Impact of patients' refusal to undergo adjuvant treatment measures on survival.

PURPOSE: Breast cancer patients receive treatment recommendations from multidisciplinary tumour boards. To determine the consequences of patients' refusal of such recommendations, we analysed the database of the Centre for Breast Cancer at the Ortenau Clinic in Offenburg, Germany. METHODS: A total of 4315 patients with non-metastatic primary breast cancer, treated between 1997 and 2019, were analysed with descriptive analyses, Kaplan-Meier survival analyses, and Cox regression analyses regarding the effects of their refusal. RESULTS: About 10.7% of the patients rejected the treatment advice. These were significantly elderly (F = 74.4; p < 0.001; one-way ANOVA), with greater tumour size (F = 36.7; p < 0.001; one-way ANOVA), a higher number of affected lymph nodes (F = 4.2; p = .039; one-way ANOVA), and more poorly differentiated tumours (χ2 = 16.8; df = 2; p < 0.001). The refusal of adjuvant treatment resulted in higher rates of local recurrences (χ2radiotherapy = 109.1; df = 1; p < 0.001, χ2chemotherapy = 18.3; df = 1; p < 0.001, χ2endocrine = 32.5; df = 1; p < 0.001) and poorer overall survival (χ2radiotherapy = 184.9; df = 6; p < 0.001; χ2chemotherapy = 191.8; df = 6; p < 0.001). CONCLUSIONS: All parts of the adjuvant treatment of breast cancer are clearly associated with improvements regarding disease-free and overall survival. To answer open questions about the background of patients' refusal, an analysis of prospective data collections seems necessary. In addition, patient communication should be improved so that patients understand the background of the multidisciplinary tumour board and the potential consequences of their refusal.

[Integration of the radiotherapy irradiation planning in the digital workflow]. / Integration der Bestrahlungsplanung in den volldigitalen Workflow.

BACKGROUND AND PURPOSE: At the Clinic of Radiotherapy at the University Hospital Freiburg, all relevant workflow is paperless. After implementing the Operating Schedule System (OSS) as a framework, all processes are being implemented into the departmental system MOSAIQ. Designing a digital workflow for radiotherapy irradiation planning is a large challenge, it requires interdisciplinary expertise and therefore the interfaces between the professions also have to be interdisciplinary. For every single step of radiotherapy irradiation planning, distinct responsibilities have to be defined and documented. All aspects of digital storage, backup and long-term availability of data were considered and have already been realized during the OSS project. METHOD: After an analysis of the complete workflow and the statutory requirements, a detailed project plan was designed. In an interdisciplinary workgroup, problems were discussed and a detailed flowchart was developed. The new functionalities were implemented in a testing environment by the Clinical and Administrative IT Department (CAI). After extensive tests they were integrated into the new modular department system. RESULTS AND CONCLUSION: The Clinic of Radiotherapy succeeded in realizing a completely digital workflow for radiotherapy irradiation planning. During the testing phase, our digital workflow was examined and afterwards was approved by the responsible authority.

Stereotactic ablative radiotherapy for small lung tumors with a moderate dose. Favorable results and low toxicity.

BACKGROUND: Stereotactic ablative body radiotherapy (SBRT, SABR) is being increasingly applied because of its high local efficacy, e.g., for small lung tumors. However, the optimum dosage is still under discussion. Here, we report data on 45 lung lesions [non-small cell lung cancer (NSCLC) or metastases] in 39 patients treated between 2009 and 2010 by SABR. PATIENTS AND METHODS: SABR was performed with total doses of 35 Gy (5 fractions) or 37.5 Gy (3 fractions) prescribed to the 60% isodose line encompassing the planning target volume. Three-monthly follow-up CT scans were supplemented by FDG-PET/CT if clinically indicated. RESULTS: The median follow-up was 17 months. Local progression-free survival rates were 90.5% (all patients), 95.0% (NSCLC), and 81.8% (metastases) at 1 year. At 2 years, the respective local progression-free survival rates were 80.5%, 95.0%, and 59.7%. Overall survival rates were 71.1% (all patients), 65.4% (NSCLC), and 83.3% (metastases) at 1 year. Overall survival rates at 2 years were 52.7%, 45.9%, and 66.7%, respectively. Acute side effects were mild. CONCLUSION: With the moderate dose schedule used, well-tolerated SABR led to favorable local tumor control as in other published series. Standardization in reporting the dose prescription for SABR is needed to allow comparison of different series in order to determine optimum dosage.

