High-dose chemotherapy followed by autologous stem cell transplantation for metastatic rhabdomyosarcoma--a systematic review

Introduction

Patients with metastatic rhabdomyosarcoma (RMS) have a poor prognosis. The aim of this systematic review is to investigate whether high-dose chemotherapy (HDCT) followed by autologous hematopoietic stem cell transplantation (HSCT) in patients with metastatic RMS has additional benefit or harm compared to standard chemotherapy.

Methods

Systematic literature searches were performed in MEDLINE, EMBASE, and The Cochrane Library. All databases were searched from inception to February 2010. PubMed was searched in June 2010 for a last update. In addition to randomized and non-randomized controlled trials, case series and case reports were included to complement results from scant data. The primary outcome was overall survival. A meta-analysis was performed using the hazard ratio as primary effect measure, which was estimated from Cox proportional hazard models or from summary statistics of Kaplan Meier product-limit estimations.

Results

A total of 40 studies with 287 transplant patients with metastatic RMS (age range 0 to 32 years) were included in the assessment. We identified 3 non-randomized controlled trials. The 3-year overall survival ranged from 22% to 53% in the transplant groups vs. 18% to 55% in the control groups. Meta-analysis on overall survival in controlled trials showed no difference between treatments. Result of meta-analysis of pooled individual survival data of case series and case reports, and results from uncontrolled studies with aggregate data were in the range of those from controlled data. The risk of bias was high in all studies due to methodological flaws.

Conclusions

HDCT followed by autologous HSCT in patients with RMS remains an experimental treatment. At present, it does not appear justifiable to use this treatment except in appropriately designed controlled trials.     

High-dose chemotherapy followed by autologous stem cell transplantation as a first-line therapy for high-risk primary breast cancer: a meta-analysis

Background and Objectives

Several trials have generated conflicting results about the results of high-dose chemotherapy followed by autologous stem cell transplantation (HDCT) for primary breast cancer. This meta-analysis summarizes the available evidence from all suitable studies.

Design and Methods

Prospective, randomized trials with HDCT as a first-line therapy for primary breast cancer were included in this meta-analysis. The primary outcome of interest for our analysis was survival (disease-free survival and overall survival); secondary endpoints included treatment-related mortality (TRM) and second (non-breast) cancers. We used a median age of 47, a PR positive rate of 50% and a premenopausal rate of 70% as cutoff values to complete the subgroup analyses, which were pre-planned according to the prepared protocol.

Results

Fourteen trials with 5747 patients were eligible for the meta-analysis. Compared with non-HDCT, non-significant second (non-breast) cancers (RR = 1.28; 95% CI = 0.82–1.98) and higher TRM (RR = 3.42; 95% CI = 1.32–8.86) were associated with HDCT for primary breast cancer. A significant DFS benefit of HDCT was documented (HR = 0.89; 95% CI = 0.79–0.99). No difference in OS (overall survival) was found when the studies were pooled (HR = 0.91; 95% CI = 0.82–1.00, p = 0.062). In subgroup analysis, age and hormone receptor status had a significant interaction with prolonged DFS and OS.

Conclusions

HDCT has a benefit on DFS and OS compared to SDC in some special patients with high-risk primary breast cancer.     

Oxidative stress in patients undergoing high-dose chemotherapy plus peripheral blood stem cell transplantation

Chemotherapy and radiation therapy are associated with increased formation of reactive oxygen species and depletion of critical plasma and tissue antioxidants. In patients undergoing high-dose chemotherapy, the plasma antioxidant concentration has been shown to decrease. However, these studies in which the oxidative stress status were investigated have a small number of patients and they are heterogeneous. In this study, the changes in certain trace elements together with oxidative stress parameters were investigated in 36 patients who had undergone autologous stem cell transplantation because of solid and hematological malignancies. Blood samples of the patients were examined before the high-dose chemotherapy (baseline), before stem cell transplantation (day -1), and after stem cell transplantation on day 1, 3, and 6. Erythrocyte zinc, silver, and iron levels were measured by atomic absorption spectrophotometry; malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) levels were measured by UV-vis spectrophotometry. After high-dose chemotherapy, significant increases in the levels of MDA, GSH-Px, and SOD were observed. On the other hand, Cu levels remained the same while the levels of erythrocyte Zn and Fe were increased. Significant correlation was observed among MDA, GSH-Px, and SOD (p<0.05). High-dose chemotherapy gives rise to an increase in the oxidative stress and the reactive oxygen species. Standard parenteral nutrition protocols were found to be insufficient to lower this stress.     

