Breast Neoplasms: Wenz F

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.

Souchon R, Budach W, Dunst J, Feyer P, Haase W, Harms W, Sautter Bihl ML, Wenz F, Sauer R, Anonymous00094. · No affiliation provided · Strahlenther Onkol. · Pubmed #16896587 No free full text.

This publication has no abstract.

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

This publication has no abstract.

Lohr F, Heggemann F, Papavassiliu T, El-Haddad M, Tomé O, Dinter D, Dobler B, Kraus-Tiefenbacher U, Borggrefe M, Wenz F. · Klinik für Strahlentherapie und Radioonkologie, Universitätsklinikum Mannheim, Germany. · Strahlenther Onkol. · Pubmed #19370424 No free full text.

Abstract: BACKGROUND: Postoperative radiotherapy after breast cancer surgery effectively reduces local relapses. A survival benefit after breast conservation, however, has only been proven recently which was in part due to excessive cardiac mortality of patients who had been treated with radiotherapy in the past. MATERIAL AND METHODS: The literature on postoperative radiotherapy for breast cancer was reviewed with regard to cardiac toxicity as the basis for hypothesis generation. RESULTS: From numerous publications on cardiac toxicity of breast cancer radiotherapy, the following pattern emerges: in series where a high radiation dose was applied to a significant percentage of the heart (postmastectomy and postlumpectomy series) cardiac toxicity/mortality was increased versus a nonexposed cohort or for left over right disease. If, however, a relevant exposure of cardiac muscle could be more or less excluded based on the technique used (mainly more recent postlumpectomy radiotherapy), no cardiac toxicity was observed. Series for which individual dose exposure varied or could not be clarified also came to varying conclusions. Also due to retrospectively unclear dose distributions, an exact quantification of tolerance doses/effects of different geographic dose distribution patterns could not be performed to date. A particularly difficult question to answer is the threshold volume for clinically relevant cardiotoxicity with tangential radiotherapy at prescription doses. As a consequence, this precludes an estimate in which situations multifield intensity-modulated radiotherapy (IMRT) with its characteristic dose distribution pattern of a larger volume exposed to intermediate doses and higher mean/median heart doses (as shown in Figure 1) might be preferable. CONCLUSION: This review updates the database on cardiac toxicity of breast cancer radiotherapy with special emphasis regarding the issues related to the clinical use of IMRT. Multifield IMRT may reduce the cardiac risk for a small subset of patients at excessive risk with conventional tangential radiotherapy due to unfavorable thoracic geometry, for whom partial-breast radiotherapy is not an option. Due to further concern about the effects of intermediate doses to larger heart volumes, potentially increased contralateral cancer risk and the long latency of clinically apparent toxicity, the introduction of breast IMRT should be closely followed. Accompanying functional studies may have the potential to detect cardiac toxicity at an earlier time.

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.

Vaidya JS, Tobias JS, Baum M, Wenz F, Kraus-Tiefenbacher U, D'souza D, Keshtgar M, Massarut S, Hilaris B, Saunders C, Joseph D. · University College London, United Kingdom. · Semin Radiat Oncol. · Pubmed #15809933 No free full text.

Abstract: A revolution is challenging the dogma that local treatment for all patients with breast cancer treated with breast conservation therapy must include postoperative radiotherapy delivered to the whole breast. Such prolonged postoperative radiotherapy is a burden to patients and hospitals and forces many women to chose mastectomy instead. Furthermore, for patients receiving chemotherapy, the start of conventional radiotherapy may be delayed so long as to increase the risk of local relapse. These problems might be eliminated if effective radiotherapy could be given as a single treatment intraoperatively, immediately after the surgery. Local recurrence after breast-conserving surgery usually occurs in the portion of the breast in the immediate proximity of the tumor, even when radiotherapy is omitted. Therefore, it should usually be possible to restrict radiotherapy to only the area adjacent to the tumor in selected women. Based on this premise, we have devised a new technique of partial breast irradiation, with the intention of completing all local treatment in a single session. In this article, we elaborate on the rationale and on the different methods of delivering intraoperative radiotherapy. If this approach is validated in ongoing randomized trials, it could save time, money, and breasts.

