Moeglichkeiten der systemischen Therapie im metastasierten Stadium [Treatment options for chemotherapy in metastatic gastric cancer]

Die Ergebnisse mehrerer, in letzter Zeit publizierter Phase-III-Studien haben die therapeutischen Möglichkeiten in der Behandlung des metastasierten Magenkarzinoms deutlich erweitert. Die Dauerinfusion von 5-Fluorouracil (5-FU) kann ohne Verlust an Wirkung durch Capecitabin ersetzt werden, ebenso wie Cisplatin durch Oxaliplatin. Nach den Ergebnissen der REAL-2-Studie zeigt die Kombination aus Epirubicin, Oxaliplatin und Capecitabin (EOX) eine Verbesserung des Gesamtüberlebens (9,9 vs. 11,2 Monate; HR 0,8) im Vergleich zu Epirubicin, Cisplatin und 5-FU (ECF). Die Frage, ob in der First-Line-Therapie eine Dreifachkombination oder eine Zweifachkombination eingesetzt werden sollte, ist allerdings weiterhin umstritten. Die Kombination aus Irinotecan und 5-FU stellt für solche Patienten, bei denen aufgrund von Komorbiditäten eine platinfreie Therapie bevorzugt wird, eine Alternative zur Kombination Cisplatin/5-FU dar. Docetaxel, 5-FU und Cisplatin (DCF) hat sich bezüglich des Überlebens in einer randomisierten Phase-III-Studie als statistisch signifikant überlegen erwiesen, allerdings besteht eine ausgeprägte hämatologische Toxizität, welche die Anwendbarkeit insbesondere bei den häufig älteren Patienten mit einem Magenkarzinom limitiert. Randomisierte Phase-III-Studien zum Vergleich von DCF mit anderen Dreierkombinationen, wie z. B. EOX, stehen aus. Recently published results from several phase III trials have significantly increased the therapeutic options in the treatment of metastatic stomach cancer: The continuous infusion of 5-FU can be replaced by capecitabine, and cisplatin can be replaced by oxaliplatin in both cases without impairing efficacy. According to the results of the REAL-2 trial, the combination of epirubicin, oxaliplatin and capecitabine (EOX) achieved superior results for overall survival compared to epirubicin, cisplatin und 5-FU (ECF) (9.9 versus 11.2 months, HR 0.8). However, the question of whether an optimal first line therapy should include a triplet regimen or the sequential use of doublets is a matter of debate. The combination of irinotecan and 5-FU may serve as an alternative to platinum-containing regimens in patients where, due to co-morbidity, a platinum-free regimen is preferred. The 3-drug combination of docetaxel, 5-FU and cisplatin (DCF) demonstrated a statistically significant survival benefit compared to the 2-drug combination of 5-FU and cisplatin in a randomized phase III trial, although results were limited by a particularly significant hematological toxicity, which prevents its application in the large group of elderly patients with gastric cancer. Direct randomized phase III comparisons of DCF with other 3-drug combinations, such as EOX are still missing.

The last days of dying stroke patients referred to a palliative care consult team in an acute hospital.

BACKGROUND AND PURPOSE: Needs of patients dying from stroke are poorly investigated. We aim to assess symptoms of these patients referred to a palliative care consult team, and to review their treatment strategies. METHODS: All charts of patients dying from stroke in a tertiary hospital, and referred consecutively to a palliative care consultant team from 2000 to 2005, were reviewed retrospectively. Symptoms, ability to communicate, treatments, circumstances and causes of death were collected. RESULTS: Forty-two patients were identified. Median NIH Stroke Scale on admission was 21. The most prevalent symptoms were dyspnoea (81%), and pain (69%). Difficulties or inability to communicate because of aphasia or altered level of consciousness were present in 93% of patients. Pharmacological respiratory treatments consisted of anti-muscarinic drugs (52%), and opioids (33%). Pain was mainly treated by opioids (69%). During the last 48 h of life, 81% of patients were free of pain and 48% of respiratory distress. The main causes of death were neurological complications in 38% of patients, multiple medical complications in 36%, and specific medical causes in 26%. CONCLUSIONS: Patients dying from stroke and referred to a palliative care consult team have multiple symptoms, mainly dyspnoea and pain. Studies are warranted to develop specific symptoms assessment tools in non-verbal stroke patients, to accurately assess patients' needs, and to measure effectiveness of palliative treatments.

