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W Siegert

Publications and source records attributed to W Siegert.

At least 19 recordsLinked to original sources
PubMed2006

Activity of thalidomide in patients with platinum-refractory germ-cell tumours.

The aim of this study was assess the activity of thalidomide in patients with progressive relapsed or platinum-refractory germ-cell tumours (GCT). Between April 2002 and January 2003, 15 patients with inoperable progressive GCT were treated with escalated daily doses of 200-600 mg thalidomide. All patients had failed first-line and salvage chemotherapy with a median of 6 (range 4-12) cisplatin-based treatment cycles, 13/15 (87%) patients had received high-dose chemotherapy (HDCT) and 8/15 (53%) patients were considered platinum-refractory or absolute refractory; 8/15 (53%) patients had previously received other palliative chemotherapy regimens. No patient achieved a complete remission (CR) or partial remission (PR). However, 5/15 (33%) patients achieved serological PR and 1 additional patient had stable disease for 3 months. The median duration of remissions was 3 months (range 2-12 months) including 2 patients with a progression-free survival of 9 and 12 months. Responses occurred mainly in patients with a low tumour burden, slow disease progression and alpha-foetoprotein (AFP) elevations. Responses to thalidomide were independent from platinum-sensitivity. Toxicity was mild, with lethargy and constipation in the majority of patients. Skin rash grade II developed in 2 patients and peripheral neurotoxicity grade II/III developed in 4 patients. One responding patient died suddenly from an unknown cause. It is concluded that thalidomide shows single-agent activity in patients with heavily pre-treated GCT, AFP elevations and slowly progressive disease.

Adult↗
PubMed2005

A randomised trial of high-dose chemotherapy in the salvage treatment of patients failing first-line platinum chemotherapy for advanced germ cell tumours.

BACKGROUND: Incomplete remission or relapse from first-line chemotherapy has poor prognosis in male germ cell tumour patients. This phase III randomised trial compares conventional salvage to high-dose-intensification chemotherapy. PATIENTS AND METHODS: Between February 1994 and September 2001, 280 patients from 43 institutions in 11 countries, were randomly assigned to receive either four cycles of cisplatin, ifosfamide and etoposide (or vinblastine) (arm A), or three such cycles followed by high-dose carboplatin, etoposide and cyclophosphamide (CarboPEC) with haematopoietic stem cell support (arm B). RESULTS: Similar complete and partial response rates were observed in both treatment arms (56%; 95% CI 50% to 62%). There were 3% and 7% toxic deaths in arms A and B, respectively. No significant improvements with CarboPEC were observed in either 3-year event-free survival (35% versus 42%, P=0.16) or overall survival (53%; 95% CI 46% to 59%). Complete responders with CarboPEC had a significant improvement in disease-free survival (55% versus 75% at 3 years, P <0.04). CONCLUSIONS: The single cycle of high-dose salvage chemotherapy after three cycles of standard dose chemotherapy had no effect on treatment outcomes. These results suggest that data from uncontrolled studies should not be used to justify routine use of a toxic and expensive treatment without confirmation in a randomised trial.

Adolescent↗
PubMed2005

Second-line high-dose chemotherapy in patients with mediastinal and retroperitoneal primary non-seminomatous germ cell tumors: the EBMT experience.

BACKGROUND: Results of second-line chemotherapy in patients with extragonadal non-seminomatous germ cell tumor (NSGCT) appear inferior to results in testicular NSGCT. Patients with retroperitoneal NSGCT achieve a comparable long-term survival rate of 30%, but the salvage rates of patients with mediastinal primary are less than 10%. We conducted a retrospective analysis on patients with mediastinal and retroperitoneal NSGCT treated with second-line high-dose chemotherapy (HDCT) registered with the European Group for Blood and Marrow Transplantation (EBMT). PATIENTS AND METHODS: Between 1987 and 1999, 59 registered patients with retroperitoneal (n=37) and mediastinal (n=22) primary NSGCT, median age 28 years (range 18-60), were treated with second-line HDCT. All had received cisplatin-containing chemotherapy as first-line treatment. RESULTS: Toxic death occurred in three cases (5%). With a median follow-up of 58 months (range 14-114), 18/59 patients (30%) continue to be disease-free. Of three patients who had a disease recurrence after HDCT, one patient achieved a disease-free status with further chemotherapy and surgery. In total, 19 patients (32%) are currently disease-free. Sixteen of 37 patients (43%) with retroperitoneal NSGCT, and three of 22 patients (14%) with mediastinal NSGCT are currently alive and disease-free. CONCLUSIONS: Second-line HDCT might represent a possible option for patients with retroperitoneal primary NSGCT. New salvage strategies are needed for patients with mediastinal NSGCT.