Vaidya JS, Tobias JS, Baum M, Keshtgar M, Joseph D, Wenz F, Houghton J, Saunders C, Corica T, D'Souza D, Sainsbury R, Massarut S, Taylor I, Hilaris B. · Clinical Trials Group, Department of Surgery, Royal Free and University College Medical School, London, UK. · Lancet Oncol. · Pubmed #15003199 No free full text.

Abstract: Postoperative radiotherapy, which forms part of breast-conserving therapy, may not need to encompass the whole breast. Apart from the consumption of huge resources and patients' time, postoperative radiotherapy deters many women from receiving the benefits of breast-conserving surgery, forcing them to choose a mastectomy instead. If radiotherapy could be given in the operating theatre immediately after surgery, many of these disadvantages could be overcome. One striking fact about local recurrence after breast-conserving surgery is that most occurs in the area of breast immediately next to the primary tumour; this is despite the finding that two-thirds of mastectomy samples have microscopic tumours distributed throughout the breast, even when radiotherapy is omitted. Thus, only the area adjacent to the tumour may need treatment with radiotherapy. On the basis of this premise, clinical scientists have used new technology to administer radiotherapy to the area at greatest risk of local recurrence, with the aim of completing the whole local treatment in one sitting. In this review, we have elaborated on the rationale and different methods of delivery of intraoperative radiotherapy. If this approach is validated by the results of current randomised trials, it could save time, money, and breasts.

Kraus-Tiefenbacher U, Bauer L, Scheda A, Schoeber C, Schaefer J, Steil V, Wenz F. · Department of Radiation Oncology, Mannheim Medical Center, University of Heidelberg, Theodor-Kutzer Ufer 1-3, D-68167 Mannheim, Germany. · BMC Cancer. · Pubmed #17854511 links to  free full text

Abstract: BACKGROUND: For patients suffering of recurrent breast cancer within the irradiated breast, generally mastectomy is recommended. The normal tissue tolerance does not permit a second full-dose course of radiotherapy to the entire breast after a second breast-conserving surgery (BCS). A novel option is to treat these patients with partial breast irradiation (PBI). This approach is based on the hypothesis that re-irradiation of a limited volume will be effective and result in an acceptable frequency of side effects. The following report presents a single center experience with intraoperative radiotherapy (IORT) during excision of recurrent breast cancer in the previously irradiated breast. METHODS: Between 4/02 and 11/06, 15 patients were treated for in-breast recurrences at a median of 10 years (3-25) after previous EBRT (10 recurrences in the initial tumor bed, 3 elsewhere in-breast failures, 2 invasive recurrences after previous DCIS). Additional 2 patients were selected for IORT with new primary breast cancer after previous partial breast EBRT for treatment of Hodgkin's disease. IORT with a single dose of 14.7 - 20 Gy 50 kV X-rays at the applicator surface was delivered with the Intrabeam-device (Carl Zeiss, Oberkochen, Germany). RESULTS: After a median follow-up of 26 months (1-60), no local recurrence occurred. 14 out of 17 patients are alive and free of disease progression. Two patients are alive with distant metastases. One patient died 26 months after BCS/IORT due to pulmonary metastases diagnosed 19 months after BCS/IORT. Acute toxicity after IORT was mild with no Grade 3/4 toxicities and cosmetic outcome showed excellent/good/fair results in 7/7/3 cases. CONCLUSION: IORT for recurrent breast cancer using low energy X-rays is a valuable option for patients with recurrent breast cancer after previous radiotherapy.

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.

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.

Welzel G, Fleckenstein K, Mai SK, Hermann B, Kraus-Tiefenbacher U, Wenz F. · Department of Radiation Oncology, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany. · Strahlenther Onkol. · Pubmed #19107345 No free full text.