A mathematical model for reconstitution of granulopoiesis after high dose chemotherapy with autologous stem cell transplantation

High dose chemotherapy supported with hematopoietic progenitor cells gives a characteristic neutropenic period (blood neutrophils <0.510⁹ c/l) ranging from 10 to 16 days. The question of a correlation between the CFU-GM content of the transplanted CD34+ cells and time to neutrophil recovery by patients having been given high-dose chemotherapy (HD-CT) with stem cell support was addressed by means of a mathematical model of granulopoiesis. The model utilizes a convection-reaction partial differential equation (PDE) with feedback from a cytokine compartment on proliferation, maturation, and mobilization of granulocytes from bone marrow to blood. The observed number of CFU-GM cells in the transplanted CD34+ cell autograft was used as input to the model. Using this approach, the observed gross relationship between CFU-GM content in the reinfused blood product and engraftment time could be reproduced. At the same time, the effects of assumed physiological mechanisms, especially some of the effects of G-CSF on proliferation rate, maturation rate, mobilization, and cell death, could be investigated and discussed relative to observed engraftment. The model makes it possible to explain how cytokines interfere with progenitor cell mobilization from bone marrow to blood, and it points out the implications of a regulating mechanism for the granulocyte maturation rate.     

Treatment of multiple myeloma patients with autologous stem cell transplantation - a fresh analysis

Patients with multiple myeloma (MM) treated with conventional chemotherapy have an average survival of approximately three years. High dose chemotherapy followed by autologous stem cell transplantation (ASCT), first introduced in the mid-1980s, is now considered the standard therapy for almost all patients with multiple myeloma, because it prolongs overall survival and disease free survival. Between November 1997 and October 2006, 122 patients with MM (58 females, 64 males, median age 51.0 years [± 7.98] range: 30-66 years) were transplanted in the Department of Hematooncology and Bone Marrow Transplantation at the Medical University of Lublin: 47 patients were in complete remission or in unconfirmed complete remission, 66 patients were in partial remission, and nine had stable disease. Of these, there were 95 patients with IgG myeloma, 16 with IgA myeloma, one with IgG/IgA, one with IgM myeloma, five with non secretory type, two with solitary tumor and two with LCD myeloma. According to Durie-Salmon, 62 patients had stage III of the disease, 46 had stage II and four had stage I. Most patients (69/122) were transplanted after two or more cycles of chemotherapy, 48 patients were transplanted after one cycle of chemotherapy, one patient after surgery and rtg- -therapy and four patients had not been treated. In mobilisation procedure, the patients received a single infusion of cyclophosphamide (4-6 g/m(2)) or etoposide 1.6 g/m(2) followed by daily administration of G-CSF until the peripheral stem cells harvest. The number of median harvest sessions was 2.0 (± 0.89) (range: 1-5). An average of 7.09 (± 33.28) × 106 CD34(+) cells/kg were collected from each patient (range: 1.8-111.0 × 10?/kg). Conditioning regimen consisted of high dose melphalan 60-210 mg/m(2) without TBI. An average of 3.04 (± 11.59) × 10? CD34+ cells/kg were transplanted to each patient. Fatal complications occured in four patients (treatment- -related mortality = 3.2%). In all patients there was regeneration of hematopoiesis. The median number of days for recovery to ANC > 0.5 × 10?/l was 13 (± 4.69) (range: 10-38) and platelets recovery to > 50 × 10?/l was 25 days (± 11.65) (range: 12-45). Median time of hospitalization was 22 days (± 7.14) (range: 14-50). Patients were evaluated on day 100 after transplantation: 74.9% achieved CR and nCR, 14.3% were in PR, 5.4% had SD and 5.4% had progressed. Median of OS was 45 months (± 30.67). OS at 3-years was 84% and at 7-years 59%. Median PFS was 25 months (± 26.13). PFS at 3-years was 68%, and at 7-years was 43%. At present (November 2009) 52 patients (42%) are still alive. High-dose chemotherapy followed by autologous stem cell transplantation is a valuable, well tolerated method of treatment for patients with MM that allows the achievement of long- -lasting survival.     

