Reproducibility of the CROSS Trial Results in the Multimodal Treatment of Esophageal Cancer in Daily Practice: A Single Center Retrospective Observational Study.

Background: Treatment of nonmetastatic esophageal cancer with curative intention remains a major challenge. Neoadjuvant radiochemotherapy followed by surgery, as described in the CROSS trial in 2012, has been established as a standard of care. With this retrospective observational study, we aimed to analyze the results of the CROSS regimen in daily practice over the last 10 years at the St. Clara Hospital, a Swiss center for esophageal surgery. Methods: To determine the clinical outcome in our daily practice, the medical records of all patients with potentially curable localized esophageal cancer (T1N1 or T2-3N0-1 M0) treated with radiochemotherapy in neoadjuvant intention according to the CROSS regimen were reviewed. The primary endpoint was overall survival. Furthermore, an overall survival analysis of the subgroups of patients who exactly met the inclusion criteria of the CROSS trial with respect to age and weight loss before therapy was performed. The Kaplan-Meier method was used to estimate survival and compared by the log-rank test. Results: From January 2012 to January 2022, 91 patients with T1N1 or T2-3N0-1M0 esophageal cancer underwent neoadjuvant radiochemotherapy according to the CROSS regimen. The median age was 70 years (range 31-86 years), and 26 (29%) patients were over 75 years of age. Weight loss of more than 10% was observed in 23 (25%) patients. 77 (85%) patients underwent esophagectomy, and complete resection (R0) was obtained in 73 (95%) of them. The median overall survival was 41 months, compared to 49.4 months in the CROSS trial. The overall survival rate at 12 months was 85% and at 24 months, it was 68%, very similar to the CROSS trial results. 51% of the patients fully met the inclusion criteria of the CROSS trial with respect to age and pretherapeutic weight loss. Their overall survival rate at 12 months was 94% at St. Clara Hospital versus 82% in the CROSS trial (p=0.04), and at 24 months, 81% versus 67% (p=0.05). Conclusion: Overall, in a center specialized for the multimodal treatment of nonmetastatic esophageal cancer, the results of the CROSS trial seem to be well reproducible in daily practice.

DEGRO practical guideline for partial-breast irradiation.

PURPOSE: This consensus statement from the Breast Cancer Working Group of the German Society for Radiation Oncology (DEGRO) aims to define practical guidelines for accelerated partial-breast irradiation (APBI). METHODS: Recent recommendations for relevant aspects of APBI were summarized and a panel of experts reviewed all the relevant literature. Panel members of the DEGRO experts participated in a series of conferences, supplemented their clinical experience, performed a literature review, and formulated recommendations for implementing APBI in clinical routine, focusing on patient selection, target definition, and treatment technique. RESULTS: Appropriate patient selection, target definition for different APBI techniques, and basic rules for appropriate APBI techniques for clinical routine outside of clinical trials are described. Detailed recommendations for APBI in daily practice, including dose constraints, are given. CONCLUSION: Guidelines are mandatory to assure optimal results of APBI using different techniques.

THE GERMAN DOSE RATE MONITORING NETWORK AND IMPLEMENTED DATA HARMONIZATION TECHNIQUES.

Environmental radiation monitoring networks have been established in Europe and world-wide for the purpose of protecting population and environment against ionizing radiation. Some of these networks had been established during the cold war period and were improved after the Chernobyl accident in 1986. Today, the German Federal Office for Radiation Protection (BfS) operates an early warning network with roughly 1800 ambient dose equivalent rate (ADER) stations equally distributed over the German territory. The hardware and software of all network components are developed in-house allowing the continuous optimization of all relevant components. A probe characterization and quality assurance and control program are in place. Operational and technical aspects of the network and data harmonization techniques are described. The latter allows for calculating of the terrestrial and net ADER combined with uncertainties mainly from site specific effects. Harmonized data are finally used as input to the German emergency management system and the European radiological data exchange platform.

DEGRO practical guidelines: radiotherapy of breast cancer III--radiotherapy of the lymphatic pathways.