Abstract: BACKGROUND AND PURPOSE: The objective of the current study was to evaluate the acute effects of cranial radiation therapy (CNS-RT) using different radiation doses (0, 1.8, 2, 3, >or=20 Gy) on cognitive function with special emphasis on memory. We assessed patients with and without intracranial tumors to distinguish between direct and indirect radiation effects on brain tissue. MATERIALS AND METHODS: Eighty-two patients were evaluated with neuropsychological testing before and acutely after radiotherapy (RT). Sixty-four patients received RT to the brain (55 with, 9 without intracranial tumor). Eighteen patients treated with RT to the breast served as controls. RESULTS: Patients with intracranial tumor demonstrated attention (19-38th percentile) and verbal memory scores (34-46th percentile) below the population average at baseline. The average Verbal Memory score was significantly different between patients with intracranial tumor and controls both at baseline (38th vs. 58th percentile) and after irradiation (27th vs. 52th percentile). Patients with preexisting peritumoral edema performed worse than patients without edema and controls. Radiation dose-related deficits were seen for working memory performance in patients with intracranial tumor. CONCLUSION: Our data indicate no measurable impairment of cognitive functioning acutely after prophylactic cranial irradiation. Patients with intracranial tumor show a deterioration of almost all memory functions with a dose-dependent impairment in working memory. Patients with preexisting peritumoral brain edema show the strongest deterioration.

Herskind C, Griebel J, Kraus-Tiefenbacher U, Wenz F. · Department of Radiation Oncology, University of Heidelberg, Mannheim Medical Center, Mannheim, Germany. · Int J Radiat Oncol Biol Phys. · Pubmed #19028280 No free full text.

Abstract: PURPOSE: Accelerated partial breast radiotherapy with low-energy photons from a miniature X-ray machine is undergoing a randomized clinical trial (Targeted Intra-operative Radiation Therapy [TARGIT]) in a selected subgroup of patients treated with breast-conserving surgery. The steep radial dose gradient implies reduced tumor cell control with increasing depth in the tumor bed. The purpose was to compare the expected risk of local recurrence in this nonuniform radiation field with that after conventional external beam radiotherapy. METHODS AND MATERIALS: The relative biologic effectiveness of low-energy photons was modeled using the linear-quadratic formalism including repair of sublethal lesions during protracted irradiation. Doses of 50-kV X-rays (Intrabeam) were converted to equivalent fractionated doses, EQD2, as function of depth in the tumor bed. The probability of local control was estimated using a logistic dose-response relationship fitted to clinical data from fractionated radiotherapy. RESULTS: The model calculations show that, for a cohort of patients, the increase in local control in the high-dose region near the applicator partly compensates the reduction of local control at greater distances. Thus a "sphere of equivalence" exists within which the risk of recurrence is equal to that after external fractionated radiotherapy. The spatial distribution of recurrences inside this sphere will be different from that after conventional radiotherapy. CONCLUSIONS: A novel target volume concept is presented here. The incidence of recurrences arising in the tumor bed around the excised tumor will test the validity of this concept and the efficacy of the treatment. Recurrences elsewhere will have implications for the rationale of TARGIT.

Lohr F, El-Haddad M, Dobler B, Grau R, Wertz HJ, Kraus-Tiefenbacher U, Steil V, Madyan YA, Wenz F. · Department of Radiation Oncology, Mannheim University Medical Center, University of Heidelberg, Mannheim, Germany. · Int J Radiat Oncol Biol Phys. · Pubmed #18973977 No free full text.

Abstract: PURPOSE: Three-dimensional (3D) treatment planning has reduced the cardiac dose in postoperative radiotherapy for breast cancer; however, the overall cardiac toxicity is still an issue because of more aggressive adjuvant treatment. Toxicity models have suggested that a reduction of the heart volume treated to high doses might be particularly advantageous. We compared aperture-based multifield intensity-modulated radiotherapy (IMRT) plans to 3D-planned tangent fields using dose-volume histograms, cardiac toxicity risk, and the robustness to positioning errors. METHODS AND MATERIALS: For 14 computed tomography data sets of patients with left-sided breast cancer (unfavorable thoracic geometry), a 3D treatment plan and an IMRT plan were created. The dose-volume histograms were evaluated for the target and risk organs. Excess risk of cardiac mortality was calculated for both approaches using a relative seriality model. Positioning errors were simulated by moving the isocenter. RESULTS: IMRT reduced the maximal dose to the left ventricle by a mean of 30.9% (49.14 vs. 33.97 Gy). The average heart volume exposed to >30 Gy was reduced from 45 cm(3) to 5.84 cm(3). The mean dose to the left ventricle was reduced by an average of 10.7% (10.86 vs. 9.7 Gy), and the mean heart dose increased by an average of 24% (from 6.85 to 8.52 Gy). The model-based reduction of the probability for excess therapy-associated cardiac death risk was from 6.03% for the 3D plans to 0.25% for the IMRT plans. CONCLUSION: Aperture-based IMRT for left-sided breast cancer significantly reduces the maximal dose to the left ventricle, which might translate into reduced cardiac mortality. Biological modeling might aid in deciding to treat with IMRT but has to be validated prospectively.