Adolescent↗
PubMed2004

Residual tumor resection after high-dose chemotherapy in patients with relapsed or refractory germ cell cancer.

PURPOSE: To assess the role of residual tumor resection performed after high-dose chemotherapy (HDCT) in patients with relapsed or refractory germ cell tumors (GCT). PATIENTS AND METHODS: Between July 1987 and October 1999, postchemotherapy resections of residual tumors were performed in 57 patients who had been treated with HDCT for relapsed or refractory GCT and who had achieved a partial remission to this treatment. RESULTS: Complete resections of residual masses were achieved in 52 (91%) of 57 patients who were rendered disease free; in five (9%) of 57 patients, the resections were incomplete. Resection of a single site was performed in 39 (68%) of 57 patients, and the remaining 18 (32%) of 57 patients required interventions at two or more residual tumor sites. Necrosis was found in 22 (38%) of 57 patients, mature teratoma with or without necrosis was found in nine (16%) of 57 patients, and viable cancer with or without additional necrosis or mature teratoma was found in 26 (46%) of 57 patients. Viable cancer consisted either of residual germ cell or undifferentiated cancer in 22 (85%) of 26 patients, with additional non-GCT histologies in the remaining four patients. Patients with viable cancer had a significantly inferior outcome after surgery compared with patients with necrosis and/or mature teratoma even if all cancer was completely resected. Pulmonary lesions with a diameter of more than 2 cm were the only predictive variable for viable cancer in univariate analysis. CONCLUSION: Resections of all residual tumors should be attempted in patients with relapsed or refractory GCT and partial remissions after HDCT.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2004

The role of high-dose chemotherapy in relapsed germ cell tumors.

Overall, patients with relapsed or progressive germ cell tumors after cisplatin-based chemotherapy have a low chance of cure. Using conventional-dose chemotherapy (CDCT) as salvage treatment, only 15-30% of the patients will become long-term survivors. It is well known that the majority of these patients will ultimately die of their disease. Therefore, improvement of the standard treatment is clearly desirable. In the last years, high-dose chemotherapy (HDCT) has been established as an effective salvage modality. A matched-pair analysis showed an advantage for HDCT compared with CDCT with an improvement in event-free and overall survival. Furthermore, due to increasing clinical experience in the management of side-effects, the use of peripheral blood progenitor cells and the availability of hematopoietic growth factors, HDCT has become relatively safe. Therefore, HDCT should be administered in patients with first relapse and unfavorable prognostic factors, and as second or subsequent salvage treatment followed by complete resections of tumor residuals. Patients with relapse or progressive disease after HDCT who do not qualify for desperation surgery could be salvaged with palliative chemotherapy combinations using gemcitabine, oxaliplatin and paclitaxel. This report reviews the current treatment strategies and recent developments with respect to HDCT given as salvage treatment and discusses the role of prognostic factors in the management of such situations.

Antineoplastic Agents↗
PubMed2004

Reduced-intensity conditioning with busulfan and fludarabine with or without antithymocyte globulin in HLA-identical sibling transplantation--a retrospective analysis.

