Addressing COVID-19 challenges in a randomised controlled trial on exercise interventions in a high-risk population.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic is a threat to ongoing clinical trials necessitating regular face-to-face, in-person meetings, particularly in participants with a high risk of complications. Guidance on how to handle and safely continue such trials is lacking. Chronically ill elderly individuals require-in addition to protection from infection-regular physical exercise and social contact to remain healthy. Solutions on how to handle these conflicting necessities are needed. The ENTAIER-randomised controlled trial was investigating the influence of mindful movements on fall risk, fear of falling, mobility, balance, life quality, and other outcomes. The study population was planned to comprise of 550 chronically ill elderly individuals with a high risk of falling. The movements were regularly performed in coached groups over 6 months. After the trial began, COVID-19 lockdowns stopped all in-person meetings, and it was expected that the limitations of this pandemic would continue for a long term. Therefore, the exercise programme, which involved complex movements and was typically conducted face-to-face in groups, had to be substituted by a telemedicine programme within a short timeframe. The objectives, therefore, were to identify challenges and tasks that could to be resolved and steps that could to be taken to achieve high-quality, efficacy, safety, and enable human encounter and motivation. METHODS: We proceeded with four steps: 1) A literature review on the quality and feasibility issues of telemedicine in general, and specifically, in exercise training in elderly individuals. 2) Participation in two international telemedicine task forces on integrative medicine, particularly, mind-body medicine. 3) Interviews with study therapists, (for practical purposes, eurythmy therapists and Tai Chi teachers are summarized here as therapists) personnel, and international experts on providing mindful movement exercises and other physiotherapies via live telecommunication technology, and with scientists and patient representatives. 4) Final evaluation by the core trial team and subsequent planning and implementation of changes in the trial organisation. RESULTS: Various tasks and challenges were identified: for the technical equipment for therapists and patients; for the ability of therapists and trial participants to adequately manage the technology and telemedicine intervention; the reservations and concerns about the technology among therapists and participants; safety and data protection in using the technology; and study design. The two major options found on how to continue the trial in the COVID-19 situation were a complete switch to telemedicine and a partial switch in the form of risk management implemented into the former design. CONCLUSIONS: The management of an ongoing clinical trial in a national or international crisis with a minimum of available time and extra financial resources, alongside with two checklists on steps and procedures for trial continuation and telemedicine implementation, may be informative for other researchers or healthcare providers faced with similar challenges and making similar decisions in the current situation or similar future scenarios. TRAIL REGISTRATION: www.drks.de . DRKS00016609. Registered July 30, 2019.

Differences between prolonged weaning patients from medical and surgical intensive care units.

BACKGROUND: It is not clear whether patients entering a specialized, interdisciplinary weaning unit from surgical or medical intensive care units (ICU) distinguish substantially. The purpose of the present study was to assess differences in patients with prolonged weaning being referred from surgical and medical ICU. METHODS: Data collected from April 2013 to April 2014 was conducted for retrospective analysis. Mortality rates, demographic data, clinical, and microbial differences in 150 patients with prolonged weaning were assessed (80 surgical and 70 medical). RESULTS: Surgical ICU referrals tended to be older (70.7 ± 11.3 vs. 67.3 ± 12.3, P = 0.051) and had fewer underlying pulmonary diseases (45% vs. 60%, P = 0.067). Sodium values at the time of referral to the weaning unit were significantly higher in surgical (147.1 ± 9.6) vs. medical (141.3 ± 6.7 mmol/l) patients (P < 0.001). Each 10-unit increase in sodium at the time of referral to the weaning unit was associated with a 2.5-day (95% CI -0.4, 5.4; P = 0.09) prolongation of stay in the weaning unit. Although significant differences in microbiological agents from tracheal aspiration were seen, the infection rate on the weaning unit was similar in both groups. There was no difference in weaning unit mortality between surgical and medical ICU patients (18% vs. 23%; P = 0.41). CONCLUSION: Few differences were found between patients being referred to a specialized weaning unit from surgical vs. medical ICUs. Besides differences in microbiological characteristics of tracheal secretions, there were also differences in sodium levels, which appear to influence on treatment duration.

