Achim Wöckel

Standard treatment of female patients with breast cancer decreases substantially for women aged 70 years and older: a German clinical cohort study

BACKGROUND Standard treatment of patients with breast cancer decreases with age and older persons are mostly excluded from clinical trials. We hypothesized that non-adherence to treatment guidelines occurs for women aged > or =70 years and changes overall survival (OAS) and disease-free survival (DFS). PATIENTS AND METHODS We enrolled 1922 women aged > or =50 years with histologically confirmed invasive breast cancer treated at the University of Ulm from 1992 to 2005. Adherence to guidelines and effects on OAS and DFS for women aged > or =70 years was compared with that for younger women (50-69 years). RESULTS Women >70 years less often received recommended breast-conserving therapy (70-79 years: 74%-83%; >79 years: 54%) than women aged < or =69 years (93%). Non-adherence to the guidelines on radiotherapy (<70 years: 9%; 70-79 years: 14%-27%; >79 years: 60%) and chemotherapy (<70 years: 33%; 70-79 years: 54%-77%; > 79 years: 98%) increased with age. Omission of radiotherapy significantly decreased OAS [< or =69 years: hazard ratio (HR) = 3.29; P <0.0001; > or =70 years: HR = 1.89; P = 0.0005] and DFS (< or =69 years: HR = 3.45; P <0.0001; > or =70 years: HR = 2.14; P <0.0001). OAS and DFS did not differ significantly for adherence to surgery, chemotherapy, or endocrine therapy. CONCLUSION Our study confirms that substandard treatment increases considerably with age. Omission of radiotherapy had the greatest impact on OAS and DFS in the elderly population.

Survival of patients with bilateral versus unilateral breast cancer and impact of guideline adherent adjuvant treatment: a multi-centre cohort study of 5292 patients.

UNLABELLED This retrospective multi-centre study is focussed on recurrence free and overall survival of bilateral breast cancer (BBC) versus unilateral breast cancer (UBC). The impact of BBC on survival is stratified to guideline adherence, according to the German national S3-guideline. Another aim of the study is to identify the influence of various guideline violations in adjuvant treatment on survival of BBC patients. 229 (4.3%) patients had BBC and 5063 (95.7%) had UBC. There is a significant association between BBC/UBC and recurrence free (RFS: p < 0.001) and overall survival (OAS: p = 0.003). Only 15.7% of patients with BBC are treated 100% guideline adherent (index- + contralateral tumour). 31.0% (30.5%) were guideline adherent with respect to the index (contralateral) tumour. The outcome decreases significantly with the number of guideline violations. There was no significant difference in RFS and OAS between BBC and UBC after adjusting for tumour size, nodal status, grading and if guideline adherent treatment was applied. CONCLUSION 1. Patients with BBC have primarily a worse prognosis in terms of RFS and OAS than patients with primarily UBC. 2. There is a strong association between guideline adherence and RFS/OAS of patients with BBC or UBC. The outcome decreases with the number of guideline violations. 3. If guideline adherent treatment was applied (for both tumours in case of BBC) there was no significant difference in RFS and OAS between BBC and UBC after adjusting for tumour size, nodal status, grading.

Sentinel lymph node dissection only versus complete axillary lymph node dissection in early invasive breast cancer: A systematic review and meta-analysis

BACKGROUND The Z0011-study, a landmark randomised controlled trial (RCT) challenged the benefits of complete axillary lymph node dissection (ALND) compared with sentinel lymph node dissection only (SLND) in breast cancer patients with positive sentinel nodes. The study, however, has been criticised for lack of power and low applicability. The aim of this review was to systematically assess the evidence on the comparative benefits and harms of ALND versus SLND for sentinel node positive breast cancer patients. METHODS We systematically searched PubMed, Embase, the Cochrane Library, and reference lists of pertinent review articles from January 2006 to August 2011. We dually reviewed the literature and rated the risk of bias of each study. For effectiveness, we included RCTs and observational studies of at least 1 year follow-up. In addition, we considered studies conducted in sentinel node-negative women to assess the risk of harms. If data were sufficient, we conducted random effects meta-analysis of outcomes of interest. RESULTS Meta-analysis of three studies with 50,120 patients indicated similar 5-year survival and regional recurrence rates between patients treated with ALND or SLND, although prognostic tumour characteristics varied among the 3 study-populations. Results from 6 studies on more than 11,500 patients reported a higher risk for harms for ALND than SLND. Long-term evidence on pertinent health outcomes is missing. CONCLUSION The available evidence indicates that for some women with early invasive breast cancer SLND appears to be a justifiable alternative to ALND. Surgeons need to discuss advantages and disadvantages of both approaches with their patients.

