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Biomedical subjects

L H Baker

Publications and source records attributed to L H Baker.

At least 37 records · Page 2Linked to original sources
PubMed1995

Low-dose, continuous infusion 5-fluorouracil and oral etoposide for the treatment of advanced sarcomas.

5-fluorouracil (5-FUra) and etoposide demonstrate relationships between schedule of administration and activity in a number of clinical situations. With limited information regarding 5-FUra and oral etoposide in sarcoma, and informal observations suggesting activity of infusional 5-FUra in sarcomas, a phase II study was performed. This phase II study attempted to evaluate the efficacy of the combination of low-dose continuous infusion 5-FUra (LDCI-5FUra) and oral etoposide administered to patients with advanced sarcomas. Treatment consisted of 5-FUra at 300 mg/m2/day and etoposide at 50 mg/m2/day for 21 days. Cycles were repeated at 28-day intervals or upon recovery from toxicity. Twenty patients received 50 cycles of therapy. No objective responses were seen in 19 evaluable patients (response rate 0%, 95% confidence interval 0-18%). Toxicity was mild and consisted primarily of stomatitis, diarrhea, and leukopenia. Median survival for all patients was 9 months (1.8-30+ months range). The combination of LDCI-5FUra and oral etoposide, at the doses and schedule studied, was inactive in this population with advanced sarcoma.

Administration, Oral↗
PubMed1995

Pharmacokinetics of 9-methoxy-N,N-dimethyl-5-nitropyrazolo [3,4, 5-kl]acridine-2(6H)-propanamine (PZA, PD 115934, NSC 366140) in mice: guidelines for early clinical trials1.

Pharmacokinetic studies that consisted of measuring the plasma drug profile, tissue drug distribution, and elimination in urine and feces were performed in female C57BL/6 x DBA/2 (hereafter called B6D2F1) and male B6D2F1A/2 and C57BL/6 x CH3 (hereafter called B6C3F1) mice following treatment with a 1-h i.v. infusion of the PZA, PD115934 (NSC 366140). This drug is the first of a new class of cytotoxic agents and was selected for clinical trials because of both its broad antitumor activity in vivo against murine solid tumors and human xenografts, and its in vivo toxicity profile that was predictable based on drug dose and schedule of administration. The pharmacokinetic results obtained here in mice have been used to facilitate the dose escalations during the Phase I trial and to determine pharmacokinetic drug exposure targets for its acute and sub-acute toxic effects. Plasma samples from three to four mice per time point were pooled, and then individual tissue samples from the same mice were collected at specified times following treatment. All samples were prepared using solid-phase extraction and assayed using high pressure liquid chromatography. The acute dose-limiting toxicity was neurological and occurred immediately after treatment at 300 mg/m2. The peak plasma level range at the acute maximum tolerated dose was 1040-1283 ng/ml. Thus, peak plasma levels <1000 ng/ml were the acute toxicity target. Variations in the area under the plasma drug concentration x the time curve were observed that did not appear to be related to sex or age. The previously defined subacute dose-limiting toxicity was myelosuppression that occurred at a maximum tolerated dose of 600 mg/m2 (300 mg/m2 x 2) in B6D2F1 females. Thus, the area under the plasma drug concentration x the time curve in B6D2F1 females at this dose (1048 microg/ml x min) was the area under the plasma drug concentration x the time curve target. Drug levels were detected at 60 min following treatment in all tissues examined with a plasma:tissue ratio as high as 1:500. The organs with the highest levels were kidney, pancreas, liver, lung, and brain. Fecal excretion was low (range, 0.04-0.20% of the dose administered) and was not clearly different between males and females. Urinary excretion was higher (range, 5-28% of the dose administered) and did show evidence of sex-related differences, with male urinary drug excretion being higher than female urinary drug excretion. The drug was >/=95% protein bound. Preliminary evidence for drug metabolism was found in urine and feces and will be further explored.

Acridines↗
PubMed1994

Ifosfamide and etoposide in the treatment of advanced soft tissue sarcomas.