AIM: The purpose of this work is to update the practical guidelines for adjuvant radiotherapy of the regional lymphatics of breast cancer published in 2008 by the breast cancer expert panel of the German Society of Radiation Oncology (DEGRO). METHODS: A comprehensive survey of the literature concerning regional nodal irradiation (RNI) was performed using the following search terms: "breast cancer", "radiotherapy", "regional node irradiation". Recent randomized trials were analyzed for outcome as well as for differences in target definition. Field arrangements in the different studies were reproduced and superimposed on CT slices with individually contoured node areas. Moreover, data from recently published meta-analyses and guidelines of international breast cancer societies, yielding new aspects compared to 2008, provided the basis for defining recommendations according to the criteria of evidence-based medicine. In addition to the more general statements of the German interdisciplinary S3 guidelines updated in 2012, this paper addresses indications, targeting, and techniques of radiotherapy of the lymphatic pathways after surgery for breast cancer. RESULTS: International guidelines reveal substantial differences regarding indications for RNI. Patients with 1-3 positive nodes seem to profit from RNI compared to whole breast (WBI) or chest wall irradiation alone, both with regard to locoregional control and disease-free survival. Irradiation of the regional lymphatics including axillary, supraclavicular, and internal mammary nodes provided a small but significant survival benefit in recent randomized trials and one meta-analysis. Lymph node irradiation yields comparable tumor control in comparison to axillary lymph node dissection (ALND), while reducing the rate of lymph edema. Data concerning the impact of 1-2 macroscopically affected sentinel node (SN) or microscopic metastases on prognosis are conflicting. CONCLUSION: Recent data suggest that the current restrictive use of RNI should be scrutinized because the risk-benefit relationship appears to shift towards an improvement of outcome.

INTERCAL: long-term inter-comparison experiment for dose rate and spectrometric probes.

The Schauinsland inter-calibration facility (INTERCAL) has been designed to enable long-term comparison experiments for 20 different dose rate probes from different networks. Two reference probes characterised by the European Radiation Dosimetry WG3 inter-calibration experiments in 2008 and 2009 have been installed at the INTERCAL facility. Additional instrumentation provides measured data of activity in air and nuclide-specific dose rate as well as environmental parameters such as air pressure, temperature, precipitation and soil moisture. Complementary to WG3 experiments, the INTERCAL platform is an ideal framework to investigate the long-term behaviour of dose rate probes and different spectrometry systems under environmental conditions. Two additional exposure experiments were performed in April 2009 and in May 2012.

Open-source hardware and software and web application for gamma dose rate network operation.

The German Federal Office for Radiation Protection operates a network of about 1800 gamma dose rate stations as a part of the national emergency preparedness plan. Each of the six network centres is capable of operating the network alone. Most of the used hardware and software have been developed in-house under open-source license. Short development cycles and close cooperation between developers and users ensure robustness, transparency and fast maintenance procedures, thus avoiding unnecessary complex solutions. This also reduces the overall costs of the network operation. An easy-to-expand web interface has been developed to make the complete system available to other interested network operators in order to increase cooperation between different countries. The interface is also regularly in use for education during scholarships of trainees supported, e.g. by the 'International Atomic Energy Agency' to operate a local area dose rate monitoring test network.

DEGRO practical guidelines: radiotherapy of breast cancer II: radiotherapy of non-invasive neoplasia of the breast.

PURPOSE: To complement and update the 2007 practice guidelines of the breast cancer expert panel of the German Society of Radiation Oncology (DEGRO) for radiotherapy (RT) of breast cancer. Owing to its growing clinical relevance, in the current version, a separate paper is dedicated to non-invasive proliferating epithelial neoplasia of the breast. In addition to the more general statements of the German interdisciplinary S3 guidelines, this paper is especially focused on indication and technique of RT in addition to breast conserving surgery. METHODS: The DEGRO expert panel performed a comprehensive survey of the literature comprising recently published data from clinical controlled trials, systematic reviews as well as meta-analyses, referring to the criteria of evidence-based medicine yielding new aspects compared to 2005 and 2007. The literature search encompassed the period 2008 to September 2012 using databases of PubMed and Guidelines International Network (G-I-N). Search terms were "non invasive breast cancer", "ductal carcinoma in situ, "dcis", "borderline breast lesions", "lobular neoplasia", "radiotherapy" and "radiation therapy". In addition to the more general statements of the German interdisciplinary S3 guidelines, this paper is especially focused on indications of RT and decision making of non-invasive neoplasia of the breast after surgery, especially ductal carcinoma in situ. RESULTS: Among different non-invasive neoplasia of the breast only the subgroup of pure ductal carcinoma in situ (DCIS; synonym ductal intraepithelial neoplasia, DIN) is considered for further recurrence risk reduction treatment modalities after complete excision of DCIS, particularly RT following breast conserving surgery (BCS), in order to avoid a mastectomy. About half of recurrences are invasive cancers. Up to 50 % of all recurrences require salvage mastectomy. Randomized clinical trials and a huge number of mostly observational studies have unanimously demonstrated that RT significantly reduces recurrence risks of ipsilateral DCIS as well as invasive breast cancer independent of patient age in all subgroups. The recommended total dose is 50 Gy administered as whole breast irradiation (WBI) in single fractions of 1.8 or 2.0 Gy given on 5 days weekly. Retrospective data indicate a possible beneficial effect of an additional tumor bed boost for younger patients. Prospective clinical trials of different dose-volume concepts (hypofractionation, accelerated partial breast irradiation, boost radiotherapy) are still ongoing. CONCLUSION: Postoperative radiotherapy permits breast conservation for the majority of women by halving local recurrence as well as reducing progression rates into invasive cancer. New data confirmed this effect in all patient subsets-even in low risk subgroups (LoE 1a).

