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Biomedical subjects

K Antman

Publications and source records attributed to K Antman.

At least 55 records · Page 3Linked to original sources
PubMed1992

Long-term salvageability for patients with locally recurrent soft-tissue sarcomas.

Between 1971 and 1988, 39 patients were referred because of local recurrence of soft-tissue sarcomas and data from their patient records were analyzed to determine the parameters governing local recurrence. Mean follow-up was 11.1 years, with a mean time to local recurrence of 22 months. Twenty-one patients had local recurrence only, without metastatic disease. Salvage was provided for 14 (67%) of these patients after reexcision of local recurrence, and all 14 patients remained free of disease (mean follow-up, 112 months). We conclude that (1) excisional biopsy of tumors larger than 3 cm leads to potential contamination of clean tissue planes, limits ability to achieve an adequate margin of resection, and may compromise the definitive excision, and (2) in patients with local recurrence only, there is a high rate of long-term salvage (67% for follow-up of 9.3 years) after radical compartmental excision with or without postoperative radiation therapy.

Adolescent↗
PubMed1992

A phase II study of high-dose cyclophosphamide, thiotepa, and carboplatin with autologous marrow support in women with measurable advanced breast cancer responding to standard-dose therapy.

PURPOSE: The study was designed to determine the duration of complete response (CR) for patients with unresectable or metastatic breast cancer treated with high-dose cyclophosphamide, thiotepa, and carboplatin (CTCb) while responding to conventional-dose therapy. METHODS: Eligibility criteria included histologically documented metastatic or unresectable breast cancer, at least a partial response (PR) to conventional-dose therapy, no prior pelvic radiotherapy, cumulative doxorubicin of less than 500 mg/m3, and physiologic age between 18 and 55 years. Patients with inadequate renal, hepatic, pulmonary, and/or cardiac function or tumor involvement of marrow or CNS were excluded. Cyclophosphamide 6,000 mg/m2, thiotepa 500 mg/m2, and carboplatin 800 mg/m2 were given by continuous infusion over 4 days. After recovery, sites of prior bulk disease were to be radiated or resected if feasible. RESULTS: Of 29 registered patients, one died of toxicity (3%; hemorrhage). CRs and PRs continued a median of 16 and 5 months after transplant, respectively (26 and 9 months from initiation of chemotherapy for metastatic disease). Of 10 patients transplanted in CR, four have not progressed at 17 to 31 months after transplantation (25 to 43 months after beginning standard-dose therapy). One of four patients with uptake on bone scan as their only sites of residual disease before transplant and one of three who converted from PR to CR with transplant have not progressed at 27 and 29 months, respectively, after transplant. CONCLUSIONS: CTCb is an intensification regimen with a low mortality that delivers a significantly increased dose of agents with known activity at conventional doses in breast cancer. Although the duration of PR is short as expected, CRs appear to be durable.

Adult↗
PubMed1992

Cyclophosphamide pharmacokinetics: correlation with cardiac toxicity and tumor response.

BACKGROUND: Cyclophosphamide, which forms the nucleus for virtually all preparative regimens for autologous bone marrow transplantation (ABMT), is an alkylating agent of which cytotoxicity is not directly caused by the parent compound but by its biologically active metabolites. Its nonmyelosuppressive toxicity in the ABMT setting is cardiomyopathy. We attempted to determine any correlation between plasma levels of total cyclophosphamide and the subsequent development of cardiac dysfunction. PATIENTS AND METHODS: Analyses of plasma levels and the derivation of plasma concentration-time curves (area under the curve [AUC]) were performed in 19 women with metastatic breast carcinoma, who received a continuous 96-hour infusion of cyclophosphamide, thiotepa, and carboplatin (CTCb) with ABMT. The assay for total cyclophosphamide measures the inactive parent compound; reliable assays of the active metabolites of cyclophosphamide are not yet available. RESULTS: Six of 19 women developed moderate, but transient, congestive heart failure (CHF) as assessed by clinical and radiologic criteria. These patients had a significantly lower AUC of total cyclophosphamide (median, 2,888 mumol/L/h) than patients who did not develop CHF (median, 6,121 mumol/L/h) (P less than .002). Median duration of tumor response in these patients was also more durable; at least 22 months in patients with lower AUCs versus a median of 5.25 months in those with higher AUCs (P = .008). CONCLUSION: These pharmacokinetic data support the premise that enhancement of cyclophosphamide activation may lead to both greater tumor cytotoxicity and increased but reversible end-organ toxicity. Early analysis of pharmacokinetic data may allow modulation of cyclophosphamide administration in an attempt to enhance therapeutic efficacy.