Ifosfamide is an active chemotherapeutic agent in the treatment of soft tissue sarcoma. This Phase II study attempted to evaluate the efficacy of the addition of etoposide to ifosfamide administered to patients with recurrent or metastatic soft tissue sarcoma. Treatment consisted of etoposide 100 mg/m2, followed by ifosfamide 2.0 g/m2, daily, for 4 consecutive days. Mesna was administered for uroprotection. Cycles were repeated at 21-day intervals or upon recovery from toxicity. Two partial responses were observed in 19 evaluable patients (response rate 10.5%, 95% confidence interval, 7% to 14%). Response durations were brief at 2 and 6 months. In a subset of 10 patients with gastrointestinal leiomyosarcoma, no responses were observed. Toxicity was generally mild, consisting primarily of myelosuppression and controllable nausea and emesis. No episodes of hematuria were observed. Overall survival for all eligible patients was 10 months (range: 0.2 to 34.7+ months). Etoposide, in this dose and schedule, failed to enhance the activity of ifosfamide in adult soft tissue sarcoma. Additionally, this experience and a review of the literature, suggest that ifosfamide has little activity against gastrointestinal leiomyosarcomas. Continued efforts are needed to identify novel agents with efficacy against these resistant tumors.

Adult↗
PubMed1994

Phase II trial of recombinant human macrophage colony-stimulating factor in metastatic soft tissue sarcoma.

This Phase II study was undertaken to access the activity of recombinant human macrophage colony stimulating factor (M-CSF) in metastatic soft tissue sarcoma based on the observation of a partial response in a patient with leiomyosarcoma during an earlier Phase I trial. Fifteen patients with metastatic soft tissue sarcoma (seven males and eight females) were entered on the trial between October 1990 and March 1991. Seven of these patients had leiomyosarcoma. One mg/M2 of M-CSF was administered by rapid intravenous infusion every 8 h on days 1-5 and 15-19. Treatment cycles were repeated at 35-day intervals. Patients were evaluated initially for response after the first cycle, and then following alternate cycles. One partial response was observed in a patient with metastatic small bowel leiomyosarcoma (response rate 7%, 95% confidence interval, 0-33%). Two additional patients had stable disease for 10-15 months on study. Four patients had clinically significant bleeding from tumor sites during M-CSF therapy. No evidence of toxicity directly attributable to M-CSF was observed in any patient. Mean monocyte counts increased in patients during the first 20 days of treatment (p = 0.013). At this dose and schedule, meaningful activity of M-CSF in previously treated patients with soft tissue sarcoma could not be demonstrated. However, the activity observed in patients with leiomyosarcoma in this trial and in the previous Phase I study are intriguing. Further studies of M-CSF in previously untreated patients with leiomyosarcoma may be warranted.

Adolescent↗
PubMed1993

Evaluation of combination chemotherapy and phase II agents in pancreatic adenocarcinoma. A Southwest Oncology Group study.

BACKGROUND: Pancreatic carcinoma responds poorly to conventional chemotherapy. To identify potentially useful agents, a sequence of clinical trials were done. METHODS: A series of Phase II randomized trials were done by the Southwest Oncology Group in which patients with metastatic or advanced pancreatic cancer were randomized to receive single agents (methylglyoxal-bis-guanylhydrazone [MGBG], dihydroxyanthracenedione [DHAD], and aziridinylbenzoquinone [AZQ]) or a combined regimen of 5-fluorouracil, doxorubicin, mitomycin C, and streptozotocin (FAM-S). Toxicity, response, and survival were determined. RESULTS: Seventy-one patients received FAM-S and 82, the Phase II single agents. Response rates (95% confidence intervals) for the various treatments were: FAM-S, 11% (0%, 21%); MGBG, 6% (0.8%, 21%); DHAD, 0% (0%, 12%); and AZQ, 0% (0%, 16%). The median survival times were: FAM-S Group, 4.8 months and Phase II agent Group, 3.4 months. CONCLUSIONS: The FAM-S regimen and the Phase II agents tested did not have substantial antitumor activity in pancreatic cancer. The use of new agents as initial therapy is reasonable.

Adenocarcinoma↗
PubMed1993

DNA content parameters of paraffin-embedded soft tissue sarcomas: optimization of retrieval technique and comparison to fresh tissue.