It is unknown whether the addition of antithymocyte globulin (ATG) to reduced-intensity conditioning with busulfan (BU) and fludarabine (FLU) is beneficial in HLA-identical sibling transplantation. Therefore, we analyzed retrospectively data on 83 patients, who received peripheral blood stem cells from HLA-identical siblings after conditioning with either 8 mg/kg BU and 150 mg/m2 FLU (n=45) or 8 mg/kg BU, 180 mg/m2 FLU and 40 mg/kg ATG (n=38). Graft-versus-host disease (GVHD) prophylaxis consisted of CSA alone (n=32) or a combination with either MTX or MMF (n=51). The median age was 52 years. Graft failure occurred in two patients after BU/FLU and in three after BU/FLU/ATG (P=0.66). After conditioning with BU/FLU, platelet recovery was significantly faster (P=0.017), and less platelet (P<0.001) and red blood cell (P=0.002) support was needed. Incidences of acute GVHD grades II and IV were 46 and 49%, respectively. Limited chronic GVHD occurred more often after BU/FLU compared to BU/FLU/ATG (54 vs 23%, P=0.02). The overall survival, non-relapse and relapse mortality did not differ significantly. We conclude that in peripheral blood stem cell transplantation from HLA-identical siblings after reduced-intensity conditioning with BU and FLU, ATG has no major impact on the rate of graft rejection and acute GVHD, but it reduces the incidence of limited chronic GVHD.

Acute Disease↗
PubMed2004

European consensus on diagnosis and treatment of germ cell cancer: a report of the European Germ Cell Cancer Consensus Group (EGCCCG).

Germ cell tumour is the most frequent malignant tumour type in young men with a 100% rise in the incidence every 20 years. Despite this, the high sensitivity of germ cell tumours to platinum-based chemotherapy, together with radiation and surgical measures, leads to the high cure rate of > or = 99% in early stages and 90%, 75-80% and 50% in advanced disease with 'good', 'intermediate' and 'poor' prognostic criteria (IGCCCG classification), respectively. The high cure rate in patients with limited metastatic disease allows the reduction of overall treatment load, and therefore less acute and long-term toxicity, e.g. organ sparing surgery for specific cases, reduced dose and treatment volume of irradiation or substitution of node dissection by surveillance or adjuvant chemotherapy according to the presence or absence of vascular invasion. Thus, different treatment options according to prognostic factors including histology, stage and patient factors and possibilities of the treating centre as well may be used to define the treatment strategy which is definitively chosen for an individual patient. However, this strategy of reduction of treatment load as well as the treatment itself require very high expertise of the treating physician with careful management and follow-up and thorough cooperation by the patient as well to maintain the high rate for cure. Treatment decisions must be based on the available evidence which has been the basis for this consensus guideline delivering a clear proposal for diagnostic and treatment measures in each stage of gonadal and extragonadal germ cell tumour and individual clinical situations. Since this guideline is based on the highest evidence level available today, a deviation from these proposals should be a rare and justified exception.

Europe↗
PubMed2003

[Quantitative determination of CMV-DNA in saliva of patients with bone marrow and stem cell transplantation using TaqMan-PCR].

BACKGROUND: Human cytomegalovirus (HCMV) infection is associated with severe and life-threatening diseases in immunocompromised patients, especially after bone marrow (BM) and stem cell (SC) transplantation. Prior to transplantation the potential risk of HCMV disease is therefore determined by HCMV-antibody blood testing of transplant donor (D) and recipient (R). Virus carriers are positive for anti-CMV-IgG. Virus patterns are distinguished as follows: group 1 (D+/R+), group 2 (D-/R+), group 3 (D+/R-), and group 4 (D-/R-). AIM: The aim of this study was qualitative and quantitative determination of the HCMV DNA load in saliva of BM and SC transplantation patients. PATIENTS AND METHOD: Unstimulated saliva was collected from 20 patients prior to BM and SC transplantation, during the time of conditioning, and after transplantation. DNA was isolated and analyzed for evidence of HCMV DNA with TaqMan PCR. RESULTS: HCMV DNA was isolated in seven cases. In all group 1 patients (D+/R+) HCMV DNA could be demonstrated. Only three of seven group 2 patients (D-/R+) were positive for HCMV DNA. The only group 3 patient (D+/R-) and all eight group 4 patients (D-/R-) were negative. CONCLUSION: TaqMan PCR is a reliable method for HCMV DNA quantification. In three patients (anti-HCMV-IgG positive) who received an anti-CMV-IgG negative transplant HCMV DNA was isolated. In contrast, no HCMV-DNA was evident in HCMV-negative patients who received an HCMV-negative transplant. Accordingly, the risk of HCMV reactivation is more probable than the risk of reinfection.

Adult↗
PubMed2003

Individualised dosing strategy for high-dose carboplatin in patients with germ cell cancer.