Impact of duration of untreated psychosis on pre-treatment, baseline, and outcome characteristics in an epidemiological first-episode psychosis cohort.

INTRODUCTION: To assess the impact of duration of untreated psychosis (DUP) on baseline and 18-month follow-up characteristics controlling for relevant confounders in an epidemiological first-episode psychosis (FEP) cohort. METHOD: The Early Psychosis Prevention and Intervention Centre (EPPIC) in Australia admitted 786 FEP patients from January 1998 to December 2000. Data were collected from medical files using a standardized questionnaire. Data from 636 patients were analyzed. RESULTS: Median DUP was 8.7 weeks. Longer DUP was associated with worse premorbid functioning (p<0.001), higher rate of schizophrenia-spectrum disorders (p<0.001), and younger age at onset of psychosis (p=0.004). Longer DUP was not associated with baseline variables but with a lower rate of remission of positive symptoms (p<0.001) and employment/occupation (p<0.001), a higher rate of persistent substance use (p=0.015), worse illness severity (p<0.001) and global functioning (p<0.001) at follow-up after controlling for relevant confounders, explaining approximately 5% of variance of remission of positive symptoms (p<0.001) in the total sample and 3% in schizophrenia-spectrum disorders excluding bipolar I disorder (p=0.002). Outcome was significantly worse when DUP exceeded 1-3 months. CONCLUSION: Avoiding pitfalls of non-epidemiological studies, DUP appears to be a modest independent predictor of prognosis in the medium-term. Results support the need for assertive early detection strategies.

Patterns of practice of regional nodal irradiation in breast cancer: results of the European Organization for Research and Treatment of Cancer (EORTC) NOdal Radiotherapy (NORA) survey.

BACKGROUND: Predicting outcome of breast cancer (BC) patients based on sentinel lymph node (SLN) status without axillary lymph node dissection (ALND) is an area of uncertainty. It influences the decision-making for regional nodal irradiation (RNI). The aim of the NORA (NOdal RAdiotherapy) survey was to examine the patterns of RNI. METHODS: A web-questionnaire, including several clinical scenarios, was distributed to 88 EORTC-affiliated centers. Responses were received between July 2013 and January 2014. RESULTS: A total of 84 responses were analyzed. While three-dimensional (3D) radiotherapy (RT) planning is carried out in 81 (96%) centers, nodal areas are delineated in only 51 (61%) centers. Only 14 (17%) centers routinely link internal mammary chain (IMC) and supraclavicular node (SCN) RT indications. In patients undergoing total mastectomy (TM) with ALND, SCN-RT is recommend by 5 (6%), 53 (63%) and 51 (61%) centers for patients with pN0(i+), pN(mi) and pN1, respectively. Extra-capsular extension (ECE) is the main factor influencing decision-making RNI after breast conserving surgery (BCS) and TM. After primary systemic therapy (PST), 49 (58%) centers take into account nodal fibrotic changes in ypN0 patients for RNI indications. In ypN0 patients with inner/central tumors, 23 (27%) centers indicate SCN-RT and IMC-RT. In ypN1 patients, SCN-RT is delivered by less than half of the centers in patients with ypN(i+) and ypN(mi). Twenty-one (25%) of the centers recommend ALN-RT in patients with ypN(mi) or 1-2N+ after ALND. Seventy-five (90%) centers state that age is not considered a limiting factor for RNI. CONCLUSION: The NORA survey is unique in evaluating the impact of SLNB/ALND status on adjuvant RNI decision-making and volumes after BCS/TM with or without PST. ALN-RT is often indicated in pN1 patients, particularly in the case of ECE. Besides the ongoing NSABP-B51/RTOG and ALLIANCE trials, NORA could help to design future specific RNI trials in the SLNB era without ALND in patients receiving or not PST.