Adult↗
PubMed1991

A perspective on dose-intensive therapy with autologous bone marrow transplantation for solid tumors.

The poor results seen in patients with advanced solid tumors treated with conventional-dose therapy have stimulated interest in alternative approaches, including higher than standard doses of chemotherapy. Most chemotherapeutic agents exhibit a steep dose-response curve in laboratory models that is log linear in nature. Autologous bone marrow transplantation applies this concept by employing dose-intensive therapy with chemotherapeutic agents whose dose-limiting toxicity is myelosuppression. Alkylating agents are logical choices for high-dose chemotherapy because they have a steep dose-response curve both in vitro and in vivo, and this response is maintained through multiple logs of tumor cell kill. Although at conventional doses myelosuppression is dose-limiting, at transplant doses each agent has its particular dose-limiting organ toxicity which allows alkylating agents to be employed in combination.

Alkylating Agents↗
PubMed1990

Hepatic venoocclusive disease in autologous bone marrow transplantation of solid tumors and lymphomas.

Retrospective review of 291 solid tumor and lymphoma patients undergoing autologous bone marrow transplantation (BMT) was performed to determine the influence of pretransplant characteristics and preparative regimen to the development of hepatic venoocclusive disease (VOD). Twelve patients (4.1%) developed a clinical syndrome of right upper quadrant (RUQ) tenderness or hepatomegaly, jaundice, and ascites, with or without encephalopathy, within 40 days of marrow reinfusion. Evidence of metastatic liver disease was the only pretransplant characteristic predictive for VOD (P = .0002). Sex, age, histology, hepatitis B serology, and elevated liver function tests were not predictive. No individual preparative agent had a significant effect on the development of VOD. However, a single 2-hour infusion of carmustine (BCNU) (greater than or equal to 450 mg/m2) led to an increased incidence of VOD when compared with the same dose administered in a fractionated schedule (P = .0258) when given with two other chemotherapeutic agents. Seven of eight autopsy specimens confirmed the clinical diagnosis of VOD. The four patients in whom clinical VOD resolved had lower median peak bilirubins (7.3 v 15.9 mg/dL), lower median peak creatinines (2.1 v 4.1 mg/dL), and relatively quick engraftment of neutrophils (mean, 18.7 days). One of the four patients in whom VOD resolved had other grade 4 (life-threatening) toxicities in contrast to eight of eight who succumbed. In summary, VOD is an uncommon complication in autotransplantation of solid tumors and lymphomas. Our data suggest caution in selecting patients with known metastatic liver disease and consideration of a fractionated BCNU schedule especially in combination with other alkylating agents.

Adult↗
PubMed1990

High-dose thiotepa alone and in combination regimens with bone marrow support.

Curative treatment regimens for leukemias, lymphomas, and testicular cancer have been based on laboratory observations of a clear relationship (generally linear-log) between increasing doses of chemotherapeutic agents and tumor cytotoxicity and on recognition of the need for combination chemotherapy to avoid the emergence of drug resistance. Chemotherapeutic agents have been selected for combinations based on cytotoxic activity, different mechanisms of action (to avoid cross-resistance), and different dose-limiting toxicities (to avoid additive toxicity). The ideal combinations use the highest tolerable doses of active non-cross-resistant agents to minimize the potential for drug resistance and achieve optimum cytotoxicity. Dose escalation is often limited by myelosuppression. Hematologic stem cell support from bone marrow or peripheral blood allows the administration of significantly higher doses of chemotherapy. In 1977, Thomas and colleagues in Seattle reported that 13 of 100 patients who underwent bone marrow transplantation for relapsed acute leukemia were disease-free 1 to 4.5 years later. Today, almost 50% of selected patients with acute myelogenous leukemia who undergo transplantation with human leukocyte antigen-matched sibling donor marrow during first remission are cured. Between 20% and 50% of lymphoma patients who undergo transplantation after failing conventional treatment have survived; those whose disease is responding to standard-dose therapy at the time of transplant have the best prognosis. Conditioning regimens that are sufficiently cytoreductive are not currently available for patients with solid tumors. The diversity of solid tumors makes it likely that a variety of regimens will be required. In a sequence of laboratory and clinical studies, we have constructed and evaluated a regimen comprising 6 g/m2 of cyclophosphamide, 500 mg/m2 of N,N',N''-triethylenethiophosphoramide (thiotepa), and 800 mg/m2 of carboplatin. The response rate in women with measurable breast cancer was 81%. While profound myelosuppression was noted, organ toxicity has been rare. This regimen, designed to exploit the principles of curative cancer chemotherapy, is associated with low morbidity and high cytoreductive efficacy. The regimen is currently being evaluated in a phase II trial in patients with previously untreated metastatic breast cancer who are responsive to conventional-dose chemotherapy. Of 29 patients entered in the study, only one has died of toxicity, confirming the low incidence of treatment-related toxicity associated with the regimen.

