Breast Neoplasms: Sautter-Bihl ML

Sautter-Bihl ML, Souchon R, Budach W, Sedlmayer F, Feyer P, Harms W, Haase W, Dunst J, Wenz F, Sauer R. · Municipal Hospital Karlsruhe, Karlsruhe, Germany. · Strahlenther Onkol. · Pubmed #19016032 No free full text.

Abstract: BACKGROUND AND PURPOSE: The aim of the present paper is to update the practical guidelines for radiotherapy of breast cancer published in 2006 by the breast cancer expert panel of the German Society for Radiooncology (DEGRO). These recommendations were complementing the S3 guidelines of the German Cancer Society (DKG) elaborated in 2004. The present DEGRO recommendations are based on a revision of the DKG guidelines provided by an interdisciplinary panel and published in February 2008. METHODS: The DEGRO expert panel (authors of the present manuscript) performed a comprehensive survey of the literature. Data from lately published meta-analyses, recent randomized trials and guidelines of international breast cancer societies, yielding new aspects compared to 2006, provided the basis for defining recommendations referring to the criteria of evidence-based medicine. In addition to the more general statements of the DKG, this paper emphasizes specific radiooncologic issues relating to radiotherapy after mastectomy (PMRT), locally advanced disease, irradiation of the lymphatic pathways, and sequencing of local and systemic treatment. Technique, targeting, and dose are described in detail. RESULTS: PMRT significantly reduces local recurrence rates in patients with T3/T4 tumors and/or positive axillary lymph nodes (12.9% with and 40.6% without PMRT in patients with four or more positive nodes). The more local control is improved, the more substantially it translates into increased survival. In node-positive women the absolute reduction in 15-year breast cancer mortality is 5.4%. Data referring to the benefit of lymphatic irradiation are conflicting. However, radiotherapy of the supraclavicular area is recommended when four or more nodes are positive and otherwise considered individually. Evidence concerning timing and sequencing of local and systemic treatment is sparse; therefore, treatment decisions should depend on the dominating risk of recurrence. CONCLUSION: There is common consensus that PMRT is mandatory for patients with T3/T4 tumors and/or four or more positive axillary nodes and should be considered for patients with one to three involved nodes. Irradiation of the lymphatic pathways and the optimal time point for onset of radiotherapy are still under debate.

Sautter-Bihl ML, Budach W, Dunst J, Feyer P, Haase W, Harms W, Sedlmayer F, Souchon R, Wenz F, Sauer R, Anonymous00109, Anonymous00110. · Municipal Hospital Karlsruhe, Germany. · Strahlenther Onkol. · Pubmed #18040609 No free full text.

Abstract: BACKGROUND: The present paper is an update of the practical guidelines for radiotherapy of breast cancer published in 2006 by the breast cancer expert panel of the German Society of Radiation Oncology (DEGRO) [34]. These recommendations have been elaborated on the basis of the S3 guidelines of the German Cancer Society that were revised in March 2007 by an interdisciplinary panel [18]. METHODS: The DEGRO expert panel performed a comprehensive survey of the literature, comprising lately published meta-analyses, data from recent randomized trials and guidelines of international breast cancer societies, referring to the criteria of evidence- based medicine [25]. In addition to the more general statements of the German Cancer Society, this paper emphasizes specific radiotherapeutic aspects. It is focused on radiotherapy after breast-conserving surgery. Technique, targeting, and dose are described in detail. RESULTS: Postoperative radiotherapy significantly reduces rates of local recurrence. The more pronounced the achieved reduction is, the more substantially it translates into improved survival. Four prevented local recurrences result in one avoided breast cancer death. This effect is independent of age. An additional boost provides a further absolute risk reduction for local recurrence irrespective of age. Women > 50 years have a hazard ratio of 0.59 in favor of the boost. For DCIS, local recurrence was 2.4% per patient year even in a subgroup with favorable prognostic factors leading to premature closure of the respective study due to ethical reasons. For partial-breast irradiation as a sole method of radiotherapy, results are not yet mature enough to allow definite conclusions. CONCLUSION: After breast-conserving surgery, whole-breast irradiation remains the gold standard of treatment. The indication for boost irradiation should no longer be restricted to women <or= 50 years. Partial-breast irradiation is still an experimental treatment and therefore discouraged outside controlled clinical trials. Omission of radiotherapy after breast-conserving surgery of DCIS should be restricted to individual exceptions.