DNA content analysis of formalin fixed paraffin embedded (FFPE) tissue permits determination of the influence of DNA content on the prognosis in cohorts of patients for whom the clinical outcome is known. Of key importance in such an analysis is the accuracy of DNA content determination. Variations in the quality of DNA histograms from FFPE tissues of different types prompted a comparative evaluation of the preparative methodology of FFPE soft tissue sarcomas for DNA flow cytometry. Following deparaffination and rehydration of fixed tissue, and prior to fluorochrome staining, tissue blocks of 15 DNA aneuploid soft tissue sarcomas were subjected to repeated experimental (time x concentration) enzyme exposures. The goal of these studies was to define the optimal tissue specific retrieval technique with the coefficient of variation, maintenance of DNA aneuploidy, and DNA index as endpoints. After optimizing the technique, the DNA content of 50 soft tissue neoplasms derived from FFPE specimens was compared to the corresponding fresh surgical tissue. The observed 14 percent error rate in the determination of DNA ploidy status suggest limited utility for FFPE tissue in prospective therapeutic trials of soft tissue sarcoma.

Cell Count↗
PubMed1993

Development and optimization of tissue preparative methodology for DNA content analysis of soft tissue neoplasms.

Data regarding DNA content parameters in soft tissue sarcoma is limited. Development and optimization of tissue specific preparative techniques for DNA flow cytometry was undertaken prior to routine DNA content analysis of soft tissue neoplasms; 154 soft tissue tumors were studied. Dissociation dependent differences in cellular yields, viabilities, maintenance of DNA aneuploid populations, coefficients of variation, and DNA index supported the need for these developmental studies. Fifty-six of eighty-nine patients had DNA aneuploid soft tissue sarcomas. A relationship between DNA aneuploidy and grade was seen in this series with 38% with low grade, 59% with moderate grade, and 69% with high grade tumors demonstrating DNA aneuploid populations (P < 0.005). The mean S-phase fraction for DNA diploid and aneuploid sarcomas was 7.2% and 13.3%, respectively (P < 0.001). When classified by histologic grade of the primary tumor, a greater percentage of metastatic lesions were DNA aneuploid (4 of 7 grade 2 lesions, and 15 of 16 grade 3 lesions). Decreases in cellular yields and rate of DNA aneuploidy were observed in a subgroup of patients with localized high grade sarcoma treated preoperatively, as compared to patients treated with initial surgery. Prospective correlation of DNA content parameters to prognosis and response to cytotoxic therapy are now possible and are ongoing.

Aneuploidy↗
PubMed1993

Phase II trial of merbarone in pancreatic carcinoma. A Southwest Oncology Group study.

Twenty-nine patients with advanced pancreatic adenocarcinoma were treated with merbarone, utilizing a daily intravenous schedule for 5 days. Only two partial responses of short duration were observed. The major toxicities were renal, with an increase in creatinine or proteinuria in 17 patients, and mild to moderate nausea and vomiting seen in 22 patients. Merbarone in this dose and schedule has minimal activity in pancreatic cancer.

Adenocarcinoma↗
PubMed1991

A Southwest Oncology Group phase II Trial of recombinant tumor necrosis factor in metastatic breast cancer.

New approaches are needed in the treatment of advanced breast cancer. In vitro studies have shown that recombinant tumor necrosis factor (TNF) is a growth inhibitor for the MCF-7, ZR-75-1, and BT-20 human breast cancer cell lines. Based on these considerations, the Southwest Oncology Group performed a Phase II trial of recombinant TNF (Genentech) (150 micrograms/m2) given by 30-minute intravenous infusion on days 1 to 5 of every other week for 8 weeks. Patients with metastatic breast cancer who had received one prior chemotherapy regimen for advanced disease were eligible. Of the 22 patients who were entered, 3 were ineligible. Nineteen patients who had a performance status of 2 or less could be examined (median age, 53 years). One possible fatal toxic reaction has been seen in a patient who had intracranial bleeding caused by a previously undiagnosed brain metastasis; no other treatment-related deaths have occurred. Toxicity has included nausea, vomiting, fever, chills, myalgia, and fatigue. No Grade 4 toxicity has been observed. Grade 3 toxic reactions have included hypotension (two patients), diarrhea (one patient), transient leukopenia (two patients), and reversible elevations of liver function test values (two patients). No objective responses have been observed. Twelve of 19 patients have died (median survival time, 8.5 months). Recombinant TNF is inactive as a single agent in patients with previously treated metastatic breast cancer.