DEGRO practical guidelines: radiotherapy of breast cancer I: radiotherapy following breast conserving therapy for invasive breast cancer.

BACKGROUND AND PURPOSE: The aim of the present paper is to update the practical guidelines for postoperative adjuvant radiotherapy of breast cancer published in 2007 by the breast cancer expert panel of the German Society for Radiooncology (Deutsche Gesellschaft für Radioonkologie, DEGRO). The present recommendations are based on a revision of the German interdisciplinary S-3 guidelines published in July 2012. METHODS: A comprehensive survey of the literature concerning radiotherapy following breast conserving therapy (BCT) was performed using the search terms "breast cancer", "radiotherapy", and "breast conserving therapy". Data from lately published meta-analyses, recent randomized trials, and guidelines of international breast cancer societies, yielding new aspects compared to 2007, provided the basis for defining recommendations according to the criteria of evidence-based medicine. In addition to the more general statements of the DKG (Deutsche Krebsgesellschaft), this paper addresses indications, target definition, dosage, and technique of radiotherapy of the breast after conservative surgery for invasive breast cancer. RESULTS: Among numerous reports on the effect of radiotherapy during BCT published since the last recommendations, the recent EBCTCG report builds the largest meta-analysis so far available. In a 15 year follow-up on 10,801 patients, whole breast irradiation (WBI) halves the average annual rate of disease recurrence (RR 0.52, 0.48-0.56) and reduces the annual breast cancer death rate by about one sixth (RR 0.82, 0.75-0.90), with a similar proportional, but different absolute benefit in prognostic subgroups (EBCTCG 2011). Furthermore, there is growing evidence that risk-adapted dose augmentation strategies to the tumor bed as well as the implementation of high precision RT techniques (e.g., intraoperative radiotherapy) contribute substantially to a further reduction of local relapse rates. A main focus of ongoing research lies in partial breast irradiation strategies as well as WBI hypofractionation schedules. The potential of both in replacing normofractionated WBI has not yet been finally clarified. CONCLUSION: After breast conserving surgery, no subgroup even in low risk patients has yet been identified for whom radiotherapy can be safely omitted without compromising local control and, hence, cancer-specific survival. In most patients, this translates into an overall survival benefit.

When are breast cancer patients old enough for the quitclaim of local control?

BACKGROUND: Although postoperative radiotherapy (RT) after breast-conserving surgery (BCS) halves the 10-year recurrence rate in breast cancer patients through all age groups, the question of whether RT may be omitted and replaced by endocrine therapy for women aged 70 years and older with low-risk factors has recently become an issue of debate. METHODS: Survey of the relevant recent literature (Medline) and international guidelines. RESULTS: Three randomized studies investigating the effect of RT in older women revealed significantly increased local recurrence rates when RT was omitted, and a negative impact on disease-free survival was observed in two of these trials. Despite these findings, in one of the studies omission of RT in women over 70 is recommended, leading to a respective amendment in the guidelines of the American National Comprehensive Cancer Network. Several large retrospective cohort studies analyzing the outcome of patients over 65 years with and without RT have since been published and showed a significantly improved local control in all subgroups of advanced age and stage, which predominantly translated into improved disease-free and overall survival. CONCLUSION: No subgroup of elderly patients has yet been identified that did not profit from RT in terms of local control. Therefore, chronological age alone is not an appropriate criterion for deciding against or in favor of adjuvant RT. The DEGRO breast cancer expert panel explicitly discourages determination of a certain age for the omission of postoperative RT in healthy elderly women with low-risk breast cancer. For frail elderly women, treatment decisions should be individually decided on the basis of standardized geriatric assessment.

Whole-abdominal IMRT for advanced ovarian carcinoma: planning issues and feasibility.