Immunological and virological aspects of autologous stem cell transplantation in HIV+ patients

Autologous stem cell transplantation (ASCT) is an effective therapeutic option in patients with human immunodeficiency virus-associated lymphomas (HIV-L). This review will focus on the experimental and clinical data regarding the effects of ASCT on the reconstitution of lymphocyte subsets, T-cell repertoire and thymic function in HIV-L patients. Current data on the kinetics of reactivation of HIV, Epstein-Barr virus, cytomegalovirus and hepatitis C virus during mobilization and after reinfusion of stem cells will be also analyzed.     

Clinical and quality of life responses to high-dose chemotherapy plus autologous stem cell transplantation in patients with multiple sclerosis: two case reports

During the last several years high-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) has been established as a therapeutic option for multiple sclerosis (MS) patients. We report on the long-term effects of HDCT + ASCT in two female patients affected by secondary progressive and relapsing-remitting types of MS, respectively. As a result, disease stabilization was achieved in the first case and disease improvement in the second one. Both patients were off immunosuppressive or immunomodulating therapy throughout the post-transplant period. Notably, HDCT + ASCT resulted in an excellent quality of life (QoL) response in both cases. Our findings demonstrate that HDCT + ASCT could be considered as an effective treatment for MS patients. Moreover, QoL measurement seems to be an effective approach to assessment of treatment outcomes at long-term follow-up of patients with MS.     

Correlation of residual leukocyte subsets with neutropenic fever during severe leukopenia after high-dose chemotherapy and autologous stem cell transplantation

BACKGROUND: High-dose chemotherapy with autologous stem cell transplantation is the standard treatment of eligible patients with multiple myeloma. However, this treatment is associated with a substantial risk of infectious complications during leukopenia. The aim of our pilot study was to determine the residual leukocyte subsets during severe cytopenia after high-dose melphalan and to correlate this with the occurrence of neutropenic fever. METHODS: Residual leukocyte subsets in the peripheral blood on days 4-7 following autologous stem cell transplantation were analyzed by three-color flow cytometry in 20 patients with multiple myeloma. In addition, we determined the number of T cells that were transfused with the autografts. RESULTS: Absolute numbers of lymphocytes (mean 25/microL) and monocytes (mean 4/microL) were strongly reduced but rather constant during the period of severe neutropenia. Neutrophil engraftment and duration of neutropenia were very similar in patients with and without neutropenic fever. Low absolute lymphocyte counts and absolute CD4+ T-cell counts on days 4-7 after stem cell transplantation correlated with neutropenic fever. Furthermore, T-cell numbers in the autologous stem cell grafts that the patients received were significantly lower in patients with neutropenic fever. DISCUSSION: These observations suggest that the number of T cells, and in particular CD4+ T cells, in the blood during severe cytopenia is playing a role in defense of infection. T-cell numbers in the graft could provide a predictive factor for the risk of infection in the post-transplant period. However, this needs to be confirmed in a larger study.     

Determining Toxoplasma high-risk autologous and allogeneic hematopoietic stem cell transplantation patients by systematic pre-transplant PCR screening of stem cell originated buffy coat

The diagnosis of Toxoplasma infection or disease in hematopoietic stem cell transplantation (HSCT) patients is achieved mainly by PCR screening; however screening did not find wide field of use in practice due to costly expenditures of PCR. This study aimed to determine patients at high risk of Toxoplasma infection or disease before transplantation by stem cell originated buffy coat PCR and subsequently to screen them. Buffy coats collected from 12 autologous and 18 allogeneic HSCT patients' donors were investigated by PCR before transplantation. After transplantation, blood and sera collected at fixed time intervals were screened by two PCR methods and serological assays. Screening results first time assessed a toxoplasmosis incidence level as 25% in autologous HSCT patients and increased incidence level in allogeneic HSCT patients to 22%. Importantly, buffy coat PCR was first time performed before transplantation, to determine the risk of toxoplasmosis. Buffy coat PCR results showed that four patients were at high risk of toxoplasmosis before transplantation. After transplantation, these patients experienced toxoplasmosis. In conclusion, for the determination of patients at risk of toxoplasmosis, clinicians should consider buffy coat PCR in combination with serology before transplantation. After transplantation, PCR screening can be initiated in high risk patients upon clinical suspicion.     

