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Biomedical subjects

K Antman

Publications and source records attributed to K Antman.

At least 37 records · Page 2Linked to original sources
PubMed1996

Double dose-intensive chemotherapy with autologous stem-cell support for metastatic breast cancer: no improvement in progression-free survival by the sequence of high-dose melphalan followed by cyclophosphamide, thiotepa, and carboplatin.

PURPOSE: Twenty-one percent of responding metastatic breast cancer patients remain progression-free a median 50 months following one intensification cycle of cyclophosphamide (6,000 mg/m2), thiotepa (500 mg/ m2), and carboplatin (800 mg/m2) (CTCb) with autologous bone marrow transplantation (ABMT). This trial studied whether the sequence of high-dose melphalan followed by CTCb resulted in improved disease response and duration. METHODS: Women with at least partial responses (PRS) to induction received melphalan (140 or 180 mg/ m2) with peripheral-blood progenitor cell (PBPC) and granulocyte colony-stimulating factor (G-CSF) support. They were monitored as outpatients. After recovery, patients were hospitalized for CTCb with marrow, PBPC, and G-CSF support. RESULTS: Data on 67 women, at a median of 25 months from CTCb, were examined. After melphalan, 49 (73%) required admission for fever (89%), mucositis (35%), or infection (15%) (median stay, 8 days). All received CTCb. For the first 33 patients, the median days from start of melphalan to CTCb was 24. After liver toxicity (one death from venoocclusive disease [VOD]) developed in 11 patients during CTCb, the interval between intensifications was increased to 35 days without incident. Twenty-three patients (34%) are progression-free a median of 16 months post-CTCb. The median progression-free survival (PFS) and survival times for the whole group are estimated at 11 and 20 months, respectively. CONCLUSION: Treatment with this sequence of high-dose melphalan followed by CTCb has not resulted in superior PFS to date, when compared with single-intensification CTCb. This report discusses factors related to patient selection, the role of induced drug resistance, and the schedule of administration of alkylating agenting that may adversely influence outcome.

Adolescent↗
PubMed1995

High-dose ifosfamide, carboplatin, and etoposide pharmacokinetics: correlation of plasma drug levels with renal toxicity.

An autologous bone marrow transplant regimen of ifosfamide, carboplatin, and etoposide (ICE) has been developed as treatment for certain malignancies. At maximum tolerated doses renal insufficiency precludes dose escalation. The objective was to examine whether measurement of plasma drug levels early during treatment would provide warning of renal failure. Nine patients received a 96-h continuous infusion of ifosfamide 16,000 mg/m2, carboplatin 1600 mg/m2, and etoposide 1200 mg/m2. Pharmacokinetics, including drug levels and plasma concentration-time curves, of ifosfamide, ultrafiltrable platinum (uPt) and etoposide were analyzed and correlated with renal function. One of the nine patients developed anuric renal failure requiring hemodialysis. By 17 h from the start of infusion, this patient showed substantially higher drug levels of ifosfamide (200 vs mean 217 microM) and uPt (19 vs mean 10 microM) than those patients with preserved renal function. The 95% confidence intervals suggested that a 16-22 h ifosfamide level > 153 microM and an uPt level > microM predict the development of significant renal dysfunction. Although drug levels were substantially higher at 56 h, the serum creatinine did not yet reflect kidney injury. This study suggests that high plasma ifosfamide and uPt levels, analyzed early in the course of a 96-h infusion of high-dose ICE, provide warning of severe and potentially fatal renal injury. Since ICE has substantial activity in a number of malignancies, but significant renal morbidity, real-time pharmacokinetic-guided dosing may reduce treatment-related toxicity.

Acute Kidney Injury↗
PubMed1995

High-dose therapy for breast cancer.

The high incidence of breast cancer in young women, and the unfavorable prognosis for those who present with a high number of lymph nodes involved with cancer, has encouraged the development and evaluation of new treatment strategies. The use of dose intensification is supported by laboratory and clinical models. In this review article, the use of dose intensification supported by hemopoietic growth factors, and also by hemopoietic stem cells, is discussed. The results of published studies of high-dose chemotherapy in Stage II, III, and IV breast cancer are discussed and summarized, including those randomized comparisons with more conventional therapy. Improvements in supportive care continue to reduce the risks from neutropenia and thrombocytopenia, and these and other toxicities are likely to decrease as side-effects are anticipated and experience increases.

Adult↗
PubMed1995

Prognostic factors for prolonged progression-free survival with high-dose chemotherapy with autologous stem-cell support for advanced breast cancer.