Optimizing the Anti-VEGF Treatment Strategy for Neovascular Age-Related Macular Degeneration: From Clinical Trials to Real-Life Requirements.

NlmCategory="UNASSIGNED">This Perspective discusses the pertinence of variable dosing regimens with anti-vascular endothelial growth factor (VEGF) for neovascular age-related macular degeneration (nAMD) with regard to real-life requirements. After the initial pivotal trials of anti-VEGF therapy, the variable dosing regimens pro re nata (PRN), Treat-and-Extend, and Observe-and-Plan, a recently introduced regimen, aimed to optimize the anti-VEGF treatment strategy for nAMD. The PRN regimen showed good visual results but requires monthly monitoring visits and can therefore be difficult to implement. Moreover, application of the PRN regimen revealed inferior results in real-life circumstances due to problems with resource allocation. The Treat-and-Extend regimen uses an interval based approach and has become widely accepted for its ease of preplanning and the reduced number of office visits required. The parallel development of the Observe-and-Plan regimen demonstrated that the future need for retreatment (interval) could be reliably predicted. Studies investigating the observe-and-plan regimen also showed that this could be used in individualized fixed treatment plans, allowing for dramatically reduced clinical burden and good outcomes, thus meeting the real life requirements. This progressive development of variable dosing regimens is a response to the real-life circumstances of limited human, technical, and financial resources. This includes an individualized treatment approach, optimization of the number of retreatments, a minimal number of monitoring visits, and ease of planning ahead. The Observe-and-Plan regimen achieves this goal with good functional results. Translational Relevance: This perspective reviews the process from the pivotal clinical trials to the development of treatment regimens which are adjusted to real life requirements. The article discusses this translational process which- although not the classical interpretation of translation from fundamental to clinical research, but a subsequent process after the pivotal clinical trials - represents an important translational step from the clinical proof of efficacy to optimization in terms of patients' and clinics' needs. The related scientific procedure includes the exploration of the concept, evaluation of security, and finally proof of efficacy.

Helical tomotherapy for the treatment of anal canal cancer: a dosimetric comparison with 3D conformal radiotherapy.

AIMS AND BACKGROUND: The standard treatment of anal canal cancer (ACC) is combined chemotherapy and radiation therapy (RT), which is complex because of the shape of the target volumes and the need to minimize the irradiation of normal pelvic structures. In this study we compared the dosimetric results of helical tomotherapy (HT) plans with traditional 3D conformal RT (3DRT) plans for the treatment of ACC. METHODS AND STUDY DESIGN: Twelve patients (median age 57 years, range 38-83; F/M 8/4) treated with HT and concurrent chemotherapy for locally advanced ACC were selected. All had histologically confirmed squamous-cell carcinoma. A clinical target volume including the tumor and pelvic and inguinal lymph nodes was treated with HT to a total dose of 36 Gy in 1.8-Gy daily fractions. Then a sequential boost of 23.4 Gy in 1.8-Gy daily fractions (total dose 59.4 Gy) was delivered to the tumor and involved nodes. For all 12 patients, 3DRT plans were generated for comparison. Treatment plans were evaluated by means of standard dose-volume histograms. Dose coverage of the planning target volumes (PTVs), homogeneity index (HI), and mean doses to organs at risk (OARs) were compared. RESULTS: The coverage of PTV was comparable between the two treatment plans. HI was better in the HT vs. 3DRT plans (1.25 and 3.57, respectively; p<0.0001). HT plans resulted in better sparing of OARs (p<0.0001). CONCLUSIONS: HT showed superior target dose conformality and significant sparing of pelvic structures compared with 3DRT. Further investigation should determine if these dosimetric improvements will improve clinical outcomes regarding locoregional control, survival, and treatment-related acute and late morbidity.