Effects on pulmonary rehabilitation in patients with COPD or ILD: A retrospective analysis of clinical and functional predictors with particular emphasis on gender.

BACKGROUND: The response of patients in a pulmonary rehabilitation (PR) is essentially good. However, not all patients benefit from PR to the same extent. In this analysis we wanted to identify the impact of gender and other factors on PR outcomes in patients with chronic obstructive pulmonary disease (COPD) or interstitial lung disease (ILD). METHODS: Patients suffering from COPD (n = 1492) or ILD (n = 599), treated during an inpatient PR between 1997 and 2015, were analysed according to the effects of PR on exercise capacity and quality of life with regard to the impact of gender or other predictors by univariate and multivariate analyzes. RESULTS: In the group of COPD patients, 30% did not achieve the expected physical performance during the 6-min walk test (28% of female and 32% of male patients). However, the non-responders initially have had a higher 6-min walking distance (6-MWD) (p < 0.001) and both male and female showed a significant lower BODE index (p = 0.025) in the multivariate analysis. In the ILD-group, 37% females and 43% males were classified as non-responders with regard to the 6-MWD. Also in this group, the non-responders initially have had a higher 6-MWD (p < 0.001). All other variables (age, BMI, lung function, blood gases, C-reactive Protein, Haemoglobin or rehabilitation duration) had no influence on the outcome. CONCLUSION: Our study supports the positive effects of PR in COPD and ILD patients. In both groups, patients with the biggest limitations benefit most from PR. However, relevant gender differences or other predictors could not be found.

Long-term follow-up of therapy-related myelodysplasia and AML patients treated with allogeneic hematopoietic cell transplantation.

The outcome of patients with therapy-related myelodysplasia (t-MDS) or t-AML is very poor. The only curative treatment option implements allogeneic hematopoietic cell transplantation (aHCT); however, long-term follow-up data beyond 5 years are scarce. Here we report on a cohort of 79 consecutive patients with a median age of 58 years (range (r): 20-76) at transplantation and a median follow-up of 7.5 years (r: 0.07-19.0). Only 19 (24.1%) patients were in CR before aHCT. Non-relapse mortality and relapse rates were 23% (95% confidence interval, 15-35%) and 42% (32-55%) at 5 years, and 32% (22-46%) and 44% (34-57%) at 10 years, respectively. Disease-free survival (DFS) and overall survival (OS) rates were 35% (24-46%) and 38% (27-49%) at 5 years, and 24% (14-36%) and 24% (13-36%) at 10 years, respectively. Although cytogenetic aberrations were associated with shorter DFS and higher relapse risk, persistent disease at the time of transplantation, an unrelated donor and patient age were not associated with shorter OS. In conclusion, long-term survival beyond 10 years of t-MDS/t-AML patients after aHCT is possible, even for refractory patients. Therefore, early donor search and rapid transplantation are warranted, also to decrease the risk of disease-related deterioration of patients' performance status.

Good Medicine and Good Healthcare Demand Good Information (Systems).

The demand for evidence-based health informatics and benchmarking of 'good' information systems in health care gives an opportunity to continue reporting on recent papers in the German journal GMS Medical Informatics, Biometry and Epidemiology (MIBE) here. The publications in focus deal with a comparison of benchmarking initiatives in German-speaking countries, use of communication standards in telemonitoring scenarios, the estimation of national cancer incidence rates and modifications of parametric tests. Furthermore papers in this issue of MIM are introduced which originally have been presented at the Annual Conference of the German Society of Medical Informatics, Biometry and Epidemiology. They deal as well with evidence and evaluation of 'good' information systems but also with data harmonization, surveillance in obstetrics, adaptive designs and parametrical testing in statistical analysis, patient registries and signal processing.

Distribution of internal carotid artery plaque locations among patients with central retinal artery occlusion in the Eagle study population.