Wenz F, Welzel G, Keller A, Blank E, Vorodi F, Herskind C, Tomé O, Sütterlin M, Kraus-Tiefenbacher U. · Department of Radiation Oncology, University of Heidelberg, University Medical Center Mannheim, Theodor-Kutzer Ufer 1-3, 68167 Mannheim, Germany. · Breast. · Pubmed #18650091 No free full text.

Abstract: BACKGROUND: Intraoperative radiotherapy (IORT) during breast-conserving surgery is increasingly used. We analyzed the influence of the interval between an IORT boost and external beam radiotherapy (EBRT) on late toxicity. METHODS: Forty-eight patients received 20 Gy IORT (50 kV X-rays (Intrabeam, Carl Zeiss, Oberkochen, Germany) followed by 46-50 Gy EBRT with a median interval of 36 days (14-197). Late toxicity was assessed with the modified LENT SOMA score after a median of 36 months. RESULTS: Twelve patients developed a higher grade fibrosis ( degrees II-III), three teleangiectases, one a breast edema grade degrees II, six retractions, four hyperpigmentations and five pain ( degrees II-III). The median interval between IORT and EBRT was significantly shorter in these patients (n=18) compared to the 30 patients without higher grade toxicity (29.5 days vs. 39.5 days, p=0.023, Mann-Whitney U-test). CONCLUSION: Starting EBRT about 5-6 weeks after IORT appears to be associated with a decreased risk of chronic late toxicity compared with a shorter interval. The impact on local recurrence of prolonged gaps between IORT and EBRT is not known.

Welzel G, Fleckenstein K, Schaefer J, Hermann B, Kraus-Tiefenbacher U, Mai SK, Wenz F. · Department of Radiation Oncology, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany. · Int J Radiat Oncol Biol Phys. · Pubmed #18448270 No free full text.

Abstract: PURPOSE: To prospectively compare the effect of prophylactic and therapeutic whole brain radiotherapy (WBRT) on memory function in patients with and without brain metastases. METHODS AND MATERIALS: Adult patients with and without brain metastases (n = 44) were prospectively evaluated with serial cognitive testing, before RT (T0), after starting RT (T1), at the end of RT (T2), and 6-8 weeks (T3) after RT completion. Data were obtained from small-cell lung cancer patients treated with prophylactic cranial irradiation, patients with brain metastases treated with therapeutic cranial irradiation (TCI), and breast cancer patients treated with RT to the breast. RESULTS: Before therapy, prophylactic cranial irradiation patients performed worse than TCI patients or than controls on most test scores. During and after WBRT, verbal memory function was influenced by pretreatment cognitive status (p < 0.001) and to a lesser extent by WBRT. Acute (T1) radiation effects on verbal memory function were only observed in TCI patients (p = 0.031). Subacute (T3) radiation effects on verbal memory function were observed in both TCI and prophylactic cranial irradiation patients (p = 0.006). These effects were more pronounced in patients with above-average performance at baseline. Visual memory and attention were not influenced by WBRT. CONCLUSIONS: The results of our study have shown that WBRT causes cognitive dysfunction immediately after the beginning of RT in patients with brain metastases only. At 6-8 weeks after the end of WBRT, cognitive dysfunction was seen in patients with and without brain metastases. Because cognitive dysfunction after WBRT is restricted to verbal memory, patients should not avoid WBRT because of a fear of neurocognitive side effects.

Abo-Madyan Y, Polednik M, Rahn A, Schneider F, Dobler B, Wenz F, Lohr F. · Department of Radiation Oncology, Mannheim Medical Center, University of Heidelberg, Mannheim, Germany. · Strahlenther Onkol. · Pubmed #18259700 No free full text.