Sautter-Bihl ML, Sauer R. · No affiliation provided · Strahlenther Onkol. · Pubmed #17609867 No free full text.

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Sautter-Bihl ML, Sauer R. · No affiliation provided · Strahlenther Onkol. · Pubmed #16622620 No free full text.

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Sauer R, Wenz F, Strnad V, Haase W, Souchon R, Sautter-Bihl ML. · No affiliation provided · Strahlenther Onkol. · Pubmed #15995834 No free full text.

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Sauer R, Sautter-Bihl ML, Budach W, Feyer P, Harms W, Souchan R, Wollwiener D, Kreienberg R, Wenz F. · Department of Radiation Oncology, University of Erlangen, Erlangen, Germany. · Cancer. · Pubmed #17647249 links to  free full text

Abstract: BACKGROUND: Breast-conserving surgery followed by whole-breast radiotherapy (WBRT) has become the standard treatment for the majority of patients with early breast cancer. Whereas the indications for systemic adjuvant treatment have continuously expanded, there is a tendency to restrict postoperative radiotherapy to accelerated partial breast irradiation (APBI) instead of WBRT. METHODS: The different techniques of APBI are described and their respective advantages or potential drawbacks outlined. Moreover, the results described in the literature are briefly reviewed as a basis for the consensus statements and recommendations of the German Society of Radiation Oncology, the German Society of Senology, and the Working Group for Gynecological Oncology of the German Cancer Society. RESULTS: The methods mainly used for APBI are: interstitial radiotherapy with multicatheter technique, intraoperative radiotherapy (IORT) using either electrons produced by linear accelerators or 50 kV x-rays (Intrabeam), the balloon-catheter technique (MammoSite), or 3D conformal external beam radiotherapy. These techniques have marked differences in dose distribution and homogeneity. The published range of local recurrence rates varies between 0% to 37%, the median follow-up from 8 to 72 months. CONCLUSIONS: To date, follow-up times mostly do not yet permit a definite judgment concerning the long-term effectiveness and side effects of APBI. The relevant societies in Germany support randomized clinical studies comparing APBI with WBRT in a well-defined subset of low-risk patients. However, the authors expressly discourage the routine use of APBI outside clinical trials. Until definite results show that APBI neither impairs therapeutic outcome nor cosmetic results, WBRT remains the gold standard in the treatment of early breast cancer.

Kuehn T, Bembenek A, Decker T, Munz DL, Sautter-Bihl ML, Untch M, Wallwiener D, Anonymous00053. · Department of Gynecology and Obstetrics, Interdisciplinary Breast Center, Gifhorn, Germany. · Cancer. · Pubmed #15611971 links to  free full text

Abstract: The development of standardized and reproducible clinical pathways is an important precondition for quality assurance in medicine, especially if a new method has not yet been ultimately validated. Sentinel lymph node biopsy (SLNB) is a widely accepted new surgical procedure in the treatment of early breast carcinoma. However, numerous steps of the method and details of the technique are not standardized and, thus, hamper quality assurance for SLNB. The German Society of Senology appointed an interdisciplinary consensus committee to work out guidelines for the standardized performance and quality-assured implementation of SLNB on a nationwide, homogeneous standard. The committee consisted of surgeons, gynecologists, radiooncologists, nuclear physicians, oncologists, and pathologists. Relevant questions related to patient selection, lymphatic mapping, surgery, histopathologic work-up, further local and systemic treatment decisions, patient information, training, and follow-up were evaluated with respect to clinical evidence, objectivity, and reproducibility. Clinical pathways were developed on the basis of this analysis. Requirements to the performing institutions and surgeons were defined.

Kühn T, Bembenek A, Büchels H, Decker T, Dunst J, Müllerleile U, Munz DL, Ostertag H, Sautter-Bihl ML, Schirrmeister H, Tulusan AH, Untch M, Winzer KJ, Wittekind C, Anonymous00228. · Frauenklinik und Projektgruppe interdisziplinäre Senologie Gifhorn, Bergstr. 30, 38518 Gifhorn. · Nuklearmedizin. · Pubmed #14978534 No free full text.