Stereotactic radiotherapy in the liver hilum. Basis for future studies.

BACKGROUND: A basis for future trials with stereotactic body radiotherapy (SBRT) for tumors of the liver hilum should be established. Thus, dosage concepts, planning processes, and dose constraints as well as technical innovations are summarized in this contribution. METHODS: On the background of our own data, the current literature was reviewed. The use of SBRT in the most common tumors of the liver hilum (pancreatic cancer and Klatskin tumors) was investigated. Dose constraints were calculated in 2 Gy standard fractionation doses. RESULTS: A total of 8 pilot or phase I/II studies about SBRT in the liver hilum were identified. In recent years, the SBRT technique has developed very quickly from classical stereotactic body frame radiotherapy to IGRT techniques including gating and tracking systems. In the studies using classical body frame technique, patients experienced considerable toxicities (duodenal ulcer/perforation) as compared to tolerable side effects in IGRT studies (<10% grade 3 and 4 toxicities). Dose constraints for duodenum, liver, kidneys, colon, and spinal cord were derived from the investigated studies. Survival and local tumor control data are very heterogeneous: median survival in these patients with locally advanced pancreatic or Klatskin tumors ranges between 5 and 32 months. Excellent local tumor control rates of about 80% over 24 months were achieved using SBRT. CONCLUSION: Despite a few negative results, SBRT seems to be a promising technique in the treatment of tumors of the liver hilum. Highest precision in diagnostics, positioning, and irradiation as well as strict dose constraints should be applied to keep target volumes as small as possible and side effects tolerable.

[Xerostomia. Improved care using a spray with herbal polysaccharides]. / Xerostomie. Verbesserte Linderung durch ein Spray mit pflanzlichen Polysacchariden.

BACKGROUND: In a prospective clinical study the topical use of a polysaccharide-containing spray for the treatment of xerostomia after radiotherapy in the head and neck area was tested. PATIENTS AND METHODS: A total of 83 patients (evaluable return: n=55) with xerostomia after radiotherapy in the head and neck area received a pump spray with 50 ml Saliva natura (medac, Wedel, Germany) to test for 1 week. The patients were asked to fill in a questionnaire about their xerostomia with and without use of the spray. Individual items included: xerostomia in the state of rest, difficulties speaking, eating and sleeping, frequency of the use of treatment against xerostomia, changes in taste, and saliva viscosity. Additionally, they assessed the spray in general and for taste. RESULTS: Patients reported an improvement in all areas included in the questionnaire. The greatest effect of the spray was seen in sleeping difficulties, which improved by almost a whole point from 3.65 to 2.67, as well as in the frequency of use of xerostomia treatment (averagely 15x/day without and 10x/day with the spray). On average the spray was graded as "satisfactory" (3.09), while its taste was graded as "good" (2.17). CONCLUSION: The tested spray may help improve the situation of patients with xerostomia following radiotherapy in the head and neck area. These patients should be given the opportunity to test a spray of this kind.

Blood hemoglobin level may affect radiosensitivity-preliminary results on acutely reacting normal tissues.