Adult↗
PubMed1991

Phase III comparison of doxorubicin and dacarbazine given by bolus versus infusion in patients with soft-tissue sarcomas: a Southwest Oncology Group study.

Disseminated soft-tissue sarcomas are a group of uncommon malignancies generally treated in a uniform manner. This study questioned the impact of schedule on response rate and toxicity in patients with metastatic soft-tissue sarcoma treated with the two-drug combination doxorubicin and dacarbazine. Patients were randomly assigned to receive either bolus therapy with doxorubicin at a dose of 60 mg/m2 and dacarbazine at a dose of 750 mg/m2 intravenously on day 1 (118 patients) or infusional therapy with doxorubicin at 60 mg/m2 and dacarbazine at 750 mg/m2 delivered by continuous intravenous infusion for 96 hours on days 1-4 (122 patients). Chemotherapy was to be repeated every 3 weeks. A unique feature of this cooperative group protocol was a provision for surgical resection of residual disease in patients with a partial response or with stable disease following chemotherapy. Similar overall response rates (17% in both treatment arms) and complete response rates (5% in both treatment arms) were observed. For patients receiving bolus therapy, the median response duration was 19.6 months for those in complete remission and 6.6 months for those in partial remission. For patients receiving infusional therapy, the median response duration was 12.6 months for those in complete remission and 9.3 months for those in partial remission. Examination of dose intensity received when combining treatment arms revealed a weak doxorubicin dose-response relationship. There was no difference in median survival times between the two treatment arms (bolus therapy, 10.6 months; infusional therapy, 10.5 months; logrank P = .97). Analysis of toxic effects favored infusional therapy. Significant reductions in cardiac toxicity (all events, P = .04; clinical events, P = .01) and nausea and emesis (P = .04) were seen in infusional therapy. Of 47 patients eligible for cytoreductive surgery following chemotherapy, 12 received surgery, and of those 12, eight were rendered disease free. The use of a 96-hour continuous intravenous infusion of doxorubicin-dacarbazine was comparable therapeutically with bolus dosing of these two agents and was better tolerated by the patients.

Adolescent↗
PubMed1991

Crisnatol mesylate: phase I dose escalation by extending infusion duration.

Crisnatol mesylate is a rationally designed cytotoxic arylmethylamino-propanediol with broad spectrum cytotoxic activity. A phase I study with an unconventional escalation scheme was developed using a constant drug infusion rate (mg/m2/hr) and prolonging the infusion duration from 6 to 96 hours. Sixty-five patients received crisnatol at doses from 18 mg/m2 in 6 hrs to 3400 mg/m2 in 72 hours. The dose-limiting toxicity in two of five patients at 2700 mg/m2 and two of three patients at 3400 mg/m2 was neurologic and consisted of a syndrome of confusion, agitation, and disorientation. Phlebitis mandated the use of a central line. The mean terminal phase half-life (T1/2 beta) was 3.3 hours with a total body clearance (CL) of 22.8 L/hr/m2 and a volume of distribution (Vdss) of 53 L/m2. The median steady-state peak plasma concentration (Css) at 2700 mg/m2/72 hours was 2.7 micrograms/ml and at 3400 mg/m2/72 hours was 3.8 micrograms/ml. No responses were seen. The maximum tolerated dose (MTD) on this schedule is 2700 mg/m2/72 hours in patients with no liver disease and good performance status.

Adolescent↗
PubMed1991

Gallium nitrate in advanced bladder carcinoma: Southwest Oncology Group study.

Gallium nitrate is a heavy metal anticancer agent that has demonstrated widespread activity in a number of phase I studies. This phase II study employed a starting dose of 700 mg/m2 IV every two weeks in patients with advanced bladder carcinoma. Significant nephrotoxicity observed in 4 of the first 10 patients required extending the time between cycles to three weeks in the remaining 24 patients. One complete response and six partial responses were achieved. Nephrotoxicity was the major dose-limiting toxicity. Gastrointestinal toxicity and myelosuppression were minimal. Gallium nitrate appears to be an active agent in advanced carcinoma of the bladder. Further clinical trials with this agent are warranted.