PURPOSE: Arterial emboli in the internal carotid artery (ICA) mainly cause cerebral ischemia; only 10 % of emboli reach the retinal arteries. Computational blood flow studies suggest that plaques situated in the ICA siphon may be a source of embolism to the ophthalmic artery (OA). To validate these calculated probabilities in patients with central retinal artery occlusion (CRAO), we reanalyzed digital subtraction angiography (DSA) images from the Multicenter Study of the European Assessment Group for Lysis in the Eye (EAGLE) study, a multicenter randomized study in patients with nonarteritic CRAO. METHODS: A reevaluation of 34 DSA studies was done from the interventional arm of the EAGLE study with regards to distribution of arterial plaques at specific ICA siphon locations and ICA stenosis. A comparison was made of plaque distribution to calculated probabilities for emboli reaching the OA from a computational fluid dynamics (CFD) model of a patient-specific ICA siphon. RESULTS: Most of the ICA plaques near the OA's origin were located in the cavernous ICA portion (31.3%). Of these, 12.5 % had plaques in the curvature opposite the OA origin, a location carrying the highest risk for embolization into the OA (according to the CFD model 12.6-13.2 % probability of embolisation into the OA). Also, 15.6 % had plaques in the paraclinoid ICA portion distal to the OA origin. CONCLUSIONS: There were 40.6% of the patients that had plaques in the cavernous and clinoid ICA portions presenting possible sources for embolic material generating RAO.

Transcatheter closure of atrial septal defects in children and adolescents: single-center experience with the GORE® septal occluder.

OBJECTIVES: Device closure of atrial septal defects (ASD II) is an alternative to surgery. ASD morphology and intracardiac relationships may influence device selection. Biocompatibility, techniques for closing large or multiple defects, and the risk of erosion are main issues in children BACKGROUND: The GORE® Septal Occluder (GSO) is a non-self-centering device with a flat and conformable nitinol-frame covered with expanded polytetrafluoroethylene. We hereby evaluate our initial experience in children to demonstrate feasibility, efficacy, and safety. METHODS: Single-center retrospective intention-to-treat analysis of GSO procedures in children and adolescents with hemodynamically significant ASD. All procedures were conducted under general anesthesia, fluoroscopy and transesophageal echocardiography. All defects were sized using stop-flow-technique. GSOs of 20-30 mm disc-diameter were implanted. RESULTS: GSO implantation was attempted in 45 with technical success in 41 patients, median age 6 (range 3-17) years, bodyweight 19 (12-95) kg. Median balloon-sized diameter was 13 (8-19) mm resulting in a GSO-to-ASD-ratio of 2 (1.7-2.5). Deficient retro-aortic rims (<3 mm) were found in 12 patients, and 10 of these 12 defects could be closed. We observed no complications. Four extensive or multiple ASDs were not treated successfully with GSO. After retrieval, one was closed with a different device; three patients needed surgical therapy. The median follow-up of four (range 0.2-22) months was uneventful in all patients CONCLUSIONS: We found the GSO device closure of ASDs in children to be effective. However, our initial experience is limited to short- and mid-term-follow-up of a low number of patients.

Reduced-intensity conditioning with fludarabine and thiotepa for second allogeneic transplantation of relapsed patients with AML.

A second allograft was offered to 58 relapsed AML patients after conditioning with fludarabine 90-150 mg/m(2) and thiotepa 15 mg/kg, in most cases with active disease. Median age was 53 years (range 23-69), median time to relapse after the first allo-SCT was 326 (47-2189) days and median follow-up was 6.7 years. GVHD prophylaxis consisted mainly of CsA and alemtuzumab. Response rates at 1 month were CR in 50 and persistent disease in 3/53 evaluable patients. At 3 years, the relapse incidence (95% confidence interval) was 56 (45-71)%, the TRM 31 (21-46)%, the OS rate was 18 (9-29)% and the EFS rate was 13 (5-23)%. OS improved with younger patient age, longer relapse-free interval after the first allo-SCT and the development of chronic GVHD. Patients ≥ 65 years old who relapsed >12 months after the first allograft (n=20) had a 3-year OS rate of 41 (19-62)%. Conventional cytogenetics and FLT3 mutation status did not affect outcome. Our regimen is feasible and provides at least for a subgroup of patients with AML recurrence after allo-SCT a reasonable therapeutic option in an otherwise fatal situation. Further modifications and a better understanding of the underlying biology could help lower the risk of relapse.