In contrast to conventional chemotherapy, carboplatin is still dosed per unit of body surface area (BSA) in high-dose chemotherapy protocols in clinical practice. To individualise dosing, a population pharmacokinetic model for poor-risk germ cell tumour patients receiving 1500 mg m(-2) carboplatin was developed. The typical central volume of distribution (19.9 l) and typical clearance (110 ml min(-1)) corresponded approximately to the extracellular fluid space or glomerular filtration rate, respectively. The covariate analysis identified several patient-specific factors. Carboplatin clearance was significantly related to creatinine clearance and body height, explaining 73% of the interindividual variability. Thus, an equation to predict individual clearance prior to treatment was developed (CL=0.41 x creatinine clearance+1.05 x body height-124.4). The relative frequency of developing toxicity increased significantly with higher AUC values for different types of toxicity. In addition, overall nonhaematological toxicity correlated significantly with exposure of carboplatin, leading to the assessment of a target AUC. Based on the prediction of individual clearance and the definition of a target AUC associated with moderate toxicity, an individualised dosing equation is proposed. Retrospectively, the individualised dosing strategy would have led to a higher dose on average and a broader range to be administered, compared to empirical dosing per unit BSA in the high-dose setting.

Adult↗
PubMed2003

Evidence of a graft-versus-leukemia effect in chronic lymphocytic leukemia after reduced-intensity conditioning and allogeneic stem-cell transplantation: the Cooperative German Transplant Study Group.

PURPOSE: To study whether hematopoietic stem-cell transplantation (HSCT) after reduced-intensity conditioning is effective and tolerable in patients with advanced chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS: Thirty patients with advanced B-cell CLL were included into the study. After reduced-intensity conditioning with fludarabine, busulfan, and antithymocyte globulin, patients received a transplant from related (n = 15) or unrelated donors (n = 15). Minimal residual disease (MRD) was monitored with a clone-specific polymerase chain reaction. RESULTS: After a median follow-up of 2 years, 23 patients are alive (to date). Neutrophil and platelet engraftment occurred after a median of 17.5 and 15 days, respectively. Acute graft-versus-host disease (GVHD) grade 2 to 4 was observed in 17 patients (56%), and chronic GVHD was observed in 21 patients (75%). Twelve patients (40%) achieved a complete remission (CR), and 16 patients (53%) achieved a partial remission. Late CR occurred up to 2 years after transplantation. MRD was monitored in eight patients with CR. All patients achieved a molecular CR. At last follow-up, six patients were in ongoing molecular CR. Causes of death were treatment-related complications in four patients and progressive disease in three patients. The probability of overall survival, progression-free survival, and nonrelapse mortality at 2 years was 72% (95% confidence interval [CI], 54% to 90%), 67% (95% CI, 49% to 85%), and 15% (95% CI, 1% to 29%), respectively. CONCLUSION: Treatment-related mortality after reduced-intensity conditioning followed by allogeneic HSCT was low. The procedure induced molecular remissions in patients with advanced CLL. The observation of late remissions provided evidence of a graft-versus-leukemia effect.

Adult↗
PubMed2003

Reduced intensity conditioning for allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia: disease status by marrow blasts is the strongest prognostic factor.

We analyzed predictive factors for the outcome of 113 acute myeloid leukemia patients receiving reduced-intensity conditioning prior to allogeneic hematopoietic stem cell transplantation (HSCT). Patients were ineligible for conventional-intensity HSCT. Conditioning consisted of fludarabine and 50% of the conventional dose of busulfan (n=93) or total body irradiation (n=20). The source of stem cells was blood in 102 patients, marrow in 10, and both in one. In total, 50 (44.2%) donors were HLA-matched siblings, 50 (44.2%) unrelated fully matched and 13 (11.5%) partially mismatched family (n=1) or unrelated (n=12) donors. In all, 107 (94.6%) patients showed neutrophil and platelet engraftment after a median time of 13.5 and 13 days. The probabilities of event-free survival (EFS) (median follow-up: 12 months) were 49% for patients with less than 5% blasts in the marrow, 24% for patients with 5-20% blasts (P=0.002) and 14% with >20% blasts (P<or=0.001). Death occurred because of relapse in 29 patients (25.6%), infection in 12 patients (10.6%), acute graft-versus-host disease in eight patients (7.0%) and organ toxicity in nine patients (7.9%). In multivariate analysis, higher number of blasts in the marrow, alternative donors and low Karnofsky performance score were independent adverse prognostic factors for EFS.