PURPOSE: With a median observation time of 50 months from transplant, 13 (22%) of 62 women with metastatic breast cancer treated with high-dose chemotherapy at the Dana-Farber Cancer Institute (DFCI)/Beth Israel Hospital (BIH) remain progression-free. This study determined factors prognostic for prolonged progression-free survival (PFS). METHODS: From June 1988 to January 1992, women who responded to standard chemotherapy received high-dose cyclophosphamide, thiotepa, and carboplatin with autotransplantation. Data encompassing initial breast cancer diagnosis, metastatic presentation, and response to induction treatment were examined for correlations with improved PFS. RESULTS: The 5-year PFS rate for the entire group is estimated to be 21% (95% confidence interval [CI], 10% to 32%). For those patients who attained a complete response (CR) to induction therapy, the 5-year PFS rate is estimated to be 31% (95% CI, 0% to 63%). In univariate analyses, a single metastatic site, CR to induction therapy, prolonged interval from primary diagnosis to first metastases, estrogen receptor (ER)-negative tumors, and older age (> or = 40 years) were associated with prolonged PFS. In multivariate analyses, single metastatic site (P = .002) and attainment of a CR to induction chemotherapy (P = .04) were the most significant predictors for PFS, with a strong trend observed for an interval from primary diagnosis to onset of metastatic disease of 24+ months (P = .066). CONCLUSION: We and others have shown that 10% to 25% of women with metastatic breast cancer are progression-free after high-dose chemotherapy with autotransplantation. Those with chemosensitive disease, minimal tumor bulk, and a prolonged disease-free interval appear to benefit most. Emphasis should continue to focus on the development of more effective cytotoxic regimens and biologic approaches to increase the percentage of patients who may benefit from this approach.

Adolescent↗
PubMed1994

High-dose cyclophosphamide, thiotepa, and carboplatin with autologous marrow support in women with measurable advanced breast cancer responding to standard-dose therapy: analysis by age.

The analysis was undertaken to determine if the time to progression and survival for women with breast cancer treated with high-dose chemotherapy after a conventional-dose induction therapy differs significantly for women younger and older than 40 years of age. All patients treated in phase II or III protocols of high-dose chemotherapy for breast cancer are included in this analysis. Women were treated on one of six protocols: four sequential phase II protocols for metastatic breast cancer involving cyclophosphamide at a dose of 6000 mg/m2, thiotepa at 500 mg/m2, and carboplatin at 800 mg/m2 (CTCb) chemotherapy; one phase II study of CTCb chemotherapy for stage III or inflammatory breast cancer; and a Cancer and Leukemia Group B phase III study of cyclophosphamide, carmustine, and cisplatin for women with more than 10 involved lymph nodes after primary therapy. Eligibility criteria for the patients with metastatic disease included histologically documented breast cancer, at least a partial response to conventional dose therapy, no prior pelvic radiotherapy, cumulative doxorubicin of less than 500 mg/m2, and physiologic age of 18-55 years. Patients with inadequate renal, hepatic, pulmonary, and cardiac function or tumor involvement of marrow or central nervous system were excluded. Of 99 registered patients, three (3%) died of toxicity. There were no toxic deaths in protocols for stage II and III disease, and to date none of these patients have relapsed. Thus, there are no differences by age for these studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Reimbursement issues facing patients, providers, and payers.

Escalating costs of health care delivery and the current constraints imposed by the federal budget deficit seriously threaten to compromise patient care and innovative biomedical research. Recent third-party refusal to cover some patients treated in protocols has had considerable impact on trial research. In addition, reimbursement for conventional care sometimes has been refused if delivered as part of a study (e.g., MOPP therapy versus ABVD therapy) or for an indication that is not specifically cited on the Food and Drug Administration label. Who should cover the patient care costs of patients participating in clinical trials? One approach would have patients cover these costs themselves. A second approach is the reinstitution of patient care costs into research grants. A third possibility is that the pharmaceutical industry support patient care costs of clinical research. Historically, hospital expenses of patients participating in studies have been paid by health insurance policies. In the absence of a clinical trial, many patients would be treated with Food and Drug Administration-approved therapies despite a lack of substantial benefit. Such marginal treatments are compensated by third-party payers routinely. The current system is arbitrary and expensive, compromises research and development, and equates new treatment with no treatment. By refusing to reimburse the patient care costs of investigational therapy, third-party carriers are, in fact, making medical decisions. There is a growing and legitimate concern that the pace of clinical research will be impeded significantly at a time when many exciting developments will be ready for clinical trials. The molecular steps in carcinogenesis are being documented rapidly for common malignancies, such as colon cancer. Immunologic, biologic, and hormonal approaches, and emerging technologies, such as marrow transplant or antibody toxin conjugates, already are being studied in the clinic. Health policy legislation and decisions by the insurance industry have a direct impact on physicians, facilitating, or often impeding, the care physicians are able to provide. Who makes health policy decisions? Increasingly, these decisions are being made not by physicians, but by public health experts, economists, and, more recently, large industries grappling with the cost of providing insurance coverage (and its effects on competitive pricing in a world market). Therefore, physicians need to position themselves to influence the development of medical policy, particularly as it relates to the prevention, diagnosis, and treatment of patients with cancer.