INTRODUCTION: Despite enormous efforts to improve therapeutic strategies for patients with advanced ovarian carcinoma, outcome remains poor even with the advent cisplatinum-based chemotherapy regimen or taxanes with over 70% of patients developing local failure. Several trials were able to establish the potential benefit of adjuvant whole abdominal RT (WAI) though at the cost of sometimes marked side-effects. New technologies like IMRT have the potential of sparing normal tissues thus also potentially limiting treatment-related toxicity, hence a phase I trial was initiated to evaluate potential clinical benefit of WAI with IMRT. We intended to demonstrate that whole-abdominal IMRT is feasible and can be used in a routine clinical setting. METHODS: A water-equivalent phantom containing OARs was created simulating organ shape of the upper abdomen to investigate the necessary number of beams for the upper abdominal target irrespective of the number of segments and hence treatment times. We prescribed a total dose of 30 Gy in 1.5 Gy fractions to the median of the target. IMRT treatment plans for three patients with advanced ovarian cancer were created using 2 isocentres and between 12 and 14 beams while restricting the number of segments so as to restrict treatment times to less than 45 min. Dose to OARs such as kidneys and liver was strictly limited even below established maxima. RESULTS: In the phantom plans, no clear indication as to the optimum number of beams could be shown though there seems to be a slight trend toward a higher number of beams yielding better results. Examples demonstrating clinically inacceptable dose distributions for plans using only 9 beams. Acceptable treatment plans for real patients could be achieved using 12-14 beams and 2 isocentres. Treatment plans consisted of 264-286 segments resulting in an overall treatment time of approximately 37-45 min. Mean doses to the kidneys could be limited to 29.3% [23.1-33.2%] (right), and 26.8% [21-30.4%] (left). 50% of the liver received less than 72.4% [61-83%]. CONCLUSION: IMRT for whole abdominal irradiation in patients with advanced ovarian carcinoma is applicable and feasible though treatment planning is complex and time-consuming. There is a significant reduction of dose to critical organs by using IMRT while maintaining target volume coverage.

Neoadjuvant chemoradiation in patients with pancreatic adenocarcinoma.

In spite of the high mortality in pancreatic cancer, significant progress is being made. This review discusses multimodality therapy for patients with pancreatic cancer. Surgical therapy currently offers the only potential monomodal cure for pancreatic adenocarcinoma. However, only 10-20% of patients present with tumors that are amenable to resection, and even after resection of localized cancers, long-term survival is rare. The addition of chemoradiation therapy significantly increases median survival. To achieve long-term success in treating this disease it is therefore increasingly important to identify effective neoadjuvant/adjuvant multimodality therapies. Preoperative chemoradiation for potentially resectable pancreatic cancer has the following advantages: (1) neoadjuvant treatment would eliminate the delay of adjuvant treatment due to postoperative complications; (2) neoadjuvant treatment could avoid unnecessary surgery for patients with metastatic disease evident on restaging after neoadjuvant therapy; (3) down-staging after neoadjuvant therapy may increase the likelihood of negative surgical margins; and (4) neoadjuvant treatment could prevent peritoneal tumor cell implantation and dissemination caused during surgery. This review systematically summarizes the current status, controversies, and prospects of neoadjuvant treatment of pancreatic cancer.

Daytime pulsed dose rate brachytherapy as a new treatment option for previously irradiated patients with recurrent oesophageal cancer.

The aim of this study was to evaluate the feasibility, effects, and toxicity of pulsed dose rate (PDR) brachytherapy for re-irradiation of oesophageal carcinoma. A total of 16 patients (median age 67 years) with inoperable recurrences from oesophageal cancer after primary radio-(chemo)-therapy (median 50 Gy) were re-irradiated using PDR brachytherapy ((192)Ir, 37 GBq). Treatment was carried out on an outpatient basis applying a weekly 5 Gy daytime schedule (0.5 Gy pulse(-1) h(-1), total dose 15-20 Gy). The dose was prescribed 10 mm from the mid-dwell position and encompassed the clipped tumour extension with 2 cm margins. The use of clips for delineation of tumour extent and catheter movement during irradiations was evaluated. All 61 PDR treatments were applied safely. The median catheter movement was 5 mm, range 2-12 mm. After a median follow-up of 8 months, three patients had a complete and five a partial remission. Body weight increased in 5 of 16 (31%) and was stable in 4 of 16 (25%) patients, respectively. The median grade 2 (RTOG/EORTC) dysphagia-free survival was 17 months. Seven patients experienced grade 1, five grade 2, and one grade 3 late toxicity. Three patients with uncontrolled locoregional disease showed grade 4 complications (oesophago-tracheal fistulae (n=2), fatal arterial bleeding (n=1). Daytime PDR brachytherapy proved to be feasible and provided effective palliation. Toxicity remains a major problem. Thus, total dose should be restricted to <15 Gy in this palliative situation.