Adult↗
PubMed1989

Enhancement of superoxide anion release by granulocytes harvested from patients receiving granulocyte-macrophage colony-stimulating factor.

We examined the rate and quantity of superoxide anion (O2-) generation by granulocytes harvested from the blood of patients before and after a 12-24 h constant intravenous infusion with recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSFrh). Seven previously untreated patients with sarcomas who exhibited no bone marrow involvement by their disease were studied. Granulocytes were harvested from the peripheral blood of each patient before and after intravenous infusion with GM-CSFrh. The total quantity of O2- produced and the kinetics of its release were then determined following in vitro activation of the cells by the chemotactic peptide N-formyl methionyl-leucylphenylalanine (fMLP) or by phorbol myristate acetate (PMA). In all cases, the amount of O2- generated and the rate of its release were significantly increased after GM-CSFrh infusion. Our findings indicate that intravenous administration of GM-CSFrh to patients heightens the functional responsiveness of circulating granulocytes.

Adult↗
PubMed1989

Bone marrow autotransplantation for solid tumors--prospects.

Autologous bone marrow transplantation (AuBMT) is in clinical trial for patients with metastatic solid tumors, particularly breast cancer. This review deals with the potential of this approach. AuBMT is curative for the leukemias and lymphomas. Curative cancer chemotherapy has, almost without exception, required combinations of agents wherein dose was well maintained. However, curative chemotherapy strategies for the hematologic neoplasms have not proven successful for the common solid tumors. An important exception is that standard adjuvant chemotherapy can "cure" some micrometastatic tumors. Preclinical studies indicate the effectiveness of alkylating agents in terms of maintained dose effect through multiple logs of tumor cell kill; difficulty in developing drug resistance; general lack of cross resistance; and synergy for alkylating agents used in combination. There is an increasingly effective experimental basis for the construct of intensification regimens employing combinations of alkylating agents. Differing nonmyelosuppressive toxicity for alkylating agents provides a basis for maintaining dose when employed in combination in the autologous marrow situation. The aforementioned studies and cytokinetic analyses of combined intensive alkylating agent therapy for breast cancer support the potential of this approach. Clinical trials indicate a high response rate in refractory breast cancer. Trials involving induction chemotherapy followed by combined alkylating agent intensification have produced substantial complete remission rates. The duration of response has, in most studies, been short. This approach is associated with major toxicity, including mortality, and is expensive. Experimental and preliminary clinical evidence as marshalled in this review indicate that this is a promising area for therapeutic research.

Antineoplastic Agents↗
PubMed1989

A phase I clinical and pharmacokinetic study of carboplatin and autologous bone marrow support.

A series of 33 patients were treated with a four-day continuous infusion of carboplatin in a phase I study to determine the maximum-tolerated dose (MTD) of this agent when used with autologous bone marrow reinfusion. Doses were escalated from 375 to 2,400 mg/m2; autologous bone marrow reinfusion was added to the regimen at doses of 1,600 mg/m2 and above. The MTD was determined to be 2,000 mg/m2. Dose-limiting toxicity consisting of reversible hepatotoxicity, renal dysfunction, and moderate to severe ototoxicity was observed with a dose of 2,400 mg/m2. There were ten responses in 31 heavily pretreated patients, including six responses in 11 patients with recurrent ovarian cancer. Pharmacokinetic studies revealed a systemic clearance (Clss) of 4.5 L/m2/h. This value is consistent with clearances reported for carboplatin administered at lower doses and by different schedules. No evidence for saturation of systemic clearance at higher doses was observed. Carboplatin appears to be an active drug that can undergo considerable dose escalation when used in conjunction with autologous bone marrow support.

Adult↗
PubMed1988

Cyclophosphamide and thiotepa with autologous bone marrow transplantation in patients with solid tumors.

Autologous bone marrow transplantation to avoid dose-limiting myelosuppression may allow significant drug dose escalations and exploitation of the linear-log correlation between chemotherapy and tumor cytotoxicity. In a phase I trial of cyclophosphamide and thiotepa (with subsequent addition of melphalan), 23 patients were entered; there were two deaths due to toxic effects. The maximum tolerated dose was 6 g of cyclophosphamide/m2 and 720 mg of thiotepa/m2. No significant dose of melphalan could be added. Stomatitis was dose limiting. Eleven of 20 patients who were able to be evaluated responded. Plasma thiotepa concentrations correlated more closely with toxicity and response than with drug dose level. Continuous infusion cyclophosphamide and thiotepa is an active core regimen for the further design of high-dose combination chemotherapy regimens.