Intra-individual head-to-head comparison of Sirolimus®- and Paclitaxel®-eluting stents for coronary revascularization. A randomized, multi-center trial.

BACKGROUND: Despite the known effects of drug-eluting stents (DES), other cofactors attributed to patient characteristics affect their success. Interest focused on designing a study minimizing these factors to answer continuing concerns on the heterogeneity of response to different DESs. The study's aim was to investigate the feasibility and impact of an intra-individual comparison design in patients (pts) with two coronary artery stenosis treated with a Sirolimus- (SES) and a Paclitaxel- (PES) eluting stent. METHODS AND RESULTS: The study was conducted as a prospective, randomized, multi-center trial in 112 pts who consented to treatment with a SES and a PES. Pts were eligible if they suffered from the presence of two single primary target lesions in two different native coronary arteries. Lesions were randomized to either SES or PES treatment. The primary endpoint was in-stent luminal late loss (LLL), as determined by quantitative angiography at 8 months; clinical follow up was obtained at 1, 8, and 12 months additionally. The LLL (0.13 ± 0.28 mm SES vs. 0.26 ± 0.35 mm PES, p=0.011) showed less neointima in SES. With a predefined cut-off criterion of 0.2mm difference in LLL, 53/87 pts SES and PES were similar effective. 34/87 pts had a divergent result, 26 pts had greater benefit from SES while 8 pts had greater benefit from PES. Overall, MACE (MI, TLR, and death) occurred in 19 (17%) pts. Based on lesion analysis of 108 lesions treated with SES and 110 lesions treated with PES, 5 (4.6%) lesions with SES and 3 (2.7%) lesions with PES required repeated TLR. CONCLUSION: An intra-individual comparison design to assess differences in efficacy of different DESs is feasible, safe and achieves similar results to inter-individual studies. This study is among the first to show that failure of one DES does not necessarily implicate failure of another DES and vice versa.

Multicentre phase II trial of trastuzumab and capecitabine in patients with HER2 overexpressing metastatic pancreatic cancer.

BACKGROUND: New therapeutic options for metastatic pancreatic cancer are urgently needed. In pancreatic cancer, overexpression of the epidermal growth factor receptor 2 (HER2) has been reported in up to 45%. This multicentre phase II study investigated the efficacy and toxicity of the HER2 antibody trastuzumab combined with capecitabine in the patients with pancreatic cancer and HER2 overexpression. METHODS: Primary endpoint was progression-free survival (PFS) after 12 weeks. A total of 212 patients were screened for HER2 expression. RESULTS: Immunohistochemical (IHC) HER2 expression was: 83 (40%) grade 0, 71 (34%) grade 1, 31 (15%) grade 2, 22 (11%) grade 3. A total of 17 patients with IHC +3 HER2 expression or gene amplification could be assessed for the treatment response. Grade 3/4 treatment toxicities were: each 7% leucopenia, diarrhoea, nausea and hand-foot syndrome. Progression-free survival after 12 weeks was 23.5%, median overall survival (OS) 6.9 months. CONCLUSION: This study demonstrates +3 HER2 expression or gene amplification in 11% of patients. Contrary to breast and gastric cancer, only 7 out of 11 (64%) patients with IHC +3 HER2 expression showed gene amplification. Although the therapy was well tolerated, PFS and OS did not perform favourably compared with standard chemotherapy. Together, we do not recommend further evaluation of anti-HER2 treatment in patients with metastatic pancreatic cancer.

[Comparison of superselective intraarterial fibrinolysis with conservative therapy. Use in patients with acute non-arteritic central retinal artery occlusion]. / Vergleich der superselektiven intraarteriellen Fibrinolyse mit konservativer Therapie. Einsatz bei Patienten mit akutem nichtarteriitischem Zentralarterienverschluss.

