Conventional Adjuvant Chemotherapy with or without High-Dose Chemotherapy and Autologous Stem-Cell Transplantation in High-Risk Breast Cancer

150

104

Summary:Cardiac toxicity is an uncommon but potentially serious complication of high-dose (HD) chemotherapy and little is known about incidence, severity and underlying mechanisms. We have systematically reviewed the literature of the last 30 years to summarize and appraise the published evidence on cardiac toxicity associated with HD chemotherapy. HD cyclophosphamide-containing regimens have been most commonly associated with cardiac toxicity, with a progressively decreasing incidence over time. Dosage, application regimens and coadministration of other chemotherapeutic agents emerged as risk factors. While cardiac toxicity has been rarely associated with other cytotoxic drugs, an unexpected incidence of severe cardiotoxicity resulted from reduced-intensity conditioning regimens containing melphalan and fludarabine. Predictive value of cardiologic examination of patients is limited, and patients with a slight depression of cardiac performance could tolerate HD chemotherapy. Clinical examination, resting electrocardiography and dosage adjustment in overweight patients remain the mainstay of prevention, with bidimensional echocardiography (2D echo) for patients with a history of anthracycline exposure. Strategies to decrease the long-term negative impact of anthracycline administration on cardiac performance are being investigated. New 2D echo-based techniques and circulating markers of cardiac function hold promise for allowing identification of patients at high risk for and early diagnosis of cardiac toxicity.

“…26,28,[30][31][32][33][34][35] However, the risk for HD cyclophosphamide-associated cardiac toxicity may be increased by the concomitant administration of cytarabine or mitoxantrone.…”

Section: Combinations Including Cyclophosphamidementioning

confidence: 99%

Cardiac toxicity of high-dose chemotherapy

Morandi

Ruffini

Benvenuto

et al. 2004

150

104

“…As such, breast cancer is no longer the most frequent indication for an autologous HSCT. [16][17][18] Numbers alone do not explain the reasons behind these changes. Numbers, however, leave room for interpretation.…”

Section: Discussionmentioning

confidence: 98%

“…This ambiguity is illustrated by two recent publications and an editorial in the year 2003. [16][17][18] Few indications overall in solid tumours can be regarded as accepted indications outside clinical study protocols.…”

Section: Discussionmentioning

confidence: 99%

Haematopoietic stem cell transplantation (HSCT) in Europe 2002. Changes in indication and impact of team density. A report of the EBMT activity survey

Gratwohl

Schmid

Baldomero

et al. 2004

Summary:This 2002 European Group for Blood and Marrow Transplantation (EBMT) activity survey concentrates on current status, increase and decrease in haematopoietic stem cell transplantation (HSCT) activity in Europe and investigates the association of transplant rates with team density. In 2002, there were 20 207 HSCT, 6915 allogeneic (34%), 13 292 autologous (66%) and 3947 additional re-or multiple transplants collected from 586 centres in 39 European countries. Main indications were leukaemias (6523 (32%; 76% allogeneic)); lymphomas (10 760 (53%; 92% autologous)); solid tumours (1913 (9%; 92% autologous)) and nonmalignant disorders (874 (4%; 92% allogeneic)). Compared to 2001, there were increases (410%) for AML, ALL 1st CR, CML not 1st cP, MDS, SAA and CLL in allogeneic HSCT and for MDS, Ewing's sarcoma, soft-tissue sarcoma and ovarian cancer in autologous HSCT. Decreases (410%) were observed in autologous HSCT for acute leukaemias beyond 1st CR, CML cP, glioma, breast cancer and lung cancer. Correlation of transplant rates (number of transplants per 10 million inhabitants) with team density (number of transplant teams per 10 million inhabitants) suggests different diffusion patterns for autologous compared to allogeneic HSCT. These data describe current practice for blood and marrow transplantation in Europe and give some hints about mechanisms involved in HSCT rates. Bone Marrow Transplantation (2004Transplantation ( ) 34, 855-875. doi:10.1038 Keywords: haematopoietic stem cell; team density; transplant rates; diffusion of technology Haematopoietic stem cell transplantation (HSCT) has seen a rapid increase and substantial change over the last decade. It is an established therapy for many severe acquired or congenital disorders of the haematopoietic system and for chemosensitive, radiosensitive or immunosensitive malignancies. Haematopoietic stem cells from bone marrow, peripheral blood or cord blood are used as the stem cell source. They are derived for autologous use from the patients themselves. Donors for allogeneic HSCT include HLA-identical siblings, other family members or unrelated volunteers from one of the increasing worldwide donor pools or cord blood banks. [1][2][3][4] There are many reasons for this increase of HSCT in Europe. It is based on increased numbers of HSCT in teams already active in 1990 5 as well as on an increase in transplant teams and an extension of transplant activity to countries with previously none or limited numbers of active transplant teams. Numbers of HSCT did not increase at the same rate for autologous and allogeneic HSCT. They did not increase for all indications alike. 6,7 Specifically, numbers of autologous HSCT for solid tumours declined after a peak in 1997 almost as rapidly as they had previously increased. They were substituted for by increasing numbers of autologous HSCT for lymphoproliferative disorders. For allogeneic HSCT, there remains a steady increase in transplants for all indications with one major exception. Numbers of transplants for CML have been d...

“…While the first-and early secondgeneration randomized transplant trials in the adjuvant settings suggest a benefit in disease-free survival (DFS) in some of the trials, there appears to be no survival benefit in any of the randomized trials except for one. [1][2][3][4][5][6][7] It has been hypothesized that when patients relapse, it is from presumed sub-clinical occult disease and this can be in either the adjuvant or metastatic setting. Many approaches have been employed to tackle the issue of sub-clinical occult disease that includes consolidation at sites of bulk disease (by surgery or radiation), hormonal manipulation and various immunotherapeutic manipulations.…”

Section: Introductionmentioning

confidence: 99%

Randomized trial of low-dose interleukin-2 vs cyclosporine A and interferon-γ after high-dose chemotherapy with peripheral blood progenitor support in women with high-risk primary breast cancer

Vahdat

Cohen

Zipin

et al. 2007

High-risk primary breast cancer patients treated with high-dose chemotherapy (HDC) and stem cell support (SCS) have shown prolonged disease-free survival (DFS) in many studies; however, only one trial has demonstrated an overall survival benefit (OS). We hypothesize that the period following myeloablative therapy is ideal for immunologic manipulation and studied the effects of two different methods of immunotherapy following HDC with SCS aimed at the window of immune reconstitution. Seventy-two women with high-risk stage II or III breast cancer were randomized following HDC to receive either interleukin 2 (IL-2) at 1 million units/m 2 SQ daily for 28 days or combined cyclosporine A (CsA) at 1.25 mg/kg intravenously daily from day 0 to þ 28 and interferon gamma (IFN-c) 0.025 mg/m 2 SQ every 2 days from day þ 7 to þ 28. At a median follow-up of 67 months, no significant difference was observed in DFS or OS between the two treatment groups. The IL-2 arm had a 59% DFS (95% CI (0.45, 0.78)) and a 72% OS (95% CI (0.58, 0.88)) at 5 years. The CsA/INF-c arm had a similar outcome with a 55% DFS (95% CI (0.40, 0.76)) and a 78% OS (95% CI (0.65, 0.94)) at 5 years. Treatment was well tolerated, without increased toxicity.