I-II study. Since the combination of biological response modifiers and chemotherapeutic agents could alter drug disposition, we evaluated the pharmacokinetics of DTIC and its major metabolite, 5-amino-imidazole 4-carboxamide (AIC), before and after rIL-2 administration. DTIC (1 g/m2, 24-h i.v. infusion) was given on day 1 and rIL-2 (2-4 million Cetus units/m2, 30-min i.v. injection), on days 15-19 and 22-26 of each course of therapy. The second DTIC dose was given on day 29, i.e., 3 days after the last rIL-2 administration. DTIC and AIC were assayed by reversed-phase HPLC. DTIC plasma levels showed a significant decrease after rIL-2 administration as compared with DTIC values obtained in the same patients before rIL-2 administration. DTIC area under the curve (AUC) values obtained after rIL-2 were lower than those obtained on day 1 before rIL-2 administration (P = 0.02). After rIL-2, the total body clearance (ClT) was increased (P = 0.04), as was the volume of distribution at steady state (Vss; P = 0.02). The decrease in AUC after rIL-2 administration became more pronounced as the rIL-2 dose was increased (P = 0.03). No significant difference was detected in the elimination phase of DTIC when half-lives obtained before and after rIL-2 administration were compared; the mean half-lives were 0.7 and 2.8 h for the alpha- and beta-phases, respectively. The model-independent mean residence time was 3.4 h. The plasma AUC for the metabolite AIC did not charge after rIL-2 administration. AIC biphasic plasma elimination was also similar after rIL-2 administration, with alpha- and beta-half-lives of 0.7 and 11.4 h, respectively. Urinary excretion of DTIC and AIC did not differ after rIL-2 administration; the overall DTIC excretion was 39% of the dose over 48 h, and AIC urinary excretion was 25% of the DTIC dose. The observed decrease in the DTIC plasma AUC after rIL-2 administration appears to be due to an increase in the volume of distribution, since other factors such as half-lives, urinary excretion, and metabolism were not significantly altered. The clinical consequences of the rIL-2-DTIC interaction remain difficult to assess based on presently available data, but this drug interaction should be taken into consideration in the development of future chemo-immunotherapy regimens that include high-dose rIL-2.

Chromatography, High Pressure Liquid↗
PubMed1990

Phase II study of deoxydoxorubicin in previously untreated metastatic breast cancer.

With the objective of identifying new chemotherapeutic agents active against breast cancer, we administered the phase II agent deoxydoxorubicin (DxDx) to 25 patients who had received no prior chemotherapy for their metastatic breast cancer. A dose of 30-35 mg/M2 given at 3 week intervals resulted in a response rate of 12%. The patients were subsequently treated with a combination of 5-fluorouracil, methotrexate, vincristine, cyclophosphamide, and prednisone. A response rate of 38% was achieved with this combination as second line therapy. Toxicity of DxDx was predominantly hematopoietic. One patient developed congestive heart failure. Median survival from onset of treatment with DxDx was 39 weeks. DxDx appears to be minimally active against metastatic breast cancer. Whether the administration of phase II agents as first line therapy offers an advantage in the overall management of metastatic cancer, needs further evaluation.

Adult↗
PubMed1990

The role of adjuvant surgery in the combined modality therapy of small-cell bronchogenic carcinoma after a chemotherapy-induced partial remission.

Twenty-six patients with a limited-disease presentation of small-cell bronchogenic carcinoma (SCBC) had surgery after achieving a partial remission with three cycles of chemotherapy. Persistent SCBC was found in 15 patients (58%), non-small-cell bronchogenic carcinoma (NSCBC) in six patients (23%), and no malignancy in five patients (19%). Twelve patients have died since surgery. Tumor-node-metastasis (TNM) staging prior to or after chemotherapy was not predictive of outcome, but an N0 status found at pathological examination of the surgical specimen was predictive of long-term survival. Median survival for this group of patients was 25 months. Adjuvant surgery is feasible and may be beneficial.

Adult↗
PubMed1990

A phase I trial of recombinant interleukin-2 combined with recombinant interferon-gamma in patients with cancer.