The results of conservative treatment for central retinal artery occlusion (CRAO) vary considerably and although local intraarterial fibrinolysis (LIF) is a promising treatment, outcomes have not been compared in randomized trials. The prospective randomized multicenter study by the European Assessment Group for Lysis in the Eye (EAGLE) is the first clinical trial to compare treatment outcomes of conservative standard treatment (CST) and LIF for acute non-arteritic CRAO. Patients (age 18-75 years) with CRAO present for less than 20 h and best-corrected visual acuity (BCVA) <0.5 logMAR were randomized to either CST or LIF group. Primary endpoint was BCVA after 1 month and secondary endpoint was safety. Mean BCVA (logMAR) improved significantly in both groups and did not differ between the groups. Because of similar efficacy and the higher rate of adverse events in the LIF group the study was halted after the first interim analysis. Due to the similar outcomes of the two therapies and the higher rate of adverse reactions associated with LIF superselective lysis cannot be recommended for the management of acute CRAO.

Skin disinfection with octenidine dihydrochloride for central venous catheter site care: a double-blind, randomized, controlled trial.

To compare the efficacy of two commercially available, alcohol-based antiseptic solutions for preparation and care of central venous catheter (CVC) insertion sites, with and without octenidine dihydrochloride, a double-blind, randomized, controlled trial was undertaken in the haematology units and in one surgical unit of two university hospitals. Adult patients with a non-tunnelled CVC were randomly assigned to two different skin disinfection regimens at the insertion site: 0.1% octenidine with 30% 1-propanol and 45% 2-propanol, and as control 74% ethanol with 10% 2-propanol. Endpoints were (i) skin colonization at the insertion site; (ii) positive culture from the catheter tip (> or = 15 CFU); and (iii) occurrence of CVC-associated bloodstream infection (defined according to criteria set by the CDC). Four hundred patients with inserted CVC were enrolled from May 2002 through April 2005. Both groups were similar in respect of patient characteristics and co-morbidities. Skin colonization at the CVC insertion site during the first 10 days was significantly reduced by octenidine treatment (relative difference octenidine vs. control: 0.21; 95%CI: 0.11-0.39, p <0.0001). Positive culture of the catheter tip was significantly less frequent in the octenidine group (7.9%) than in the control group (17.8%): OR = 0.39 (95%CI: 0.20-0.80, p 0.009). Patients treated with octenidine had a non-significant reduction in catheter-associated bloodstream infections (4.1% vs. 8.3%; OR = 0.44; 95%CI: 0.18-1.08, p 0.081). Side effects were similar in both groups. This randomized controlled trial supports the results of two observational studies demonstrating octenidine in alcoholic solution to be a better option than alcohol alone for the prevention of CVC-associated infections.

Randomized trial of high-dose adjuvant chemotherapy with autologous hematopoietic stem-cell support versus standard-dose chemotherapy in breast cancer patients with 10 or more positive lymph nodes: overall survival after 6 years of follow-up.

Investigation of high-dose chemotherapy (HD-CT) compared with standard-dose chemotherapy (SD-CT) as adjuvant treatment in patients with primary breast cancer and >/=10 axillary lymph nodes. From November 1993 to September 2000, 307 patients were randomized to receive after four cycles of epirubicin (90 mg/m(2)), cyclophosphamide (600 mg/m(2)) i.v. (every 21 days) and either HD-CT of cyclophosphamide (1500 mg/m(2)), thiotepa (150 mg/m(2)) and mitoxantrone (10 mg/m(2)) i.v. for four consecutive days followed by stem cell transplantation or a SD-CT of three cycles CMF (cyclophosphamide 500 mg/m(2), methotrexate 40 mg/m(2), 5-fluorouracil 600 mg/m(2), i.v. on day 1 and 8, respectively, every 28 days). After a median follow-up of 6.1 years, 166 events with respect to event-free survival (EFS) (SD-CT: 91, HD-CT: 75) have been observed. The hazard ratio of HD-CT versus SD-CT is estimated as 0.80 [95% confidence interval (0.59, 1.08)], P = 0.15. The trend to a superiority of HD-CT as compared with SD-CT with respect to EFS seems to be more pronounced in premenopausal patients as compared with postmenopausal patients and in patients with tumor grade 3 as compared with patients with tumor grade 1/2. With a follow-up of 6 years, there was a trend in favor of HD-CT with respect to EFS not being significant. A proper meta-analysis needs to be undertaken for an evaluation of subgroups of patients who might benefit from HD-CT.