Adult↗
PubMed1988

Malignant mesothelioma: prognostic variables in a registry of 180 patients, the Dana-Farber Cancer Institute and Brigham and Women's Hospital experience over two decades, 1965-1985.

All mesothelioma patients identified by a computer search of pathologic diagnoses at the Dana-Farber Cancer Institute (DFCI) between 1965 and 1985 were the subjects of this analysis. A total of 180 patients were identified, 136 with pleural and 37 with peritoneal mesothelioma. There were five pericardial and two testicular primaries. Of the two decades included in the study, later patients were significantly older, with a more advanced disease stage, and a lower performance status than those accrued early in the study. Factors at diagnosis associated with a significantly prolonged survival for all patients with mesothelioma included a 0 to 1 performance status, absence of chest pain, age less than 50 years, and epithelial histology. Factors at diagnosis associated with prolonged survival for the subset of patients with pleural mesothelioma included epithelial histology, 0 to 1 performance status, the absence of chest pain, an interval of greater than 6 months from onset of symptoms, and treatment with chemotherapy and pleuropneumonectomy. This last result must be interpreted with caution, since this was not a randomized study.

Boston↗
PubMed1988

Advanced breast cancer: high-dose chemotherapy and bone marrow autotransplants.

The response of human breast cancer to drugs and radiation is dose-dependent, with higher doses producing increased response rates. However, dose escalation of several agents active against breast cancer is limited by bone marrow toxicity. This limitation can be overcome in some instances by transplantation of bone marrow cells. We evaluated 27 trials of bone marrow autotransplants in 172 patients who received single or multiple drug chemotherapy, radiation, or both. The overall response rate was 58%. Response rates were highest in trials involving multiple alkylating agents (76%) or previously untreated patients (81%). These data suggest that high-dose therapy and bone marrow autotransplants can produce remissions in patients with advanced breast cancer unresponsive to conventional therapy. A critical evaluation of this approach will require controlled trials in high-risk persons.

Antineoplastic Agents↗
PubMed1988

Granulocyte-macrophage colony-stimulating factor induces the expression of the CD11b surface adhesion molecule on human granulocytes in vivo.

The CD11b (Mol) molecule is a member of a family of surface glycoproteins that are essential for adhesion-dependent granulocyte functions. Brief exposure of granulocytes to human granulocyte-macrophage colony-stimulating factor (GM-CSF) in vitro increases the surface expression of CD11b and increases granulocyte adhesiveness. To assess the possible in vivo significance of these observations we studied the effect of GM-CSF on CD11b, CD11a (LFA-1), and CD11c (gp 150, 95) expression on granulocytes from nine adult patients with sarcoma who were receiving GM-CSF as part of a phase I trial. GM-CSF was administered as a continuous infusion at a dose of 32 or 64 micrograms/kg/d. Granulocyte CD11b, CD11a, and CD11c expression was determined by indirect immunofluorescence staining of whole blood, thereby minimizing in vitro manipulation. A transient leukopenia developed within 15 minutes of initiation of GM-CSF treatment that was associated with a marked increase in the surface antigen density of CD11b. A mean 1.7-fold increase (P = .001) in the percentage of CD11b-positive granulocytes and a mean 2.1-fold increase (P = .002) in CD11b surface antigen density was noted after 12 hours of treatment. No change in CD11a or CD11c expression was observed over the first 12 hours. The level of CD11b expression was followed in six patients for up to 5 days of treatment with GM-CSF. Compared with the 12-hour value, three of six patients showed a subsequent decrease in CD11b expression, two remained constant, and one showed a continued increase in CD11b surface density. Fluorescence-activated cell sorting of granulocytes into high- and low-density CD11b-positive groups revealed a preponderance of immature myeloid forms in the low-density CD11b fraction, which suggests that the late decrease in CD11b expression in some patients may be related to a greater proportion of circulating immature myeloid forms in the peripheral blood. This study suggests that GM-CSF administered as a continuous infusion rapidly upregulates the expression of granulocyte CD11b in vivo. The influence of this phenomenon on in vivo granulocyte aggregation may be clinically relevant with regard to the toxicity of GM-CSF and deserves further investigation.

Antigens, Differentiation↗