Antineoplastic Agents↗
PubMed1991

Second-line treatment of advanced measurable ovarian cancer with iproplatin: a Southwest Oncology Group study.

105 patients with advanced ovarian cancer previously treated with cisplatin or carboplatin were entered into a study of iproplatin as second-line therapy. Patients were either clinically resistant to cisplatin or carboplatin, or had relapsed after complete response to these agents. Patients were treated intravenously at an initial dosage of 270 mg/m2 with dosage adjustments to 340, 200 or 135 based on observed toxicity. Of 101 eligible patients, 7 responses (3 complete, 4 partial; 12%) were observed in 60 patients resistant to cisplatin. 2 partial responses (11%) occurred in 18 patients resistant to carboplatin. 2 complete and 3 partial responses were observed in 19 patients (26%) previously treated with but not resistant to cisplatin. Response durations were 2-20 months. Toxicities of iproplatin included thrombocytopenia in 93% of patients, leukopenia in 76% of patients, anaemia in 68% of patients, and diarrhoea in 40% of patients. Thus iproplatin shares cross-resistance with cisplatin and carboplatin in the treatment of ovarian cancer and is not recommended as an effective second-line agent for platinum-resistant ovarian cancer.

Adult↗
PubMed1990

A common cytogenetic abnormality and DNA content alterations in dedifferentiated chondrosarcoma.

Dedifferentiated chondrosarcoma is an uncommon and aggressive variant of chondrosarcoma. The authors report the flow cytometric characteristics and cytogenetic findings in culture of two cases of dedifferentiated chondrosarcoma. The first case was DNA diploid by flow cytometry but had cytogenetic abnormalities consisting of breaks in the short arms of both chromosomes 1, resulting in deletion in one homolog and recombination in the other. In addition, cells from this tumor showed a balanced translocation between chromosomes 4 and 5, deletion of chromosome 9, and monosomy for chromosome 10. The second case was DNA aneuploid and more complex cytogenetically but had, in common with the first case, rearrangement and translocation at the same band on chromosome 1. These cytogenetic changes are compared with abnormalities previously reported for chondrosarcoma. Possible relationships between the nonrandom chromosomal abnormalities and subclassification among chondrosarcomas are discussed.

Aged↗
PubMed1990

High-dose cisplatin for metastatic soft tissue sarcoma.

Between August 1984 and January 1987, the Southwest Oncology Group (SWOG) registered 46 patients with metastatic sarcomas on SWOG 8465, a Phase II trial of high-dose cisplatin in patients with metastatic soft tissue sarcoma. Six patients were ineligible for the following reasons: poor performance status (two patients); ineligible diagnosis (three patients, two with Ewing's sarcoma of bone and one with metastatic chondrosarcoma); and evaluable but nonmeasurable disease (one patient with bone-only disease). Of the 40 fully evaluable patients, 34 had received prior chemotherapy; treatment was with cisplatin (40 mg/m2/d for 5 consecutive days). Cisplatin was mixed in 250 ml of 3% NaCl and hydrated with a normal saline solution at a rate of 250 ml/h, beginning 12 hours before the first dose of cisplatin was specified. The second treatment was given 3 weeks after the first, with all subsequent treatments given every 4 weeks. After three cycles of treatment, responding patients were treated at a cisplatin dose of 20 mg/m2/d for 5 consecutive days. Leukopenia was of Grade 3 or 4 in seven patients, whereas thrombopenia was of Grade 3 or 4 in eight patients. More severe myelosuppression was produced in patients who had received prior radiotherapy. A single case of reversible Grade 4 nephrotoxicity was produced; neurotoxicity was observed in 11 cases, but was of Grade 3 in only 2 cases. Of the 40 evaluable cases, six showed partial responses or no responses, for a major response rate of 15%. High-dose cisplatin has minor activity and major toxicity in the treatment of metastatic soft tissue sarcomas, and should be considered investigational.

Adult↗