Abstract: The international consensus conference from St. Gallen concerning the treatment of early breast cancer concluded in 2003, that sentinel node biopsy was now accepted as method allowing axillary staging in breast cancer. This procedure may avoid complete lymph node dissection in appropriate cases. Since numerous questions associated with the technique are still not defined and the procedure itself is not yet standardized, the German Society of Senology defined the conditions for the routine clinical use of sentinel node biopsy in an interdisciplinary consensus meeting.

Chang-Claude J, Popanda O, Tan XL, Kropp S, Helmbold I, von Fournier D, Haase W, Sautter-Bihl ML, Wenz F, Schmezer P, Ambrosone CB. · Division of Clinical Epidemiology and Toxicology, German Cancer Research Center, Heidelberg, Germany. · Clin Cancer Res. · Pubmed #16000577 links to  free full text

Abstract: PURPOSE: Several DNA repair gene polymorphisms have been described, which affect DNA repair capacity and modulate cancer susceptibility. We evaluated the association of six polymorphisms in the DNA repair genes: XRCC1 (Arg194Trp, Arg280His, and Arg399Gln), APE1 (Asp148Glu), and XPD (Lys751Gln and Asp312Asn), with the risk of acute skin reactions following radiotherapy. DESIGN: We conducted a prospective study of 446 female patients with breast cancer who received radiotherapy after breast-conserving surgery. Individual genetic polymorphisms were determined using melting point analysis of sequence-specific hybridization probes. The development of acute skin reactions (moist desquamation) associated with DNA repair gene polymorphisms was modeled using Cox proportional hazards, accounting for cumulative biologically effective radiation dose. RESULTS: Overall, the development of acute toxicity, which presented in 77 patients, was not associated with the genetic variants studied, although the hazard ratios (HR) were generally below 1. Risks were however differential by body mass index. Among normal-weight patients only, both carriers of the APE1 148Glu and the XRCC1 399Gln alleles had decreased risk of acute skin reactions after radiotherapy (HR, 0.49 and 0.51, respectively). The results for XRCC1 were confirmed by haplotype analysis. When considering joint effects, we observed that compared with homozygote carriers of the wild-type allele in both genes, the risk was most strongly reduced in carriers of both APE1 148Glu and XRCC1 399Gln alleles with normal weight [HR, 0.19; 95% confidence interval (95% CI), 0.06-0.56] but not in those with overweight (HR, 1.39; 95% CI, 0.56-3.45; Pinteraction = 0.009). CONCLUSION: The XRCC1 399Gln or APE1 148Glu alleles may be protective against the development of acute side effects after radiotherapy in patients with normal weight.

Sautter-Bihl ML. · No affiliation provided · Strahlenther Onkol. · Pubmed #10577246 No free full text.

This publication has no abstract.

Chang-Claude J, Ambrosone CB, Lilla C, Kropp S, Helmbold I, von Fournier D, Haase W, Sautter-Bihl ML, Wenz F, Schmezer P, Popanda O. · Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany. · Br J Cancer. · Pubmed #19367277 No free full text.

Abstract: Breast-conserving surgery followed by radiotherapy is effective in reducing recurrence; however, telangiectasia and fibrosis can occur as late skin side effects. As radiotherapy acts through producing DNA damage, we investigated whether genetic variation in DNA repair and damage response confers increased susceptibility to develop late normal skin complications. Breast cancer patients who received radiotherapy after breast-conserving surgery were examined for late complications of radiotherapy after a median follow-up time of 51 months. Polymorphisms in genes involved in DNA repair (APEX1, XRCC1, XRCC2, XRCC3, XPD) and damage response (TP53, P21) were determined. Associations between telangiectasia and genotypes were assessed among 409 patients, using multivariate logistic regression. A total of 131 patients presented with telangiectasia and 28 patients with fibrosis. Patients with variant TP53 genotypes either for the Arg72Pro or the PIN3 polymorphism were at increased risk of telangiectasia. The odds ratios (OR) were 1.66 (95% confidence interval (CI): 1.02-2.72) for 72Pro carriers and 1.95 (95% CI: 1.13-3.35) for PIN3 A2 allele carriers compared with non-carriers. The TP53 haplotype containing both variant alleles was associated with almost a two-fold increase in risk (OR 1.97, 95% CI: 1.11-3.52) for telangiectasia. Variants in the TP53 gene may therefore modify the risk of late skin toxicity after radiotherapy.