Twenty-six patients with metastatic cancer were entered into a phase I trial of concurrent recombinant interleukin-2 (IL-2) and recombinant interferon-gamma (IFN-gamma). IL-2 was administered as a continuous intravenous infusion for 5 days. IFN-gamma was administered by a daily intramuscular (IM) injection during the 5 days of IL-2 administration. Treatment was repeated twice after 9-day rest periods. After a 2-week rest, patients without evidence of tumor progression were retreated. Natural killer (NK)- and lymphokine-activated killer (LAK)-cell activity were assayed in each patient before treatment, on day 1, and on day 5 of each cycle. Constitutional symptoms occurred in most patients but were not dose-limiting. Other toxicities included hypotension responsive to fluids, transient elevations in liver function tests, erythema/pruritus, eosinophilia, and transient leukopenia/thrombocytopenia. The maximum-tolerated dose (MTD) of the combination was 1 x 10(6) U/m2/d of IL-2 combined with 0.50 mg/m2/d of IFN-gamma. The dose-limiting toxicity was pulmonary manifesting as rales and shortness of breath. The dose of the combination that resulted in the optimal generation of in vivo LAK-cell activity was a dose of at least 0.25 mg/m2/d of IFN-gamma combined with 1 x 10(6) U/m2/d of IL-2. Objective clinical responses were seen in five of 26 patients. These included a partial response of 2 months duration in a patient with non-Hodgkin's lymphoma (NHL), mixed responses in a patient with NHL and two patients with renal cell carcinoma (RCC), and an ongoing assessable response in a patient with bone metastases from RCC. The recommended dose for phase II trials of this combination is 0.50 mg/m2 of IFN-gamma and 1 x 10(6) U of IL-2.

Adolescent↗
PubMed1990

Scintigraphic findings in patients with shoulder pain caused by interleukin-2.

Interleukin-2 is receiving widespread interest as an immunotherapeutic agent in the treatment of certain cancers. Severe arthralgias recently have been reported as a significant side effect, and the cause of pain is unknown. Because interleukin-2 is an immune modulator, we reviewed the 99mTc-methylene diphosphonate scintigrams in nine patients who had developed shoulder arthralgias while receiving interleukin-2 for metastatic melanoma. In eight of the patients, the scintigrams showed diffuse increased uptake of radionuclide in the shoulders. Four patients had radiographs of their shoulders, all of which were normal. Bone scintigraphy in patients receiving interleukin-2 as immunotherapy for metastatic melanoma shows increased radionuclide activity in the shoulders. This process may relate to the role of interleukin-2 as a mediator in the inflammatory response.

Adult↗
PubMed1979

Ftorafur, adriamycin, cyclophosphamide and BCG in the treatment of metastatic breast cancer.

Ftorafur is a 5-fluorouracil analogue which is slowly metabolized to 5-FU, resulting in prolonged therapeutic levels of this latter drug. Ninety-one evaluable patients with metastatic breast cancer were treated with Ftorafur, Adriamycin, cyclophosphamide, and BCG (ACFTOR-BCG), in an attempt to increase the effectiveness of the program or decrease its myelosuppressive toxicity. The results of this trial were compared to those previously reported with the combination of 5-FU, Adriamycin, cyclophosphamide, and BCG (FAC-BCG). Overall objective response rates were 65% and 76% for ACFTOR-BCG and FAC-BCG, respectively. Durations of response were 12 months and 14 months for ACFTOR-BCG and FAC-BCG (p = 0.53). The median survival of responders was 22 and 23.9 months, respectively. Substantial toxicity was observed with Ftorafur: nausea and vomiting severe enough to cause weight loss was observed in a substantially higher fraction of the patients treated with this drug than with 5-FU. Other side-effects, which were not observed with the 5-FU combination, were somnolence, dizziness, personality changes, tremor, ataxia, and confusion. No differences in myelosuppressive toxicity were observed between the two combinations, and the incidence of infectious complications was identical. The combination of Ftorafur, Adriamycin, cyclophosphamide and BCG did not offer any advantages with respect to increased effectiveness or reduced toxicity over the FAC-BCG regimen in breast carcinoma.

Adult↗
PubMed1979

Adriamycin, BCNU, ftorafur chemotherapy of pancreatic and biliary tract cancer.