Multicenter study of the European Assessment Group for Lysis in the Eye (EAGLE) for the treatment of central retinal artery occlusion: design issues and implications. EAGLE Study report no. 1 : EAGLE Study report no. 1.

BACKGROUND: The natural course of central retinal artery occlusion (CRAO) often leads to legal blindness in the affected eye. To date, none of the conservative therapies had proven effective in retrospective studies. In 1991, a new minimally invasive therapy was started in patients with an acute CRAO. This therapy, namely, local intra-arterial fibrinolysis, is comparable to the minimally invasive therapy in patients with an acute ischemic stroke. In pilot studies, it showed promising results in comparison with conservative treatments. The efficacy of this method is now being investigated in a randomized multicenter study. METHODS: The European Assessment Group for Lysis in the Eye (EAGLE) started a prospective and randomized multicenter study in 2002 to evaluate therapeutic efficacy. Inclusion criteria are age between 18 and 75 years and a CRAO not older than 20 h with a visual acuity less than 0.32. The most important exclusion criteria are branch retinal artery occlusion (BRAO), cilioretinal arteries supplying the macula, and serious general disease. After randomization the patient is treated by conservative or local intra-arterial lysis therapy. The conservative regime included bulbus massage, lowering intraocular pressure with topical beta-blocker and acetazolamide, acetylsalicylic acid, heparin, and-depending on the hematocrit-isovolemic hemodilution. In case of local intra-arterial fibrinolysis, a maximum of 50 mg rtPA is injected into the ophthalmic artery by the neuroradiologist. During the following 5 days, all patients are treated with heparin. Primary study end point is visual acuity 1 month after therapy in comparison with visual acuity before therapy. The calculated sample size is 100 patients per subtrial (a total of 200 patients). The study was started in June 2002. To April 2005, 47 patients were included. CONCLUSIONS: The EAGLE Study is the first randomized prospective clinical trial to compare conservative medical treatment and local intra-arterial fibrinolysis in patients with CRAO. The results of this study should enable ophthalmologists and neuroradiologists to improve the therapy of patients with acute CRAO. To April 2005, treatment is only justified in randomized multicenter studies because of the limited therapeutical visual outcome. We welcome new study centers to join.

[The 12th amendment to the German Drug Law. Chances and obstacles for investigator-initiated clinical trials]. / Die 12. Novelle des Arzneimittelgesetzes in Deutschland. Chancen und Hindernisse für Investigator-initiierte Studien.

The European Union's so called Clinical Trials Directive 2001/20/EC was implemented in national law in Germany in August 2004, leading to the 12th amendment of the German Drug Law (Arzneimittelgesetz). The directive is intended to harmonize the clinical trial's regulatory environment across the European Union and to improve protection of human subjects. It lays down the principles and guidelines of Good Clinical Practice (GCP). As the regulation applies to all clinical trials on medicinal products for human use, and as only non-interventional studies are excluded, academic, investigator-initiated clinical trials will also have to comply with the EU clinical trials directive implemented in the German Drug Law. In an investigator-initiated trial in which the investigator takes the responsibility of a sponsor, the investigator-sponsor must take total legal and financial responsibility for the clinical trial. Since publicly funded clinical trials make a large contribution to improved care, concern has been expressed that non-commercial research projects will be reduced and the vital medical research conducted at academic institutions curtailed. Nonetheless GCP ensures a valid study design, qualified data management, analysis and monitoring of the trial and thereby promotes more valid data and protection of study participants. The trials are more likely to lead to reliable results leading to new therapies, strategies or a better understanding of diseases. What is needed, therefore, is an increase in public funding and the establishment of clinical trial units/organizations associated with the universities or hospitals where independent researchers have the possibility to obtain theoretical advice and practical help, professional training and support. In the end, the directive may serve as a stimulus to build a better national research environment and to promote public funding, and may lead to fewer but more valid clinical trials.

High-dose chemotherapy with autologous hematopoietic stem-cell support compared with standard-dose chemotherapy in breast cancer patients with 10 or more positive lymph nodes: first results of a randomized trial.