Kuptsova N, Chang-Claude J, Kropp S, Helmbold I, Schmezer P, von Fournier D, Haase W, Sautter-Bihl ML, Wenz F, Onel K, Ambrosone CB. · Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY 14263, USA. · Int J Cancer. · Pubmed #18027873 No free full text.

Abstract: Telangiectasia and subcutaneous fibrosis are the most common late dermatologic side effects observed in response to radiation treatment. Radiotherapy acts on cancer cells largely due to the generation of reactive oxygen species (ROS). ROS also induce normal tissue toxicities. Therefore, we investigated if genetic variation in oxidative stress-related enzymes confers increased susceptibility to late skin complications. Women who received radiotherapy following lumpectomy for breast cancer were followed prospectively for late tissue side effects after initial treatment. Final analysis included 390 patients. Polymorphisms in genes involved in oxidative stress-related mechanisms (GSTA1, GSTM1, GSTT1, GSTP1, MPO, MnSOD, eNOS, CAT) were determined from blood samples by MALDI-TOF. The associations between telangiectasia and genotypes were evaluated by multivariate unconditional logistic regression models. Patients with variant GSTA1 genotypes were at significantly increased risk of telangiectasia (OR 1.86, 95% CI 1.11-3.11). Reduced odds ratios of telangiectasia were noted for women with lower-activity eNOS genotype (OR 0.58, 95% CI 0.36-0.93). Genotype effects were modified by follow-up time, with the highest risk observed after 4 years of radiotherapy for gene polymorphisms in ROS-neutralizing enzymes. Decreased risk with eNOS polymorphisms was significant only among women with less than 4 years of follow-up. All other risk estimates were nonsignificant. Late effects of radiation therapy on skin appear to be modified by variants in genes related to protection from oxidative stress. The application of genomics to outcomes following radiation therapy holds the promise of radiation dose adjustment to improve both cosmetic outcomes and quality of life for breast cancer patients.

Lilla C, Ambrosone CB, Kropp S, Helmbold I, Schmezer P, von Fournier D, Haase W, Sautter-Bihl ML, Wenz F, Chang-Claude J. · Division of Cancer Epidemiology, C020, German Cancer Research Center, im Neuenheimer Feld 280, 69120 , Heidelberg, Germany. · Breast Cancer Res Treat. · Pubmed #17221151 No free full text.

Abstract: BACKGROUND AND PURPOSE: Radiotherapy after breast-conserving surgery is commonly applied to reduce recurrence of breast cancer but may cause acute and late side effects. To identify prognostic factors for the development of late toxicity after radiotherapy, we conducted a prospective study of breast cancer patients. PATIENTS AND METHODS: We assessed late complications of radiotherapy and collected information on epidemiologic factors in a cohort of breast cancer patients who had received radiotherapy after breast-conserving surgery. Among 416 patients with complete follow-up data, the association between possible risk factors and development of late complications was evaluated using multivariate logistic regression analysis. RESULTS: After a median follow-up time of 51 months, 131 (31.4%) patients presented with telangiectasia and 28 (6.7%) patients with fibrosis. We observed a strong association between development of telangiectasia and fibrosis (p < 0.01). Increasing age of the patient was a risk factor for both telangiectasia and fibrosis (p-value for trend <0.01 and 0.03, respectively). Patients with acute skin toxicity (odds ratio (OR) 1.8, 95% confidence interval (CI) 1.0-3.1) were at higher risk to develop telangiectasia. Long-term smoking was associated with a significant increase in risk of telangiectasia compared to non-smokers (OR 2.3, 95% CI 1.2-4.6). CONCLUSIONS: Our study revealed several factors other than radiation dose that may predispose to late complications following radiotherapy. Further understanding of differences in response to irradiation may advance individualized treatment and improve cosmetic outcome.