PURPOSE: To evaluate the influence of blood hemoglobin concentration on the radiosensitivity of acutely reacting normal tissues. METHODS AND MATERIALS: Weekly scores (EORTC/RTOG criteria) for acute reactions of skin and mucosa are available for 60 patients with cancer of the head and neck undergoing a standard conventional radiotherapy. The prognostic significance of blood hemoglobin levels on the development of acute reactions is studied by multivariate analysis (Cox Proportional Hazards Model). Further, the incidence and the time to development of these reactions is looked at in cohorts of patients with different mean blood hemoglobin concentrations during radiotherapy. Patients are therefore classified into a "severely anemic group" (hemoglobin < 11.0 g/100 mL), and into a cohort with a blood hemoglobin value equal or above 11.0 g/100 mL. RESULTS: Normal tissue scoring and monitoring of blood hemoglobin levels allows for a detailed analysis of possible correlations. A decrease in the mean blood hemoglobin value of 1 g/100 mL predicts a reduced risk to develop a skin reaction of Grade 2 or 3 (RR = 0.9; p = 0.08; RR = 0.8; p = 0.26, respectively) or a mucosa reaction of Grade 3 (RR = 0.8; p = 0.16), independent from the radiation dose, the treatment time and from previous surgery within the radiation volume (multivariate analysis). Likewise, patients with severe anemia develop grade 3 mucositis or dermatitis less often (0%; 13%) as compared to those with blood hemoglobin concentrations equal or above 11.0 g/100 mL (21%; 19%). Skin and mucosa reactions further tend to occur later in the course of radiation. The observations are not statistically significant and possible reasons will be discussed. CONCLUSIONS: A decreased blood hemoglobin concentration may-perhaps by an impaired tissue oxygenation-reduce the radiosensitivity of normal tissue such as skin and mucosa. However, the data is preliminary and needs further confirmation.

Protective effect of amifostine on dental health after radiotherapy of the head and neck.

PURPOSE: The cytoprotective agent amifostine has been shown to reduce the radiation-induced acute and chronic xerostomia in head and neck cancer patients. The purpose of this study was to evaluate whether or not amifostine also reduces the incidence of dental caries associated with the radiation-induced xerostomia. METHODS AND MATERIALS: The dental status before and 1 year after radiotherapy was retrospectively compared in 35 unselected patients treated as part of the prospective randomized and multicenter open-label Phase III study (WR-38) at the University Hospitals of Heidelberg, Freiburg, and Erlangen. The WR-38 study compared radiotherapy in head and neck cancer with and without concomitant administration of amifostine. RESULTS: Patient and treatment characteristics (particularly the radiation dose and percentage of parotids included in the treatment volume) were equally distributed between the patients who received (n = 17) or did not receive (n = 18) amifostine. Fifteen patients of the amifostine group showed no deterioration of the dental status 1 year after radiotherapy as compared to 7 patients who did not receive the cytoprotector (p = 0. 015, two-tailed Fisher exact test). CONCLUSION: Our data suggest a protective effect of amifostine on the dental health after radiotherapy of the head and neck. The dental status should be used as a primary endpoint in future studies on amifostine.

Alteration of radiation-induced hematotoxicity by amifostine.

PURPOSE: To investigate whether amifostine can reduce radiation hematotoxicity. PATIENTS AND METHODS: Seventy-three patients undergoing radiotherapy for squamous cell carcinoma of the head and neck at the university clinics of Freiburg, Heidelberg, and Erlangen were evaluated. All received 60 Gy (50-70 Gy) at 5 x 2 Gy fractions per week employing standard techniques. Thirty-five were randomized to receive 200 mg/m(2) amifostine i.v. 30 min before radiation; 38 served as control patients. Blood counts (total n = 501) were determined before, during, and while completing radiotherapy. Changes of leukocyte, platelet, and hemoglobin levels were determined and compared using the t test. RESULTS: The blood hemoglobin level and the platelet count were not affected by irradiation, for either the amifostine-treated or control patients. Similarly, the leukocyte counts of amifostine-treated patients did not change during irradiation. However, control patients experienced a decrease in leukocyte count from 8.1 x 10(3)/mm(3) to 5.8 x 10(3)/mm(3) (difference: 2.3 x 10(3)/mm(3)). This seems to be line specific: Whereas amifostine does not affect lymphocyte count, a radiation-induced decrease of neutrophil granulocytes seems to be prevented. CONCLUSION: Amifostine protects from radiation hematotoxicity, particularly affecting the granulocytopoiesis. These data confirm results from our former study.