PURPOSE: Investigation of high-dose chemotherapy (HD-CT) followed by autologous hematopoietic stem-cell support compared with standard-dose chemotherapy (SD-CT) as adjuvant treatment in patients with primary breast cancer and 10 or more positive axillary lymph nodes. PATIENTS AND METHODS: Between November 1993 and September 2000, 307 patients were randomized to receive (following four cycles of epirubicin 90 mg/m(2) and cyclophosphamide 600 mg/m(2), intravenously every 21 days) either HD-CT of cyclophosphamide 1500 mg/m(2), thiotepa 150 mg/m(2), and mitoxantrone 10 mg/m(2), intravenously for 4 consecutive days followed by stem-cell support; or SD-CT in three cycles of cyclophosphamide 500 mg/m(2), methotrexate 40 mg/m(2), and fluorouracil 600 mg/m(2) intravenously on days 1 and 8, every 28 days. The primary end point was event-free survival. RESULTS: After a median follow-up of 3.8 years, 144 events with respect to event-free survival have been observed (HD-CT: 63 events; SD-CT: 81 events). The first event of failure (HD-CT v SD-CT) was an isolated locoregional recurrence (nine v 11), a distant failure (52 v 68), and death without recurrence (two v two). The estimated relative risk of HD-CT versus SD-CT was 0.75 (95% CI, 0.54 to 1.06; P =.095). Overall survival showed no difference (HD-CT: 40 deaths; SD-CT: 49 deaths). CONCLUSION: There was a trend in favor of HD-CT with respect to event-free survival, but without statistical significance. Further follow-up and a meta-analysis of all randomized studies will reveal the effect of HD-CT as compared with SD-CT as adjuvant treatment in high-risk primary breast cancer.

Radiation therapy after breast-conserving surgery; first results of a randomised clinical trial in patients with low risk of recurrence.

To study the role of radiotherapy and tamoxifen after breast-conserving surgery (BCS) in patients with a favourable prognosis, a clinical trial was initiated by the German Breast Cancer Study Group. Between 1991 and 1998, 361 patients (pT1pN0M0, aged 45-75 years, receptor positive, grade I-II) were randomised to radiotherapy (yes/no) and tamoxifen for 2 years (yes/no) in a 2x2 factorial design; the exclusion of seven centres (14 patients) left 347 patients in the analysis. After a median follow-up of 5.9 years, 77 events concerning event-free survival have been observed. Since a strong interactive effect between radiotherapy and tamoxifen has been established, the results are presented in terms of the treatment effects for all four treatment groups separately. Mainly due to the presence of local recurrences, the event rate was about three times higher in the group with BCS only than in the other three groups. No difference could be established between the four treatment groups for distant disease-free survival rates. It is concluded that even in patients with a favourable prognosis, the avoidance of radiotherapy and tamoxifen after BCS increases the rate of local recurrences substantially.

Prognosis of older patients with acute myeloid leukemia receiving either induction or noncurative treatment: a single-center retrospective study.

Since few studies focus on prognostic factors in unselected elderly acute myeloid leukemia (AML) patients, a retrospective analysis of 138 consecutive patients aged >55 years (median age: 67, range: 56-89) with AML diagnosed at a single center over an 8-year period was performed: 69% had de novo AML and 31% secondary (s) AML; 67% of the patients were karyotyped. Of the patients, 73 (53%) were treated with standard induction therapy protocols and 65 (47%) received palliative treatment only. Univariate and multivariate analyses of the effects of the following factors on overall survival (OS) were performed: sex, age > or = vs <65 years, de novo vs sAML, serum (s) lactate dehydrogenase (LDH) > or = vs <400 U/l, leukocytes > or = vs <50,000/ microl, induction therapy, and karyotype. Additionally, in patients receiving induction therapy, complete remission (CR) rates and survival from CR were analyzed. CR rate was 47% [95% confidence interval (35%, 59%)], 53% (39%, 66%) in de novo AML, and 21% (5%, 51%) in sAML. After a median follow-up of 4 years, 130 deaths were observed (94%). In a univariate analysis, significant factors for longer OS were induction therapy, age <65 years, sLDH <400 U/l, and de novo AML. In a multivariate analysis, significant factors for longer OS were sLDH <400 U/l and induction therapy. However, the difference between treatment outcome may also be due to selection criteria not captured, such as performance status, comorbid conditions, wish of the patient, etc. The effects of intensive and nonintensive treatment in this patient group need to be investigated in prospective, randomized trials in which these clinical parameters of high relevance for treatment decisions in older patients are also considered.