Ahn J, Ambrosone CB, Kanetsky PA, Tian C, Lehman TA, Kropp S, Helmbold I, von Fournier D, Haase W, Sautter-Bihl ML, Wenz F, Chang-Claude J. · Division of Cancer Prevention and Population Science, Department of Epidemiology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA. · Clin Cancer Res. · Pubmed #17145829 links to  free full text

Abstract: PURPOSE: Because radiotherapy exerts cytotoxic effects via generation of massive oxidative stress, we hypothesized that catalase, manganese superoxide dismutase, myeloperoxidase (MPO), and endothelial nitric oxide synthase (eNOS) genotypes might result in greater risk of radiotoxicity. EXPERIMENTAL DESIGN: Cases (n = 446) were Caucasian women with breast cancer who received radiotherapy following lumpectomy. Genotypes were determined by matrix-assisted laser desorption/ionization time-of-flight. The development of acute reactions (moist desquamation) associated with genotypes was modeled using the Cox proportional hazards model, accounting for cumulative biologically effective radiation dose. RESULTS: Genotypes associated with higher levels of reactive oxygen species (ROS) were not associated with risk of radiotoxicity. However, relationships between overweight/obesity [body mass index (BMI), >25] and radiotoxicity risk seemed to be modified by eNOS and MPO genotypes associated with higher generation of nitric oxide and ROS, respectively. Women with high BMI (>25) and eNOS GG genotypes were at more than a 6-fold increase in risk (hazard ratio, 6.39; 95% confidence interval, 2.53-16.15) compared with those with BMI <25, and for MPO, those with high BMI (>25) and GG genotypes also had greater risk of radiotoxicity (hazard ratio, 3.61; 95% confidence interval, 1.78-7.35) compared with those with BMI <25. Overweight/obesity was not a strong risk factor among women with other eNOS and MPO genotypes. Exploratory analysis using classification and regression trees indicated that total number of risk alleles contributed, in part, to acute toxicity outcomes among a subgroup of women. CONCLUSIONS: Associations between BMI and radiotoxicity risk may be most apparent among women with genotypes related to higher levels of oxidative stress. Regression trees may be useful in future studies to examine the contributions of multiple factors to individual susceptibility to adverse effects of cancer treatment.

Ambrosone CB, Tian C, Ahn J, Kropp S, Helmbold I, von Fournier D, Haase W, Sautter-Bihl ML, Wenz F, Chang-Claude J. · Department of Epidemiology, Division of Cancer Prevention and Population Science, Roswell Park Cancer Institute, Buffalo, New York, USA. · Breast Cancer Res. · Pubmed #16848913 links to  free full text

Abstract: INTRODUCTION: The cytotoxic effects of radiation therapy are mediated primarily through increased formation of hydroxyl radicals and reactive oxygen species, which can damage cells, proteins and DNA; the glutathione S-transferases (GSTs) function to protect against oxidative stress. We hypothesized that polymorphisms encoding reduced or absent activity in the GSTs might result in greater risk for radiation-associated toxicity. METHODS: Women receiving therapy in radiation units in Germany following lumpectomy for breast cancer (1998-2001) provided a blood sample and completed an epidemiological questionnaire (n = 446). Genotypes were determined using Sequonom MALDI-TOF (GSTA1, GSTP1) and Masscode (GSTM1, GSTT1). Biologically effective radiotherapy dose (BED) was calculated, accounting for differences in fractionation and overall treatment time. Side effects considered were grade 2c and above, as classified using the modified Common Toxicity Criteria. Predictors of toxicity were modelled using Cox regression models in relation to BED, with adjustment for treating clinic, photon field, beam energy and boost method, and potential confounding variables. RESULTS: Low activity GSTP1 genotypes were associated with a greater than twofold increase in risk for acute skin toxicities (adjusted hazard ratio 2.28, 95% confidence interval 1.04-4.99). No associations were noted for the other GST genotypes. CONCLUSION: These data indicate that GSTP1 plays an important role in protecting normal cells from damage associated with radiation therapy. Studies examining the effects of GSTP1 polymorphisms on toxicity, recurrence and survival will further inform individualized therapeutics based on genotypes.