Adolescent↗
PubMed2003

Cytomegalovirus infections in allogeneic stem cell recipients after reduced-intensity or myeloablative conditioning assessed by quantitative PCR and pp65-antigenemia.

Since the incidence of cytomegalovirus (CMV) infections after hematopoietic stem cell transplantation (HSCT) may depend on the intensity of the pretreatment, we studied the incidence of CMV infections after reduced-intensity compared to myeloablative conditioning. A total of 82 patients with matched related or unrelated donors were prospectively monitored for CMV infections after HSCT by CMV-PCR techniques, CMV-antigenemia and clinical observation. A total of 45 patients received reduced-intensity conditioning consisting of fludarabine, busulfan and ATG and 37 patients received myeloablative conditioning. Leukocyte engraftment occurred after a median of 15 vs 18 days (P=0.012) and platelet engraftment after 12 days vs 20 days (P=0.001), respectively. Acute graft-versus-host disease (GVHD) grade II-IV was observed in 58 vs 54% patients (P=0.737), respectively. The onset and peak values of CMV-antigenemia and DNAemia and the incidence of CMV infections did not differ statistically significantly between the two treatment groups. Multivariate analysis confirmed CMV seropositivity of the recipient (P=0.035), acute GVHD II-IV (P=0.001) but not the type of conditioning as significant risk factors for CMV-antigenemia. In conclusion, the kinetics of CMV-antigenemia and DNAemia and the incidence of CMV infections were not statistically different in patients who received HSCT after reduced-intensity conditioning with fludarabine, busulfan and ATG compared to myeloablative conditioning.

Adolescent↗
PubMed2003

Response to imatinib in patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukemia.

We studied 128 patients with chronic myeloid leukemia (CML) relapsing after allogeneic stem cell transplantation (SCT). Disease at the time of treatment with Imatinib was in chronic phase (CP) in 51 patients, accelerated phase (AP) in 31 and blastic crisis (BC) in 46. Of the 51 patients in CP, 14 were in cytogenetic and two in molecular relapses. The median interval between relapse and Imatinib therapy was 5 months (0-65). A total of 50 patients had failed treatment with donor lymphocyte infusions prior to Imatinib. The overall hemato-logical response rate was 84% (98% for patients relapsing in CP). The complete cytogenetic response (CCR) was 58% for patients in CP, 48% for AP and 22% for patients in BC. Complete molecular responses were obtained in 25 patients (26%), of whom 21 were in CP or AP. With a median follow-up of 9 months, the estimated 2-year survival for CP, AP and BC patients was 100, 86 and 12%, respectively. Out of 79 evaluable patients, 45 (57%) achieved full donor and 11 (14%) mixed chimerism after Imatinib. We conclude that Imatinib has significant activity against CML in relapse after allogeneic SCT. Durable cytogenetic and molecular remissions are obtainable in patients in CP.

Adult↗
PubMed2002

Influence of amifostine on reconstitution of lymphocyte subpopulations after conventional- and high-dose chemotherapy in patients with germ cell tumor.

We assessed the influence of amifostine on immune reconstitution after conventional-dose paclitaxel, ifosfamide, cisplatin and high-dose carboplatin, etoposide and thiotepa followed by autologous peripheral blood progenitor cell (PBPC) rescue in patients with germ cell tumor (GCT). A total of 40 patients were treated with one cycle of paclitaxel and ifosfamide (TI) followed by granulocyte-colony stimulating factor (G-CSF) to mobilize PBPC, three cycles of paclitaxel, ifosfamide and cisplatin (TIP) and one course of high-dose carboplatin, etoposide and thiotepa (CET) plus PBPC rescue. Patients were randomized to receive an absolute dose of 500 mg amifostine (group A, n=20) on each day of chemotherapy or no amifostine (group B, n=20). Prior to each cycle of chemotherapy, after hematologic engraftment from CET, 6 weeks and 3 months after transplantation the subpopulations of lymphocytes were phenotyped. Between the two study groups no statistically significant differences were observed concerning reconstitution of lymphocyte subpopulations. Throughout treatment with TIP or CET lymphocyte counts and their subpopulations remained low without severe clinical complications. Delayed reconstitution of the CD4(+) cell compartment after PBPC rescue was observed in both study groups, but did not result in any severe or atypical infections. Treatment with amifostine administered at this dose did not significantly influence the reconstitution of lymphocyte subpopulations. Low numbers of lymphocytes during chemotherapy and delayed reconstitution of CD4(+) cells and other lymphocyte subpopulations after PBPC rescue had no clinical relevance for patients with GCT.