Making SENSE - Sustained Effort Network for treatment of Status Epilepticus as a multicenter prospective registry.

BACKGROUND: Evidence regarding the different treatment options of status epilepticus (SE) in adults is scarce. Large randomized trials cover only one treatment at early stage and suggest the superiority of benzodiazepines over placebo, of intravenous lorazepam over intravenous diazepam or over intravenous phenytoin alone, and of intramuscular midazolam over intravenous lorazepam. However, many patients will not be treated successfully with the first treatment step. A large randomized trial covering the treatment of established status (ESETT) has just been funded recently by the NIH and will not start before 2015, with expected results in 2018; a trial on the treatment of refractory status with general anesthetics was terminated early due to insufficient recruitment. Therefore, a prospective multicenter observational registry was set up; this may help in clinical decision-making until results from randomized trials are available. METHODS/DESIGN: SENSE is a prospective, multicenter registry for patients treated for SE. The primary objective is to document patient characteristics, treatment modalities and in-house outcome of consecutive adults admitted for SE treatment in each of the participating centres and to identify predictors of outcome. Pre-treatment, treatment-related and outcome variables are documented systematically. To allow for meaningful multivariate analysis in the patient subgroups with refractory SE, a cohort size of 1000 patients is targeted. DISCUSSION: The results of the study will provide information about risks and benefits of specific treatment steps in different patient groups with SE at different points of time. Thus, it will support clinical decision-making and, furthermore, it will be helpful in the planning of treatment trials. TRIAL REGISTRATION: DRKS00000725.

Undergraduate palliative care teaching in Swiss medical faculties: a nationwide survey and improved learning objectives.

BACKGROUND: In 2007, a first survey on undergraduate palliative care teaching in Switzerland has revealed major heterogeneity of palliative care content, allocation of hours and distribution throughout the 6 year curriculum in Swiss medical faculties. This second survey in 2012/13 has been initiated as part of the current Swiss national strategy in palliative care (2010 - 2015) to serve as a longitudinal monitoring instrument and as a basis for redefinition of palliative care learning objectives and curriculum planning in our country. METHODS: As in 2007, a questionnaire was sent to the deans of all five medical faculties in Switzerland in 2012. It consisted of eight sections: basic background information, current content and hours in dedicated palliative care blocks, current palliative care content in other courses, topics related to palliative care presented in other courses, recent attempts at improving palliative care content, palliative care content in examinations, challenges, and overall summary. Content analysis was performed and the results matched with recommendations from the EAPC for undergraduate training in palliative medicine as well as with recommendations from overseas countries. RESULTS: There is a considerable increase in palliative care content, academic teaching staff and hours in all medical faculties compared to 2007. No Swiss medical faculty reaches the range of 40 h dedicated specifically to palliative care as recommended by the EAPC. Topics, teaching methods, distribution throughout different years and compulsory attendance still differ widely. Based on these results, the official Swiss Catalogue of Learning Objectives (SCLO) was complemented with 12 new learning objectives for palliative and end of life care (2013), and a national basic script for palliative care was published (2015). CONCLUSION: Performing periodic surveys of palliative care teaching at national medical faculties has proven to be a useful tool to adapt the national teaching framework and to improve the recognition of palliative medicine as an integral part of medical training.

Identification of imaging selection patterns in acute ischemic stroke patients and the influence on treatment and clinical trial enrollment decision making.