Popanda O, Tan XL, Ambrosone CB, Kropp S, Helmbold I, von Fournier D, Haase W, Sautter-Bihl ML, Wenz F, Schmezer P, Chang-Claude J. · Division of Toxicology and Cancer Risk Factors, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120, Heidelberg, Germany. · Cancer Epidemiol Biomarkers Prev. · Pubmed #16702393 links to  free full text

This publication has no abstract.

Tan XL, Popanda O, Ambrosone CB, Kropp S, Helmbold I, von Fournier D, Haase W, Sautter-Bihl ML, Wenz F, Schmezer P, Chang-Claude J. · Division of Clinical Epidemiology, German Cancer Research Center, Heidelberg, Germany. · Breast Cancer Res Treat. · Pubmed #16331344 No free full text.

Abstract: p53 and p21 play an important role in G1/S checkpoint control in response to ionizing radiation. Yet the genetic polymorphisms in these genes have not been investigated with respect to radiation toxicity in patients. We therefore assessed the association between TP53 Arg72Pro, p53PIN3 and p21 Ser31Arg polymorphisms and the risk of acute skin toxicity after radiotherapy in a prospective study of 446 female breast cancer patients (average age 60.3+/-9.0 years) receiving radiotherapy after breast conserving surgery. The p53PIN3 polymorphism was determined by standard PCR, and TP53 Arg72Pro and p21 Ser31Arg polymorphisms using melting point analysis of sequence-specific hybridization probes. The development of acute skin toxicity (moist desquamation) was modelled using Cox proportional hazards, accounting for cumulative biologically effective radiation dose. Overall, the development of acute skin toxicity, which presented in 77 patients, was not significantly associated with the polymorphisms studied. Risks were however differential by body mass index. Compared to non-carriers, TP53 72Pro carriers had a non-significantly decreased risk of acute skin toxicity in normal weight women (hazard ratio 0.46, 95% CI, 0.18-1.18) but not in overweight patients (hazard ratio 1.07, 95% CI, 0.61-1.89) (p(interaction) =0.14). Haplotype analysis for the TP53 polymorphisms suggested that effect modification by TP53 72Pro may differ according to the p53PIN3 allele (p(interaction)=0.06). Furthermore, in TP53 72Pro carriers with p21 Ser/Ser genotype, the occurrence of acute toxicity was reduced in normal weight but not overweight patients. In conclusion, the TP53 72Pro variant may be associated with the development of acute skin toxicity after radiotherapy in patients with normal weight. Large clinical studies are needed to clearly confirm this association.

Kühn T, Bembenek A, Büchels H, Decker T, Dunst J, Müllerleile U, Munz DL, Ostertag H, Sautter-Bihl ML, Schirrmeister H, Tulusan AH, Untch M, Winzer KJ, Wittekind C, Anonymous00124. · Frauenklinik und Projektgruppe interdisziplinäre Senologie, Gifhorn. · Pathologe. · Pubmed #15188789 No free full text.

This publication has no abstract.

Twardella D, Popanda O, Helmbold I, Ebbeler R, Benner A, von Fournier D, Haase W, Sautter-Bihl ML, Wenz F, Schmezer P, Chang-Claude J. · German Cancer Research Center, Division of Clinical Epidemiology, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. · Radiother Oncol. · Pubmed #14643951 No free full text.

Abstract: BACKGROUND AND PURPOSE: Intrinsic and extrinsic factors can affect the occurrence of side effects of radiotherapy. The influence of therapy modalities, personal characteristics and individual DNA repair capacity on the risk of acute skin toxicity was thus evaluated. MATERIALS AND METHODS: In a prospective study of 478 female breast cancer patients receiving adjuvant radiotherapy of the breast after breast-conserving surgery, acute skin toxicity was documented systematically using a modified version of the common toxicity criteria. Prognostic personal and treatment characteristics were identified for the entire cohort. Individual DNA repair capacity was determined in a subgroup of 113 patients with alkaline comet assay using phytohemagglutinin stimulated lymphocytes. Using proportional hazards analysis to account for cumulative biologically effective radiation dose, the hazard for the development of acute skin reactions (moist desquamation) associated with DNA repair capacity was modeled. RESULTS: Of the 478 participants, 84 presented with acute reactions by the end of treatment. Higher body mass index was significantly associated with an increased risk for acute reactions (hazard ratio=1.09 per 1 kg/m(2)), adjusted for treating hospital and photon beam quality. The comet assay parameters examined, including background DNA damage in non-irradiated cells, DNA damage induced by 5 Gy, and DNA repair capacity, were not significantly associated with risk of acute skin toxicity. CONCLUSIONS: Higher BMI is predictive of acute skin toxicity, however, individual repair parameters as determined by the alkaline comet assay are not informative enough. More comprehensive analyses including late effects of radiotherapy and repair kinetics optimized for different radiation-induced DNA lesions are warranted.