Adult↗
PubMed2002

High-dose chemotherapy as salvage treatment for seminoma.

Between October 1989 and February 1997, 13 patients with refractory or relapsed seminomas were treated with high-dose chemotherapy (HDCT) as part of consecutive phase I/II studies. Six patients had failed prior cisplatin-based first-line treatments and seven patients had also failed cisplatin-based salvage treatments. After HDCT 4/12 (33%) patients became disease-free, 4/12 (33%) patients achieved partial remissions and 4/12 (33%) patients suffered progressive disease despite HDCT. One patient developed multiorgan failure and died. With a median follow-up of 4.5 years (range 3.4 to 8 years) five patients (38%) are alive and eight patients (62%) have died. Patients with non-pulmonary visceral metastases, with short relapse-free intervals and with cisplatin-refractory tumors were more likely to fail. HDCT can be curative in seminoma patients even if offered as second salvage treatment.

Adult↗
PubMed2002

High-dose versus conventional-dose chemotherapy as first-salvage treatment in patients with non-seminomatous germ-cell tumors: a matched-pair analysis.

BACKGROUND: The purpose of this study was to compare high-dose chemotherapy (HDCT) with conventional-dose chemotherapy (CDCT) as first-salvage treatment in patients with relapsed or refractory non-seminomatous germ-cell tumors (NSGCT). PATIENTS AND METHODS: One hundred and ninety-three patients with relapsed or refractory NSGCT, between 1981 and 1995, were identified from two large databases. In 74 of these, intensification of first-salvage treatment by HDCT was planned. Patients were matched based on primary tumor location, response to first-line treatment, duration of this response and serum levels of the tumor markers, human chorionic gonadotrophin (HCG) and alpha-fetoprotein (AFP). Multivariate analyses were performed using event-free survival and overall survival as primary endpoints. RESULTS: Full matches on all five factors were found for 38 pairs of patients; for a further 17 pairs, matches on at least four factors could be identified. Hazard ratios in favor of HDCT were obtained between 0.72 and 0.84 [confidence interval (CI) 0.59-1.01] for event-free survival and between 0.77 and 0.83 (CI 0.60-0.99) for overall survival, depending on the type of analysis. CONCLUSIONS: The current analysis suggests a benefit from HDCT, with an estimated absolute improvement in event-free survival of between 6 and 12% and in overall survival of between 9 and 11% at 2 years. This benefit is lower than expected from previous phase I/II studies.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2002

Reduced non-relapse mortality after reduced intensity conditioning in advanced chronic lymphocytic leukemia.

We studied in 30 patients with progressive or relapsing chronic lymphocytic leukemia (CLL) if hematopoietic stem cell transplantation (HSCT) after conditioning with fludarabine, busulfan and ATG is effective and if treatment related mortality can be reduced compared to myeloablative conditioning regimens. Patients had 15 matched related and 15 matched unrelated donors. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine alone or a combination with "short course" methotrexate or mycophenolate mofetil. The median follow-up is 24 months. At last follow up 11 patients were in complete and 13 in partial remission. Six patients had stable or progressive disease. Late complete remissions occurred up to one year after transplantation and the number of patients with CR is still increasing. Four patients died due to treatment related complications resulting in a probability of treatment-related mortality of 15% (CI 95%, 1% to 29%) at 2 years. The probability of overall survival and progression free survival at two years was 79% and 61%, respectively. In conclusion, HSCT after reduced conditioning may lower the treatment-related toxicity and has the capacity to induce complete remissions.

Busulfan↗