BACKGROUND AND PURPOSE: For the STroke Imaging Research (STIR) and VISTA-Imaging Investigators The purpose of this study was to collect precise information on the typical imaging decisions given specific clinical acute stroke scenarios. Stroke centers worldwide were surveyed regarding typical imaging used to work up representative acute stroke patients, make treatment decisions, and willingness to enroll in clinical trials. METHODS: STroke Imaging Research and Virtual International Stroke Trials Archive-Imaging circulated an online survey of clinical case vignettes through its website, the websites of national professional societies from multiple countries as well as through email distribution lists from STroke Imaging Research and participating societies. Survey responders were asked to select the typical imaging work-up for each clinical vignette presented. Actual images were not presented to the survey responders. Instead, the survey then displayed several types of imaging findings offered by the imaging strategy, and the responders selected the appropriate therapy and whether to enroll into a clinical trial considering time from onset, clinical presentation, and imaging findings. A follow-up survey focusing on 6 h from onset was conducted after the release of the positive endovascular trials. RESULTS: We received 548 responses from 35 countries including 282 individual centers; 78% of the centers originating from Australia, Brazil, France, Germany, Spain, United Kingdom, and United States. The specific onset windows presented influenced the type of imaging work-up selected more than the clinical scenario. Magnetic Resonance Imaging usage (27-28%) was substantial, in particular for wake-up stroke. Following the release of the positive trials, selection of perfusion imaging significantly increased for imaging strategy. CONCLUSIONS: Usage of vascular or perfusion imaging by Computed Tomography or Magnetic Resonance Imaging beyond just parenchymal imaging was the primary work-up (62-87%) across all clinical vignettes and time windows. Perfusion imaging with Computed Tomography or Magnetic Resonance Imaging was associated with increased probability of enrollment into clinical trials for 0-3 h. Following the release of the positive endovascular trials, selection of endovascular only treatment for 6 h increased across all clinical vignettes.

Nouveautés et perspectives dans la prise en charge des cancers colorectaux et gastriques avancés [News and perspectives in the treatment of advanced gastric and colorectal cancers].

Colorectal and gastric cancers are the fourth and third leading causes of cancer death world-wide. Unfortunately, gastric cancer is usually diagnosed at an advanced stage after becoming metastatic in distant sites, so that palliative therapy is the mainstay of treatment. Major progress in the understanding of the biology, the development of valid biomarkers and molecular targeted drugs have improved the treatment options and prognosis of both cancers significantly in the last years. Here, we review the current standards of care for patients with advanced and metastatic colorectal and gastric cancer and outline the perspectives for the future.

Listening to parents: The role of symptom perception in pediatric palliative home care.

OBJECTIVE: This study analyzes symptom perception by parents and healthcare professionals and the quality of symptom management in a pediatric palliative home care setting and identifies which factors contribute to a high quality of palliative and end-of-life care for children. METHODS: In this retrospective, cross-sectional study, parents were surveyed at the earliest three months after their child's death. All children were cared for by a specialized home pediatric palliative care team that provides a 24/7 medical on-call service. Questionnaires assessed symptom prevalence and intensity during the child's last month of life as perceived by parents, symptom perception, and treatment by medical staff. The responses were correlated with essential palliative care outcome measures (e.g., satisfaction with the care provided, quality-of-life of affected children and parents, and peacefulness of the dying phase). RESULTS: Thirty-eight parent dyads participated (return rate 84%; 35% oncological disorders). According to parental report, dyspnea (61%) and pain (58%) were the dominant symptoms with an overall high symptom load (83%). Pain, agitation, and seizures could be treated more successfully than other symptoms. Successful symptom perception was achieved in most cases and predicted the quality of symptom treatment (R 2, 0.612). Concordant assessment of symptom severity between parents and healthcare professionals (HCPs) improved the satisfaction with the care provided (p = 0.037) as well as the parental quality-of-life (p = 0.041). Even in cases with unsuccessful symptom control, parents were very satisfied with the SHPPC team's care (median 10; numeric rating scale 0-10) and rated the child's death as highly peaceful (median 9). Significance of the results: The quality and the concordance of symptom perception between parents and HCPs essentially influence parental quality-of-life as well as parental satisfaction and constitute a predictive factor for the quality of symptom treatment and palliative care.