German National Consensus Recommendations on Nutrition and Lifestyle in Pregnancy by the 'Healthy Start - Young Family Network'

Diet and physical activity before and during pregnancy affect short- and long-term health of mother and child. The energy needs at the end of pregnancy increase only by about 10% compared to nonpregnant women. An excessive energy intake is undesirable since maternal overweight and excessive weight gain can increase the risks for a high birth weight and later child overweight and diabetes. Maternal weight at the beginning of pregnancy is especially important for pregnancy outcome and child health. Women should strive to achieve normal weight already before pregnancy. Regular physical activity can contribute to a healthy weight and to the health of pregnant women. The need for certain nutrients increases more than energy requirements. Before and during pregnancy, foods with a high content of essential nutrients should be preferentially selected. Supplements should include folic acid and iodine, iron (in case of suboptimal iron stores), the ω-3 fatty acid docosahexaenoic acid (in case of infrequent consumption of ocean fish) and vitamin D (in case of decreased sun exposure and decreased endogenous vitamin D synthesis). Pregnant women should not smoke and not stay in rooms where others smoke or have smoked before (passive smoking). Alcohol consumption should be avoided, since alcohol can harm unborn children.

A comparison of international breast cancer guidelines – Do the national guidelines differ in treatment recommendations?

AIM OF THE STUDY Clinical practice guidelines (CPG) are an appropriate method to optimise routine clinical care. Numerous CPGs for the diagnosis and treatment of breast cancer have been developed by national health institutions or medical societies. While a comparison of methodological criteria has been undertaken before, it is unknown whether these CPGs differ in their actual treatment recommendations. METHODS We included national breast cancer CPGs from the USA, Canada, Australia, the UK, and Germany that satisfy internationally recognised methodological criteria and are in widespread use in daily clinical care. Treatment recommendations for adjuvant invasive breast cancer including surgery, radiation, endocrine therapy, chemotherapy and anti-HER2-therapy were compared. RESULTS Recommendations for endocrine therapy show discordances regarding optimal usage of ovarian function suppression for premenopausal patients and aromatase inhibitors for postmenopausal patients. However, most other treatment recommendations exhibit a large degree of congruency. This reflects the fact that they rest on the same evidence base, and that many national guidelines are adopted from other guidelines so that well accepted guidelines are cited within other guidelines. CONCLUDING STATEMENT Considering that the development of guidelines is a very expensive and resource-intensive task the question arises whether the development of national guidelines in numerous countries is worth the effort since the recommendations differ only marginally.

Adherence to treatment guidelines and survival in triple-negative breast cancer: a retrospective multi-center cohort study with 9156 patients

BackgroundTriple-negative breast cancer (TNBC) remains a challenging topic for clinical oncologists. This study sought to evaluate TNBC versus other breast cancer subtypes with respect to survival parameters. We evaluated possible differences in survival in TNBC by age and by the extent to which evidence-based treatment guidelines were adhered.MethodsThis German retrospective multi-center cohort study included 9156 patients with primary breast cancer recruited from 1992 to 2008.ResultsThe rates of guideline adherence are significantly lower in TNBC compared to non-TNBC subtypes. These lower rates of guideline adherence can be observed in all age groups and are most pronounced in the >65 subgroup [<50 (20.9% vs. 42.0%), 50–64 (25.1% vs. 51.1%), and >65 (38.4% vs. 74.6%)]. In TNBC patients of all age groups, disease-free survival and overall survival were associated with an improvement by 100% guideline-adherent adjuvant treatment compared to non-adherence. Furthermore, TNBC patients of all ages had similar outcome parameters if 100% guideline-adherent adjuvant treatment was applied.ConclusionThe rates of guideline-adherent treatment were significantly lower in TNBC, even though guideline adherence was strongly associated with improved survival. In the case of 100% guideline-adherent treatment, no difference in survival was observed over all the age groups examined, even in the group of >65-year-old TNBC patients.

First Revision of the German S3 Guideline ‘Diagnosis, Therapy, and Follow-Up of Breast Cancer’

The development and implementation of evidence-based, interdisciplinary, consensus-based guidelines is a very important step towards decreasing breast cancer mortality and optimizing the process of early detection, diagnosis, therapy, and follow-up of breast cancer. A revised version of the German S3 guideline was published in February 2008. Different working groups, departments, and organizations participate as coeditors of the new guideline. To fulfill international methodic requirements, a systematic search of the literature with selection of new publications (used as evidence) in the established data bases (Medline, BIOSIS, Previews, CDSR, ACP Journal Club, DARE, CCTR, CINHAL) and the Guidelines International Network (GIN) was performed for the time period of 2003–2006. Varied specialist opinions concerning diagnosis, therapy, and follow-up of breast cancer were considered in formal consensus processes. In different steps, Nominal Group Process techniques, the Delphi technique, and formal consensus processes were used. Besides differently weighted, study-based recommendations, statements resulting from structured consensus finding by the interdisciplinary group – in terms of good clinical practice – were postulated.