Duration of adjuvant chemotherapy for breast cancer: a joint analysis of two randomised trials investigating three versus six courses of CMF.

Cyclophosphamide, methotrexate and fluorouracil adjuvant combination chemotherapy for breast cancer is currently used for the duration of six monthly courses. We performed a joint analysis of two studies on the duration of adjuvant cyclophosphamide, methotrexate and fluorouracil in patients with node-positive breast cancer to investigate whether three courses of cyclophosphamide, methotrexate and fluorouracil might suffice. The International Breast Cancer Study Group Trial VI randomly assigned 735 pre- and perimenopausal patients to receive 'classical' cyclophosphamide, methotrexate and fluorouracil for three consecutive cycles, or the same chemotherapy for six consecutive cycles. The German Breast Cancer Study Group randomised 289 patients to receive either three or six cycles of i.v. cyclophosphamide, methotrexate and fluorouracil day 1, 8. Treatment effects were estimated using Cox regression analysis stratified by clinical trial without further adjustment for covariates. The 5-year disease-free survival per cents (+/-s.e.) were 54+/-2% for three cycles and 55+/-2% for six cycles (n=1024; risk ratio (risk ratio: CMFx3/CMFx6), 1.00; 95% confidence interval, 0.85 to 1.18; P=0.99). Use of three rather than six cycles was demonstrated to be adequate in both studies for patients at least 40-years-old with oestrogen-receptor-positive tumours (n=594; risk ratio, 0.86; 95% confidence interval, 0.68 to 1.08; P=0.19). In fact, results slightly favoured three cycles over six for this subgroup, and the 95% confidence interval excluded an adverse effect of more than 2% with respect to absolute 5-year survival. In contrast, three cycles appeared to be possibly inferior to six cycles for women less than 40-years-old (n=190; risk ratio, 1.25; 95% confidence interval, 0.87 to 1.80; P=0.22) and for women with oestrogen-receptor-negative tumours (n=302; risk ratio, 1.15; 95% confidence interval, 0.85 to 1.57; P=0.37). Thus, three initial cycles of adjuvant cyclophosphamide, methotrexate and fluorouracil chemotherapy were as effective as six cycles for older patients (40-years-old) with oestrogen-receptor-positive tumours, while six cycles of adjuvant cyclophosphamide, methotrexate and fluorouracil might still be required for other cohorts. Because endocrine therapy with tamoxifen and GnRH analogues is now available for younger women with oestrogen-receptor-positive tumours, the need for six cycles of cyclophosphamide, methotrexate and fluorouracil is unclear and requires further investigation.

Long-term follow-up of patients in four prospective studies of the German Breast Cancer Study Group (GBSG): A summary of key results.

Evaluation of treatment modalities and prognostic factors in early breast cancer requires a long-term follow-up of patients in prospective studies. The German Breast Cancer Study Group (GBSG) started four nationwide studies in 1983 in which a total of 2,746 patients have been enrolled and followed for about 10 years. Questions that have been addressed in these studies are still relevant today and comprise the role of breast-conserving therapy, the duration of adjuvant chemotherapy, and whether adjuvant radiotherapy is needed. The key results of these studies are highlighted including some important findings on prognosis, e.g., the role of isolated locoregional recurrence and the prognosis of patients with 10 or more positive lymph nodes. The data of all randomized patients were regularly included into the overviews of the Early Breast Cancer Trialists' Collaborative Group; the data of the nonrandomized patients have been used to examine the external validity of treatment comparisons. Overall, it can be concluded that the GBSG studies have made valuable and internationally recognized contributions to the prognosis and treatment of patients with early breast cancer.