Is there any correlation between MDR1, GST-pi-expression and CEA?

BACKGROUND: The levels of mRNA-expression of multidrug resistance (MDR1) and glutathione-S-transferase pi (GST-pi) were measured and correlated with the immunohistochemical expressions of tumour markers. MATERIALS AND METHODS: Analysis of total mRNA was performed by Northern and slot blots. The expression of carcinoembryonic antigen (CEA) and other tumour markers was assessed by immunohistochemistry. The tumour panel comprised tumours of different histologies. RESULTS: CEA-positive tumours showed a significantly higher ex-pression of MDR1 and GST-pi than CEA-negative tumours. Wilcoxon-Test: mean rank of the MDR1 expression (14.3 vs. 7.8; p < 0.05) and GST-pi expression (15.3 vs. 5.9; p < 0.001). No other correlation could be found. CONCLUSIONS: The relationship of MDR1 and GST-pi with the tumour marker CEA implies that evaluation of CEA can help in discriminating between tumours with high or low expression of drug resistance. Furthermore, correlation between MDR1, GST-pi and CEA indicates that there might be a common mechanism, regulating drug resistance and expression of CEA.

Use of complementary and alternative medicine in breast cancer patients and their experiences: a cross-sectional study.

Complementary and Alternative Medicine (CAM) refers to various treatments not considered as part of conventional care. CAM is used by a high number of breast cancer patients. This is a cross-sectional study employing a validated questionnaire with the aim of studying CAM use and of exploring the needs of information and communication in female breast cancer patients. Experiences associated with discussing CAM within a conventional oncology setting were examined. Answers of patients not using CAM were also elicited. Predictors for CAM use were a higher degree of education and being of a younger age. The study demonstrated that patients were reluctant to initiate communication within standard oncology care. They rather relied on family and friends (49%), on the general practitioner (40%) or media sources (39%) for information. Reasons for not talking about CAM were not having been asked (25%) or not having perceived the inpatient physician to be the adequate person to talk to (11%). Reasons for not using CAM were mainly considering conventional therapy as sufficient (34%) and not having thought about CAM (31%). Particularly within conventional oncological care it is important to train physicians to have knowledge of supportive CAM options as this is what patients look for, but restrain from seeking within the speciality system.

[Palliative medicine content in German-language medical textbooks]. / Palliativmedizinische Inhalte in deutschsprachigen medizinischen Lehrbüchern.

BACKGROUND: There is a need for improved end-of-life care, especially in the light of demographic changes with an increased incidence of cancer. Although medical textbooks are central to the training of medical students and also serve as a reference for more experienced clinicians, only few data exist on the extent to which medical textbooks address end-of-life care. We analysed the quantity and quality of information on end-of-life care given in German textbooks on different medical disciplines. MATERIAL AND METHODS: 26 top-selling German medical textbooks were analysed for the presentation of end-of-life care in chapters that address the 13 most common causes of death worldwide RESULTS: In the 159 chapters analysed for information on traditional topics, like risk factors or early diagnosis (group A), such information was provided in 52% compared with only 9% on end-of-life topics, such as symptom management or manner of death (group B) (p=0.0001). There was no statistically significant difference between the different medical specialities (p=0.22). Line-by-line analysis showed that the phrase death or related terms was mentioned in only 57 of 159 chapters dealing with the most common causes of death worldwide. CONCLUSION: The top-selling German textbooks that were analysed generally offer little helpful information on end-of-life care of patients.