Abstract: PURPOSE: Evaluation of a simplified intensity-modulated irradiation (IMRT), a three-field (MFT), and a conventional two-tangential-field technique regarding dose homogeneity, target coverage, feasibility and, for the first time, dosimetric reliability in patients with large breasts treated postoperatively for breast cancer on a low-energy linac. MATERIAL AND METHODS: CT datasets of ten patients with relatively large breast volumes treated for breast cancer were selected. For each patient, four treatment plans were created: low-energy conventional (C-LE), high-energy conventional (C-HE), three-field (MFT), and a two-field aperture-based IMRT technique. Apertures for the IMRT and MFT were created with the aid of a three-dimensional dose display. Dosimetric accuracy of each technique was evaluated in an anthropomorphic thorax/breast phantom. RESULTS: The mean of planning target volumes receiving < 95% or > 105% of the prescribed total dose was reduced from 16.0% to 13.9% to 10.4% to 8.9% in the C-LE, C-HE, MFT, and IMRT plans, respectively. Phantom dose measurements agreed well with the calculated dose within the breast tissue. CONCLUSION: Aperture-based IMRT using two tangential incident beam directions, as well as a three-field technique with inverse optimization, provide a better alternative to the standard wedged tangential beams for patients with large breasts treated on low-energy linacs while maintaining the efficiency of the treatment-planning and delivery process.

Polednik M, Abo Madyan Y, Schneider F, Wolff D, Bannach B, Lambrecht U, Wallin A, Cwiekala M, Maurer K, Reif F, Lohr F, Wenz F, Anonymous00111. · Department of Radiation Oncology, Mannheim University Hospital, University of Heidelberg, Mannheim Medical Center, Germany. · Strahlenther Onkol. · Pubmed #18040610 No free full text.

Abstract: PURPOSE: To evaluate the accuracy of dose calculation algorithms of different planning systems for postoperative tangential radiotherapy in breast cancer. MATERIAL AND METHODS: On a CT dataset of an anthropomorphic phantom, a structure set of the left lung, clinical target volume (CTV), planning target volume, heart, and external contour were delineated. The dataset was processed by six radiation oncology centers participating in this multicenter dosimetry project. Conventional plans with two tangential wedged fields were generated in MasterPlan, Pinnacle, Eclipse, TMS, and PrecisePLAN. Plan calculations were done using the beam data of local linacs. The dose distributions were verified under local conditions with Gafchromic-EBT films. RESULTS: In all planning systems, deviations between calculation and measurement were around +/-3% in the CTV in the measured plane. Only small areas with deviations of +/-5% were detected. Pencil-beam (PB) calculations overestimated the dose inside the lung by up to 23%. Collapsed cone (CC) underestimated the lung dose by up to 6%. CONCLUSION: CC calculates the dose distribution more accurately than PB. Inside regions with electron disequilibrium, however, the dose is slightly underestimated.

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.

Wasser K, Schoeber C, Kraus-Tiefenbacher U, Bauer L, Brade J, Teubner J, Wenz F, Neff W. · Department of Radiology, University Hospital Mannheim, University of Heidelberg, Heidelberg, Germany. · Eur Radiol. · Pubmed #17237946 No free full text.

Abstract: The aim of this study was to evaluate mammographic and sonographic changes at the surgical site within the first 2 years after IORT as a boost followed by whole-breast radiotherapy (WBRT), compared with a control group treated with WBRT alone. All patients had breast-conserving surgery for early-stage breast cancer. Group A: n = 27, IORT (20 Gy) followed by WBRT (46 Gy). Group B (control group): n = 27, WBRT alone (56-66 Gy). Mammography: fat necrosis in 14 group A versus four group B patients (P < 0.001); parenchymal scarring classified as unorganized at the last follow-up in 16 vs seven cases, respectively (P = 0.03). Ultrasound: overall number of patients with circumscribed findings 27 vs 18 (P < 0.001); particular hematomas/seromas in 26 vs 13 patients (P < 0.001). Synopsis of mammography and ultrasound: overall postoperative changes were significantly higher classified in group A (P = 0.01), but not judged to have a significantly higher impact on interpretation. Additional diagnostic procedures, due to unclear findings at the surgical site, were performed on four patients of both groups. Within the first 2 years after IORT as a boost, therapy-induced changes at the original tumor site are significantly more pronounced compared with a control group. There is no evidence that the interpretation of findings is complicated after IORT.