Popanda O, Ebbeler R, Twardella D, Helmbold I, Gotzes F, Schmezer P, Thielmann HW, von Fournier D, Haase W, Sautter-Bihl ML, Wenz F, Bartsch H, Chang-Claude J. · Division of Toxicology and Cancer Risk Factors, German Cancer Research Center, Heidelberg, Germany. · Int J Radiat Oncol Biol Phys. · Pubmed #12654430 No free full text.

Abstract: PURPOSE: Repair of radiation-induced DNA damage plays a critical role for both the susceptibility of patients to side effects after radiotherapy and their subsequent cancer risk. The study objective was to evaluate whether DNA repair data determined in vitro are correlated with the occurrence of acute side effects during radiotherapy. METHODS AND MATERIALS: Breast cancer patients receiving radiation therapy after a breast-conserving surgery were recruited in a prospective epidemiologic study. As an indicator for clinical radiosensitivity, adverse reactions of the skin were recorded. Cryo-preserved lymphocytes from 113 study participants were gamma-irradiated with 5 Gy in vitro and analyzed using the alkaline comet assay. Reproducibility of the assay was determined by repeated analysis (n = 26) of cells from a healthy donor. A coefficient of variation of 0.3 was calculated. RESULTS: The various parameters determined to characterize the individual DNA repair capacity showed large differences between patients. Eleven patients were identified with considerably enhanced DNA damage induction, and 7 patients exhibited severely reduced DNA repair capacity after 15 and 30 min. Six patients were considered as clinically radiosensitive, indicated by moist desquamation of the skin after a total radiation dose of about 50 Gy. CONCLUSIONS: Using the alkaline comet assay as described here, breast cancer patients were identified showing abnormal cellular radiation effects, but this repair deficiency corresponded only at a very limited extent to the acute radiation sensitivity of the skin. Because impaired DNA repair could be involved in the development of late irradiation effects, individuals exhibiting severely reduced DNA repair capacity should be followed for the development of late clinical symptoms.

Kim BS, Park JJ, Edler L, Von Fournier D, Haase W, Sautter-Bihl ML, Gotzes F, Thielmann HW. · Department of Applied Statistics, Yonsei University, Seoul, South Korea. · Environ Mol Mutagen. · Pubmed #12211076 No free full text.

Abstract: Since its introduction by Ostling and Johanson [1984; Biochem Biophys Res Commun 123:291-298] and independent modifications by Singh et al. [1990; Exp Cell Res 175:184-191] and Olive et al. [1988; Radiat Res 112:86-94], the comet assay has been widely used in genetic toxicology, environmental biomonitoring, molecular and human epidemiology, and clinical investigations. There are still several issues to be resolved before the comet assay is accepted as a standard assay for detecting DNA damage and repair in a single cell. One of the major issues is the proper quantification of DNA damage/repair. The aim of this article is to develop a new quantitative measure of DNA damage/repair which is represented in the dose-time-response surface. We propose to use the second derivative (2D) of the dose-time-response surface for measuring DNA repair activity. This approach enables us to represent the DNA repair activity of cells exposed to a DNA-damaging agent with a single number by combining all the information of a dose-time-response experiment. The computation procedure includes the application of linear regression. An SAS/AF-based program, "Comet Assay," was developed for this computation and is freely available on the Internet. We considered the response of each of four DNA damage parameters: tail moment, tail length, tail DNA, and tail inertia for constructing the dose-time-response surface. Using data from 25 patients, we observed that 2Ds based on tail moment and tail DNA were highly correlated and that tail inertia might provide information on a somewhat different aspect of DNA damage/repair.