Intercomparison experiments of systems for the measurement of xenon radionuclides in the atmosphere.

Radioactive xenon monitoring is one of the main technologies used for the detection of underground nuclear explosions. Precise and reliable measurements of (131m)Xe, (133g)Xe, (133m)Xe, and (135g)Xe are required as part of the International Monitoring System for compliance with the Comprehensive Nuclear-Test-Ban Treaty (CTBT). For the first time, simultaneous testing of four highly sensitive and automated fieldable radioxenon measurement systems has been performed and compared to established laboratory techniques. In addition to an intercomparison of radioxenon monitoring equipment of different design, this paper also presents a set of more than 2000 measurements of activity concentrations of radioactive xenon made in the city of Freiburg, Germany in 2000. The intercomparison experiment showed, that the results from the newly developed systems agree with each other and the equipment fulfills the fundamental requirements for their use in the verification regime of the CTBT. For 24-h measurements, concentrations as low as 0.1 mBqm(-3) were measured for atmospheric samples ranging in size from 10 to 80 m(3). The (133)Xe activity concentrations detected in the ambient air ranged from below 1 mBqm(-3) to above 100 mBqm(-3).

[Reirradiation of chest wall local recurrences from breast cancer]. / Rebestrahlung der Thoraxwand bei lokal rezidivierenden Mammakarzinomen.

OBJECTIVE: The aim of this article was to describe the radio-therapeutic treatment options in previously irradiated patients suffering from breast cancer local recurrences and to review the literature. MATERIAL AND METHODS: Reirradiation of the chest wall can be performed using electron beams or alternatively CLDR/PDR (continuous/pulsed low dose rate) brachytherapy techniques with large skin moulds. With both techniques high doses can be applied to the chest wall while deeper-seated organs (lung, heart) can be spared to a large extent. Electron-beam therapy is readily available and the depth of treatment can be easily controlled by selecting the appropriate energy. The protracted irradiation schedule of CLDR/PDR brachytherapy results due to radiobiological reasons in a broad therapeutic ratio and safe treatment time. RESULTS: In the literature, more than 250 cases being reirradiated for chest wall local recurrences have been published. After retreatment using electron beams complete remissions were obtained in 41-74 % of the patients (brachytherapy 79-82 %). Severe grade IV complications (RTOG/EORTC) occurred in less than 10 % of the patients. CONCLUSIONS: With regard to the limited treatment options reirradiation of chest wall local recurrences resulted in high local control rates while toxicity remained acceptable. These data weaken the radio-therapeutic dogma that reirradiation of the chest wall may not be possible.

[Diagnosis with (18)F-FDG PET scan after larynx preservation by primary radiochemotherapy]. / Diagnostik mittels (18)F-FDG-PET nach Larynxorganerhalt durch primäre Radiochemotherapie.

PATIENTS AND METHODS: In a group of 20 patients undergoing chemoradiation for larynx organ preservation after diagnosis of laryngeal and hypopharyngeal carcinoma, (18)F-fluordeoxyglucose positron emission tomography ((18)F-FDG-PET) was performed before the start of therapy. After i.v. application of 240 MBq FDG, a dynamic PET in 3-D-mode was performed over 90 min (Siemens CTI ECAT EXACT HR(+)). Analysis was done visually and semiquantitatively (60-90 min p.i.) following iterative reconstruction. Additional (18)F-FDG-PET investigations were done and correlated with the clinical outcome in 16/20 patients at 3 months and in 14/20 patients at 6 months after the end of therapy. RESULTS: In 17/20 patients (85%), the preclinical (18)F-FDG-PET correlated well with the histologically confirmed primary tumor. Three cases were false negatives. In one case this was due to an increased glucose value (203 mg%). After 3 months, 8/13 (62%) patients showed a positive correlation between clinical and PET results (sensitivity 100%, specificity 70%). After 6 months, 9/11 (82%) patients presented clinically normal PET results. PET results were false negative in one case (sensitivity 67%, specificity 88%). CONCLUSION: The data of our trial slightly reduce the enthusiasm of early (18)F-FDG-PET detection of residual disease after chemoradiation in resectable laryngeal or hypopharyngeal cancer. Further trials should optimize the calculation integrating the exact quantification of glucose metabolism with the aim of improving sensitivity and specificity.