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.

Vaidya JS, Baum M, Tobias JS, Massarut S, Wenz F, Murphy O, Hilaris B, Houghton J, Saunders C, Corica T, Roncadin M, Kraus-Tiefenbacher U, Melchaert F, Keshtgar M, Sainsbury R, Douek M, Harrison E, Thompson A, Joseph D. · Department of Surgery and Molecular Oncology, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK. · Int J Radiat Oncol Biol Phys. · Pubmed #17084562 No free full text.

Abstract: PURPOSE: Patients undergoing breast-conserving surgery were offered boost radiotherapy with targeted intraoperative radiotherapy (TARGIT) using the Intrabeam system to test the feasibility, safety, and efficacy of the new approach. METHODS AND MATERIALS: We treated 302 cancers in 301 unselected patients. This was not a low-risk group. One-third of patients (98/301) were younger than 51 years of age. More than half of the tumors (172, 57%) were between 1 cm and 2 cm, and one-fifth (62, 21%) were >2 cm; 29% (86) had a Grade 3 tumor and, in 29% (87), axillary lymph nodes contained metastasis. After primary surgery, 20 Gy was delivered intraoperatively to the surface of the tumor bed, followed by external-beam radiotherapy (EBRT), but excluding the usual boost. RESULTS: The treatment was well tolerated. The follow-up ranged from 3 to 80 months (164 and 90 patients completed 2 and 3 years follow-up, respectively). Four patients (1.3%) had local recurrence. The Kaplan-Meier estimate of local recurrence is 2.6% (SE = 1.7) at 5 years. This compares favorably with the 4.3% recurrence rate in boosted patients from the EORTC boost study, in which only 8.1% patients were node-positive, as opposed to 29% in our series. CONCLUSION: Targeted intraoperative radiotherapy combined with EBRT results in a low local recurrence rate. This could be attributed to both accurate targeting and timeliness of the treatment. These data support the need for a randomized trial to test whether the TARGIT boost is superior to conventional external boost, especially in high-risk women.

Kraus-Tiefenbacher U, Bauer L, Scheda A, Fleckenstein K, Keller A, Herskind C, Steil V, Melchert F, Wenz F. · Department of Radiation Oncology, Mannheim Medical Center, University of Heidelberg, Mannheim, Germany. · Int J Radiat Oncol Biol Phys. · Pubmed #16887294 No free full text.

Abstract: PURPOSE: Intraoperative radiotherapy (IORT) as a boost for breast cancer delivers a high single dose of radiation to a late-reacting tissue; therefore late toxicity is of particular interest, and long-term follow-up is warranted. To date there are only limited data available on breast cancer patients treated with IORT using low energy X-rays. We analyzed toxicity and cosmesis after IORT as a boost with a minimum follow-up of 18 months. METHODS AND MATERIALS: A total of 73 patients treated with IORT (20 Gy/50 kV X-rays; INTRABEAM [Carl Zeiss Surgical, Oberkochen, Germany]) to the tumor bed during breast-conserving surgery as a boost followed by whole-breast radiotherapy (WBRT, 46 Gy) underwent a prospective, predefined follow-up (median, 25 months; range 18-44 months), including clinical examination and breast ultrasound at 6-months and mammographies at 1-year intervals. Toxicities were documented using the common toxicity criteria (CTC)/European Organization for Research and Treatment of Cancer and the LENT-SOMA score. Cosmesis was evaluated with a score from 1 to 4. RESULTS: The IORT in combination with WBRT was well tolerated, with no Grade 3 or 4 skin toxicities and no telangiectasias. Fibrosis of the entire breast was observed in 5% of the patients. A circumscribed fibrosis around the tumor bed was palpable in up to 27% with a peak around 18 months after therapy and a decline thereafter. The observed toxicitiy rates were not influenced by age, tumor stage, or systemic therapy. The cosmetic outcome was good to excellent in>or=90% of cases. CONCLUSIONS: After IORT of the breast using low-energy X-rays, no unexpected toxicity rates were observed during long-term-follow-up.

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.