[Xerostomia after radiotherapy. More effective treatment by a mucin-containing spray?]. / Xerostomie nach Strahlentherapie. Effektivere Behandlung durch ein mucinhaltiges Spray?

INTRODUCTION: After radiotherapy (XRT) for head and neck tumors, xerostomia is observed as a chronic side effect. We investigated whether the topical use of a mucin-containing spray can help patients to cope with this problem. PATIENTS AND METHODS: A total of 73 patients with xerostomia post XRT received a bottle of the mucin spray (Saliva medac) and a questionnaire, 59 of which were completed and returned. RESULTS: All patients had received some form of prior treatment, which had been applied 16 times/day on average (median: 15 times/day). The mucin spray had to be used less frequently, i.e., 11 times/day (median: 5 times/day), (p < 0.001, Wilcoxon's rank test). Additionally, they reported being able to sleep significantly better when using the mucin spray (2.9 vs 3.9 in the German school grading system: 1 = very good, 6 = poor; p < 0.001, Wilcoxon's rank test). The spray was well accepted by the patients. CONCLUSIONS: The spray was useful against xerostomia in irradiated patients.

Cadmium is more toxic to LLC-PK1 cells than to MDCK cells acting on the cadherin-catenin complex.

Cadmium toxicity to renal cells was investigated in Madin-Darby canine kidney (MDCK) and LLC-PK1 cells as models of the distal tubule/collecting duct and proximal tubule, respectively. Cells were grown on two-compartment filters and exposed to 0.1-50 microM Cd2+. In MDCK cells, Cd2+ was more toxic from the basolateral than from the apical side and dependent on the extracellular Ca2+ concentration. Toxicity was evident within 24 h, as shown by a decrease in transepithelial resistance (TER), reduced proliferation (bromodeoxyuridine incorporation), reduction in ATP concentration, and morphological changes. On confocal microscopy, E-cadherin and alpha-catenin staining patterns indicated interference with the cadherin-catenin complex. LLC-PK1 cells showed a similar toxicity pattern, which was evident at lower Cd2+ concentrations. An increase of E-cadherin and alpha-catenin molecules in the Triton X-100-insoluble fraction was detectable at high Cd2+ concentrations in LLC-PK1 cells but not in MDCK cells. Lactate dehydrogenase release indicated membrane leakage in LLC-PK1 cells. Rhodamine-phalloidin staining, a probe for F-actin filaments, demonstrated alterations of the actin cytoskeleton in both cell lines. In conclusion, cadmium caused ATP depletion and interfered with the cadherin-catenin complex and probably the tight junctions changing renal cell morphology and function.

[Alteration of radiation-induced hematotoxicity by amifostine (ethyol)]. / Veränderte bestrahlungsinduzierte Hämatotoxizität durch Amifostin (Ethyol).

BACKGROUND: Radiotherapy--even of small volumes--can decrease leukocyte counts. We examined whether the radio-protector amifostine can reduce this hematotoxicity. PATIENTS AND METHODS: Twenty-six patients (Table 1) undergoing radiotherapy for squamous cell carcinoma of the head and neck were evaluated. All were given 60 (to 70) Gy 5 x 2 Gy per week in standard radiation techniques. Thirteen patients are randomized to receive 200 mg/m2 amifostine i.v., 30 minutes before radiation. Blood counts and differentials were determined before, during and following radiotherapy. Differences of these parameters are calculated and compared by t-test. RESULTS: The blood hemoglobin and the thrombocyte levels did not change during the radiotherapy course, neither for the amifostine treated, nor the control patients. Similarly the leukocyte counts of amifostine treated patients did not change during irradiation. The control patients, however, had a decrease of leukocytes from 8.4 to 6.0 x 10(3)/microliter, p = 0.03 (Table 2), and the reduction of the neutrophilic granulocyte count was more impressive for these patients. CONCLUSION: In this explorative study amifostine diminished radiation induced leukocyte toxicity.