Adenosine-generating ovarian cancer cells attract myeloid cells which differentiate into adenosine-generating tumor associated macrophages - a self- amplifying, CD39- and CD73-dependent mechanism for tumor immune escape

BackgroundOvarian cancer (OvCA) tissues show abundant expression of the ectonucleotidases CD39 and CD73 which generate immunomodulatory adenosine, thereby inhibiting cytotoxic lymphocytes. Little, however, is known about the effect of adenosine on myeloid cells. Considering that tumor associated macrophages (TAM) and myeloid-derived suppressor cells (MDSC) constitute up to 20 % of OvCA tissue, we investigated the effect of adenosine on myeloid cells and explored a possible contribution of myeloid cells to adenosine generation in vitro and ex vivo.MethodsMonocytes were used as human blood-derived myeloid cells. After co-incubation with SK-OV-3 or OAW-42 OvCA cells, monocyte migration was determined in transwell assays. For conversion into M2-polarized “TAM-like” macrophages, monocytes were co-incubated with OAW-42 cells. Ex vivo TAMs were obtained from OvCA ascites. Macrophage phenotypes were investigated by intracellular staining for IL-10 and IL-12. CD39 and CD73 expression were assessed by FACS analysis both on in vitro-induced TAM-like macrophages and on ascites-derived ex situ-TAMs. Myeloid cells in solid tumor tissue were analyzed by immunohistochemistry. Generation of biologically active adenosine by TAM-like macrophages was measured in luciferase-based reporter assays. Functional effects of adenosine were investigated in proliferation-experiments with CD4+ T cells and specific inhibitors.ResultsWhen CD39 or CD73 activity on OvCA cells were blocked, the migration of monocytes towards OvCA cells was significantly decreased. In vivo, myeloid cells in solid ovarian cancer tissue were found to express CD39 whereas CD73 was mainly detected on stromal fibroblasts. Ex situ-TAMs and in vitro differentiated TAM-like cells, however, upregulated the expression of CD39 and CD73 compared to monocytes or M1 macrophages. Expression of ectonucleotidases also translated into increased levels of biologically active adenosine. Accordingly, co-incubation with these TAMs suppressed CD4+ T cell proliferation which could be rescued via blockade of CD39 or CD73.ConclusionAdenosine generated by OvCA cells likely contributes to the recruitment of TAMs which further amplify adenosine-dependent immunosuppression via additional ectonucleotidase activity. In solid ovarian cancer tissue, TAMs express CD39 while CD73 is found on stromal fibroblasts. Accordingly, small molecule inhibitors of CD39 or CD73 could improve immune responses in ovarian cancer.

Impact of Guideline Conformity on Breast Cancer Therapy: Results of a 13-Year Retrospective Cohort Study

Background: To date, few studies have investigated whether the implementation of national breast cancer guidelines fulfills the goal to optimize the national standard of care. Therefore, we aimed to evaluate retrospectively the guideline-related 13-year data on breast cancer patients treated at our institution. Patients and Methods: In a retrospective cohort study, the records of a total of 2,231 patients with primary breast cancer treated during the period of 1992–2005 at the Department of Obstetrics and Gynecology, University of Ulm, Germany, were analyzed. Based on the German national Step 3 (S3) guideline, a model was created to classify groups according to therapy ‘conforming’ and ‘non-conforming’ to guideline recommendations. Results: In 2005, 70.2% of all patients included received both surgical and systemic adjuvant therapies conforming to the guideline. Guideline-conforming treatment was accompanied with significant advantages in terms of recurrence-free survival (RFS) and overall survival (OAS) rates. Conclusions: It has to be demanded that breast cancer patients are treated in con-formity with the S3 guidelines. The reasons for a treatment not conforming to the guidelines should be analyzed for the detection of barrier factors, in order to optimize adherence to the guidelines and therefore to prolong RFS and OAS.

Pooled analysis of the prognostic relevance of progesterone receptor status in five German cohort studies

The progesterone receptor (PR) has been increasingly well described as an important mediator of the pathogenesis and progression of breast cancer. The aim of this study was to assess the role of PR status as a prognostic factor in addition to other well-established prognostic factors. Data from five independent German breast cancer centers were pooled. A total of 7,965 breast cancer patients were included for whom information about their PR status was known, as well as other patient and tumor characteristics commonly used as prognostic factors. Cox proportional hazards models were built to compare the predictive value of PR status in addition to age at diagnosis, tumor size, nodal status, grading, and estrogen receptor (ER) status. PR status significantly increased the accuracy of prognostic predictions with regard to overall survival, distant disease-free survival, and local recurrence-free survival. There were differences with regard to its prognostic value relative to subgroups such as nodal status, ER status, and grading. The prognostic value of PR status was greatest in patients with a positive nodal status, negative ER status, and low grading. The PR-status adds prognostic value in addition to ER status and should not be omitted from clinical routine testing. The significantly greater prognostic value in node-positive and high-grade tumors suggests a greater role in the progression of advanced and aggressive tumors.