Long-term outcomes of induction chemotherapy followed by intensity-modulated radiotherapy and adjuvant chemotherapy in nasopharyngeal carcinoma patients with N3 disease

ObjectivesTo evaluate long-term outcomes of induction chemotherapy (IC) followed by intensity-modulated radiotherapy (IMRT) and adjuvant chemotherapy (AC) in nasopharyngeal carcinoma (NPC) patients with N3 disease.Materials and methodsFrom September 2005 to August 2016, 143 patients confirmed NPC with the 8th AJCC/UICC staging criteria N3 were reviewed. All patients received IC followed by IMRT and AC.ResultsAfter a median follow-up of 67 months, the 5-year and 10-year overall survival (OS), progression-free survival (PFS), distant metastasis free survival (DMFS), local progression-free survival (LPFS) and regional progression-free survival (RPFS) were 75.7% and 61.6%, 61.2% and 53.4%, 73.1% and 72.1%, 92.4% and 87%, 88.9% and 81.8%, respectively. Multivariate analyses indicated that T stage (P = 0.001) appeared to be prognostic factors for OS. T stage (P = 0.001 and P = 0.002) and neck lymph node necrosis (P = 0.015 and P = 0.045) were independent predictors of PFS and DMFS. The acute toxicities were mainly grade 1/2 hematologic toxicities in patients treated with IC+IMRT+AC, and severe toxicities were uncommon.ConclusionsIC followed by IMRT and AC achieved satisfactory long-term survival outcomes in NPC patients with N3 disease. Neck lymph node necrosis and late T stage served as predictors of poor prognosis for patients.     

Long-term outcomes of induction chemotherapy followed by intensity-modulated radiotherapy and adjuvant chemotherapy in nasopharyngeal carcinoma patients with N3 disease

ObjectivesTo evaluate long-term outcomes of induction chemotherapy (IC) followed by intensity-modulated radiotherapy (IMRT) and adjuvant chemotherapy (AC) in nasopharyngeal carcinoma (NPC) patients with N3 disease.Materials and methodsFrom September 2005 to August 2016, 143 patients confirmed NPC with the 8th AJCC/UICC staging criteria N3 were reviewed. All patients received IC followed by IMRT and AC.ResultsAfter a median follow-up of 67 months, the 5-year and 10-year overall survival (OS), progression-free survival (PFS), distant metastasis free survival (DMFS), local progression-free survival (LPFS) and regional progression-free survival (RPFS) were 75.7% and 61.6%, 61.2% and 53.4%, 73.1% and 72.1%, 92.4% and 87%, 88.9% and 81.8%, respectively. Multivariate analyses indicated that T stage (P = 0.001) appeared to be prognostic factors for OS. T stage (P = 0.001 and P = 0.002) and neck lymph node necrosis (P = 0.015 and P = 0.045) were independent predictors of PFS and DMFS. The acute toxicities were mainly grade 1/2 hematologic toxicities in patients treated with IC+IMRT+AC, and severe toxicities were uncommon.ConclusionsIC followed by IMRT and AC achieved satisfactory long-term survival outcomes in NPC patients with N3 disease. Neck lymph node necrosis and late T stage served as predictors of poor prognosis for patients.     

Monitoring the level of complement components during autologous blood stem cell transplantation in patients with malignant lymphomas

The aim of this study was to determine the complement functions, the serum levels of the complement components C3 and C4, and circulating immune complexes during autologous blood stem cell transplantation. Seventeen lymphoma patients receiving transplants between 1997 and 2001 were involved in this study. High-dose chemotherapy with or without total body irradiation was used for conditioning. The transplantation resulted in complete remission without complications in 14 patients. Early relapse developed in one case and two nonrelapsed patients suffered from serious toxic infection early posttransplant. Normal values of CH50, C3, C4, and immune complexes in sera of patients were detected on day –7, before the conditioning (day of transplantation was determined as day 0). After the conditioning, on day –2, the levels of the CH50, C3, and C4 decreased significantly (p<0.05) in all patients compared with the starting values. The CH50, C3, and C4 levels exceeded the starting values in the noninfected patients from day +7. In two patients suffering from toxic infection, significantly elevated complement levels were documented early posttransplant. In the relapsed patient a significant decrease of the complement parameters was documented posttransplant accompanied by a significant elevation in the immune complex level. The results show alteration in the complement parameters during transplantation, but in the complication-free cases this remained within the normal ranges. However, an unusual elevation seemed to be the sign of infection, and the significant decrease seemed to indicate a relapse.