Twenty-six evaluable patients with disseminated or locally unresectable pancreatic or biliary tract carcinoma received Ftorafur (4 g/m2 iv day 1 and 22 and 2 g/m2 iv day 4 and 26), Adriamycin (60 mg/m1 IV day 1 and 45 mg/m2 iv day 22) and BCNU (150 MG/M2 IV DAY 1) combination chemotherapy (FAB) repeated at 6--8 week intervals. Two (29%) complete and one (14%) partial remissions were observed in 7 patients with biliary carcinoma while 5 of 19 (26%) patients with pancreatic carcinoma achieved partial remissions. Median survival for responding patients was approximately 11 months (range 7--16+) with median survivals of about 6 months (p less than 0.05 and about 3 months (p less than 0.05) for patients with stable and progressive disease. Major drug toxicity was myelosuppression with median lowest granulocyte counts of 1,000/microliters and platelet counts of 88,000/microliters. Approximately 25% of patients required antibiotic therapy for fever of unknown origin or documented infections. Other tolerable drug toxicities included nausea, vomiting and mucositis. The FAB regimen appears quite promising in biliary tract cancer and has efficacy in pancreatic carcinoma that warrants further clinical trials. Because of myelotoxicity observed with this regimen we now recommend a BCNU starting dose of 100 mg/m2 instead of 150 mg/m2.

Adult↗
PubMed1979

Kinetics of gallium nitrate, a new anticancer agent.

Pharmacokinetic studies were conducted in 8 patients with disseminated neoplasms refractory to conventional chemotherapy, who received gallium nitrate at doses of 300 to 600 mg/m2 intravenously in a phase I clinical trial. Gallium concentrations in biological fluids were determined colorimetrically. In patients with normal renal function, gallium showed a biphasic plasma disappearance with an initial half-life (t1/2) of 0.5 to 1.8 hr (mean 1.0) and a terminal t1/2 of 10.5 to 50.4 hr (mean 25.1). Gallium was distributed in total body water and often localized in some body compartment as evidenced by a volume of distribution ranging from 0.25 to 2.53 L/kg (mean 1.19). The total drug clearance from the plasma was 0.13 to 1.00 ml/kg/min (mean 0.65) in patients with normal renal function. Cumulative urinary excretion of gallium was 15% to 72% (mean 35%) of the administered dose in 24 hr (it fell to 23% in 8 days in a patient with acute oliguric renal failure). Gallium kinetics are altered in patients with acute renal dysfunction and in patients who have received multiple doses of gallium or other metal chemotherapy.

Adult↗
PubMed1979

Adenocarcinoma of unknown primary site: a clinico-pathological study.

An analysis of the clinico-pathological findings in 49 patients with adenocarcinoma of unknown primary origin indicates a short survival time. No factors were identified that influenced survival. Thromboembolic episodes and second primary tumors commonly complicate the clinical course. Metastases in widespread organs are common autopsy findings. Immunological mechanisms may explain these findings.

Abdominal Neoplasms↗
PubMed1979

Phase II evaluation of vindesine in the treatment of colorectal and esophageal tumors.

A phase II study of vindesine was carried out in 33 patients with colorectal cancer and nine patients with esophageal cancer. With the exception of six previously untreated patients with esophageal cancer, all others were refractory to 5-FU-containing regimens, w,hich included vincristine in ten patients. The initial dose of vindesine was 4 mg/m2 administered intravenously over 30 min every 2 weeks. Tumor regression less than 50% was set patients (six colorectal and two esophageal) achieved minor responses. Prior treatment with vincristine did not seem to influence response to vindesine. In general, the treatment with vindesine was well tolerated. The hematologic toxicity was acceptable and manifested mainly as moderate and transient neutropenia. The major nonhematologic toxicity was peripheral neuropathy, which became limiting. It occurred in 33% of patients who received two or more courses of vindesine. Because of the apparent antitumor activity and dose-limiting neurotoxicity of vindesine in this sutdy, further investigations of this compound should be conducted in combination chemotherapy programs for patients with metastatic gastrointestinal cancers.

Adult↗
PubMed1979

Necrotizing colitis in patients with cancer.

Necrotizing lesions of the colon occur in patients with malignancy. We identified 26 patients with cancer (23 with acute leukemia and three with solid tumors) who died from necrotizing colitis. Autopsies revealed three pathologic categories: pseudomembranous colitis in 69 per cent, agranulocytic colitis in 19 per cent and ischemic colitis in 12 per cent. Most died from sepsis. A comparison of characteristics was made with a control population matched for diagnosis, age, cause of death and duration of neoplasia. Nearly all patients in both groups had fever and were granulocytopenic secondary to chemotherapy. Most received antineoplastic and antimicrobial regimens during the month prior to their terminal illness. Abdominal pain and distention, stomatitis and necrotizing pharyngitis were frequently associated with colitis. Hyperbilirubinemia was a frequent late complication in those with colitis and the control group. Single and multiorganism septicemia were found more frequently in patients with colitis. As antemortem diagnosis was unusual, aggressive attempts at diagnosis are necessary to assess the true incidence of this disorder and the best therapy.

Adolescent↗