Clinical Trials as Topic↗
PubMed1993

The use of G-CSF or GM-CSF mobilized peripheral blood progenitor cells (PBPC) alone or to augment marrow as hematologic support of single or multiple cycle high-dose chemotherapy.

High dose chemotherapy with autologous bone marrow support (ABMT) can achieve prolonged relapse-free survival in relapsed lymphomas, leukemias, and certain solid tumors. The principal morbidity and mortality relate to the infectious complications that occur during the 3-4 week aplasia until the marrow autograft recovers. Progenitor cells can be mobilized into the peripheral blood compartment by hematopoietic growth factors, used alone or after chemotherapy. We describe four trials using cytokine-mobilized peripheral blood progenitor cells (PBPC). In the first trial, PBPC collected after GM-CSF administration were used to augment marrow. Reconstitution of trilineage marrow function occurred promptly, resulting in short hospital stays and fewer platelet transfusions. In a second study, GM-CSF/chemotherapy-mobilized PBPC were used as the sole hematopoietic support during high dose chemotherapy. Granulocyte and platelet reconstitution was rapid. Time to hematopoietic recovery, transfusion requirements, and duration of hospital stay were all significantly improved for the patients receiving PBPC compared with similar patients receiving marrow alone. While most patients experienced prompt hematopoietic recovery they showed sluggish platelet engraftment. The next two trials built on the observation that a few PBPC alone could support both granulocyte and platelet recovery and were designed to test the feasibility of sequential high-dose therapies. In one trial, PBPC given with and without marrow made it possible to deliver two sequential cycles of high-dose therapy. The second trial utilized PBPC plus cytokines to deliver four cycles of dose-intensive chemotherapy at doses that could not be given with cytokine support alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

High-dose chemotherapy with autologous stem cell support for breast cancer: a review of the Dana-Farber Cancer Institute/Beth Israel Hospital experience.

The overall median survival of women with advanced or high-risk primary breast cancer has not changed with conventional chemotherapy. Regimens employing high-dose chemotherapy with autologous stem cell support (ABMT) have been developed with the hope of optimizing tumor response and increasing survival. Early phase I studies in women with advanced refractory disease achieved high response rates of short duration. Second generation studies combined an induction phase followed by one high-dose intensification at time of maximum tumor response. The Dana-Farber Cancer Institute/Beth Israel Hospitals have developed the high-dose intensification regimen of cyclophosphamide, thiotepa, and carboplatin (CTCb) for use in women with metastatic and high-risk stage IIIB/inflammatory breast cancer. To date, approximately 19% of women with metastatic disease remain progression free using this approach, with median length of follow-up approaching 40 months. Although the median duration of follow-up for the stage IIIB women is much shorter (approximately 12 months), greater than 90% of these women are thus far disease free. With the advent of hematologic support, such as blood stem cells and colony-stimulating factors, the morbidity, mortality, and costs associated with this treatment have been substantially reduced, allowing for two or more cycles of high-dose intensification to be employed, to exploit the potential of dose-intensity to optimize response.

Adenocarcinoma↗
PubMed1993

Prognostic factors for treatment outcome in autotransplantation of intermediate-grade and high-grade non-Hodgkin's lymphoma with cyclophosphamide, carmustine, and etoposide.