Sautter-Bihl ML, Hültenschmidt B, Melcher U, Ulmer HU. · Department of Radiotherapy, Städtisches Klinikum Karlsruhe, Germany. · Strahlenther Onkol. · Pubmed #11977387 No free full text.

Abstract: BACKGROUND: Radiotherapy of internal mammary lymph nodes (IMN) in breast cancer is discussed controversially due to its potential toxicity and debatable efficacy. Aim of the present study was to assess the cardiac and lung dose in 3-D planned radiotherapy and to discuss these results with regard to arguments pro and contra IMN irradiation. PATIENTS AND METHODS: 32 patients underwent 3-D planning (Helax TMS) for irradiation of breast and IMN in three different techniques either using separate IMN fields (A, B) or a wide tangent (C). For each technique the respective doses to the heart (including the base of the aorta and the ostium of the coronary arteries) and lung were analyzed in dose volume histograms. RESULTS: The mean dose to the heart (left side irradiation) was 6.4 Gy (A), 8.1 Gy (B) and 3.8 Gy (C). The mean dose to the lung was 11.7 Gy (A), 15.4 Gy (B) and 10.2 Gy (C). The 10-Gy isodose comprised 19.5% (A), 32.9% (B) and 5.6% (C) of the heart (left breast). The respective values for the 20-Gy isodose were 7.8, 11.5 and 4.4%. The irradiated volumes of the lung were 37.7% (A), 52.7% (B) and 20% (C) in the 10-Gy isodose. The 20-Gy isodose comprised 16.7% (A), 28.3% (B) and 17.8% (C). CONCLUSION: Whether radiotherapy of the IMN may improve treatment results in breast cancer is currently unresolved. However, the present data indicate that relevant cardiovascular side effects are unlikely to occur. Thus, the indication should be considered on the basis of individual risk factors.

Hermann B, Hültenschmidt B, Sautter-Bihl ML. · Klinik für Strahlentherapie, Städtisches Klinikum Karlsruhe. · Strahlenther Onkol. · Pubmed #11370554 No free full text.

Abstract: BACKGROUND: Leptomeningeal carcinomatosis occurs in about 5% of solid tumors and may seriously compromise quality of life. Aim of the present study was to evaluate the feasibility of craniospinal irradiation with and without intrathecal chemotherapy and its efficacy with regard to symptom palliation and survival. PATIENTS AND METHODS: 16 patients (mean age 46 years; nine breast cancers, five lung cancers, one renal cell cancer, one tumor of unknown primary site) with leptomeningeal carcinomatosis occurring after a median interval from primary tumor diagnosis of 5 months (0-300 months) received craniospinal irradiation between October 1995 and May 2000. The median total dose was 36 Gy (à 1.6-2.0 Gy). Ten patients were additionally treated with intrathecal methotrexate (15 mg per cycle, 2-8 cycles). RESULTS: Median survival was 12 weeks, 8 weeks after radiotherapy alone, 16 weeks after combined modality treatment. 14 patients died from disease. Eleven patients (68%) experienced regression of their neurological symptoms during or soon after completion of radiotherapy. Seven patients regained their ability to walk, six had pain reduction, three regression of bladder and bowel incontinence. In three patients symptom progression and in two patients no change occurred. Side effects were: myelosuppression (CTC) Grade I: n = 2, Grade II: n = 4, Grade III: n = 4 patients and Grade IV: n = 1. Nine patients had dysphagia, seven mucositis, three suffered from nausea. No late toxicity was observed. CONCLUSION: Craniospinal radiotherapy is feasible and effective for palliative treatment of leptomeningeal carcinomatosis. As far as the small patient number permits any definite conclusions, combined modality treatment seems superior to irradiation alone.

Sautter-Bihl ML, Hetzel-Sesterheim M. · No affiliation provided · Strahlenther Onkol. · Pubmed #11200115 No free full text.

This publication has no abstract.

Sautter-Bihl ML. · No affiliation provided · Strahlenther Onkol. · Pubmed #11200114 No free full text.

This publication has no abstract.