PURPOSE: We examined a consecutive series of 78 patients with non-Hodgkin's lymphoma treated on prospective protocols with high-dose cyclophosphamide, carmustine (BCNU), and etoposide (CBV) plus autotransplantation to determine prognostic factors for time to treatment failure. PATIENTS AND METHODS: Patients with relapsed, refractory, or poor-risk intermediate- and high-grade non-Hodgkin's lymphoma were treated with CBV with autologous marrow or peripheral-blood progenitor cell support. Patient characteristics before transplantation were examined in univariate analyses by the log-rank test and simultaneously in a Cox proportional hazards regression analysis. A best-predictive model was determined from those variables significant (P < .10) in the univariate test. RESULTS: In univariate analysis, intermediate-grade and immunoblastic lymphoma, responsiveness to pretransplant salvage chemotherapy, and transplantation after primary therapy (first complete response [CR] or partial response [PR]) were associated with prolonged time to treatment failure. In proportional hazards multiple regression analysis, intermediate-grade and immunoblastic histology, responsive disease, and autotransplantation in first CR or PR were positive prognostic factors, and these characteristics are the basis of the best-predictive model for prolonged time to failure. Actuarial 3-year failure-free survival of patients with stable or responding disease at autotransplant was 54%. CONCLUSION: CBV is an effective conditioning regimen in intermediate-grade and immunoblastic non-Hodgkin's lymphoma. Patients with these histologies transplanted while responding to primary therapy, or those with stable disease or disease responding to salvage therapy at the time of autotransplant, are most likely to benefit. Patients with lymphoblastic lymphoma or diffuse undifferentiated lymphoma did poorly with CBV and should be offered alternative therapy.

Adolescent↗
PubMed1993

An intergroup phase III randomized study of doxorubicin and dacarbazine with or without ifosfamide and mesna in advanced soft tissue and bone sarcomas.

PURPOSE AND METHODS: Doxorubicin alone or with dacarbazine (DTIC; AD) is considered the best available therapy for metastatic adult sarcomas. Ifosfamide is active in sarcomas that have failed to respond to a doxorubicin-based regimen. This study was designed to determine if ifosfamide added to doxorubicin and DTIC (ADI) significantly effects toxicity, response rate, and survival. Patients with measurable metastatic or unresectable sarcoma were randomized to receive AD or ADI. Patients with chondrosarcomas, fibrosarcomas, and other sarcomas of bone were eligible, although those with osteosarcoma, rhabdomyosarcoma, Ewing's sarcoma, Kaposi's sarcoma, and mesothelioma were excluded, as were patients with prior chemotherapy for sarcoma or prior doxorubicin. RESULTS: Between 1987 and 1989, 340 eligible patients were randomized. Significantly more myelosuppression, a higher response rate (17% v 32%; P < .002) and longer time to progression (4 v 6 months; P < .02) were observed for patients who received ifosfamide. An overall survival advantage for the two-drug regimen (12 v 13 months; P = .04) was not significant by multivariate analysis. CONCLUSION: In all three randomized trials of doxorubicin with and without ifosfamide (Eastern Cooperative Oncology Group [ECOG], European Organization for Research and Treatment of Cancer [EORTC], and this study), the response rate was higher for the ifosfamide-containing arm, significantly so in this and the ECOG studies. An improved response rate may be particularly important for the preoperative management of high-grade, borderline resectable lesions or pulmonary metastases, particularly in younger patients. In older patients, or for low-to intermediate-grade lesions, doxorubicin and DTIC followed by ifosfamide on progression is preferred.

Adolescent↗
PubMed1993

Randomized phase II trial of cisplatin with mitomycin or doxorubicin for malignant mesothelioma by the Cancer and Leukemia Group B.

PURPOSE: The Cancer and Leukemia Group B (CALGB) conducted a randomized phase II multicenter trial to evaluate the activity of two cisplatin-containing regimens (cisplatin and mitomycin [CM], or cisplatin and doxorubicin [CD]) in patients with malignant pleural or peritoneal mesothelioma (protocol CALGB 8435). PATIENTS AND METHODS: Seventy-nine patients were entered between June 1984 and October 1986. Eligibility included a performance status of 0 to 2 by CALGB criteria, and no prior chemotherapy. Central pathology review was performed. Randomization was stratified according to the cell type (epithelial v mixed or sarcomatous) and the presence of measurable versus assessable disease. Of the 79 patients entered, 70 were included in this analysis (35 on CM and 35 on CD), including 48 with epithelial cell type and 22 with mixed or sarcomatous cell types. Sixty-six patients had pleural mesothelioma and four had peritoneal mesothelioma. There were 34 cases with measurable disease and 36 with assessable disease. RESULTS: The overall response rate was 26% for CM (two complete responses [CRs], three partial responses [PRs], and four regressions) and 14% for CD (four PRs and one regression). Median time to treatment failure was 3.6 months for CM and 4.8 months for CD, and median survival duration from study entry was 7.7 and 8.8 months, respectively, with no significant differences between treatments. Good performance status (0 or 1) was associated with significantly longer survival duration (P = .013). Both regimens were well tolerated and there were no treatment-related deaths due to toxicity. CONCLUSION: Moderate antitumor activity has been observed with both regimens. In this randomized phase II trial, the overall response rates, time to treatment failure, and overall survival appear to be similar for the two regimens tested.

Antineoplastic Combined Chemotherapy Protocols↗