IOERT (intraoperative electron radiotherapy) in breast cancer is used either as a boost (10-12 Gy) followed by whole breast irradiation (WBI) or as full-dose partial breast irradiation (PBI, 20-24 Gy) during breast-conserving surgery. IOERT has the longest evidence of all IORT techniques. When administered as a boost, excellent low local recurrence rates were observed in long-term follow-up >5 years. Even in high-risk groups like triple-negative or locally advanced breast cancers, IOERT contributes to long-term local control rates of more than 90%. For selected low-risk groups, IOERT as PBI with 21 Gy seems to be a viable treatment alternative to standard WBI. IOERT has been shown to be advantageous for several reasons: Geographic misses are avoided due to direct visualization of the tumor bed; thus, a high single dose is delivered with utmost precision to small volumes, completely sparing the skin and ensuring good long-term cosmetic outcome. Furthermore, high single doses seem to induce biological mechanisms with verifiable antitumor capability in in-vitro cell-line studies. In addition, IOERT markedly shortens the overall treatment time both in combination with (now mostly hypofractionated) WBI or as a PBI in selected low-risk constellations. (C) 2018 S. Karger GmbH, Freiburg

The role of radiotherapy (RT) for nonmetastatic pancreatic cancer is still a matter of debate since randomized control trials have shown inconsistent results. The current retrospective single-institution study includes both resected and unresected patients with nonmetastasized pancreatic cancer. The aim is to analyze overall survival (OS) after irradiation combined with induction chemotherapy.

Purpose: To assess retrospectively the role of an anticipated intraoperative tumor electron radiation therapy (IOERT) as a bed boost during breast-conserving surgery followed by conventional whole breast irradiation (WBI). Methods and Materials: An unselected cohort of 770 breast cancer patients of all risk types was analyzed in terms of local control (LC) and survival outcome. Patients were treated by breast-conserving surgery, IOERT of 10 Gy, and WBI to total median doses of 54 Gy (range, 1.6-2). Patients were retrospectively analyzed for LC, locoregional control, metastasis-free survival (MFS), overall survival (OS), and breast cancer-specific survival (BCSS). Results: After a median follow-up of 121 months (range, 4-200), 21 (2.7%) in-breast recurrences (IBRs) were observed, 107 patients (14%) died and 106 (14%) developed metastases. Ten-year rates of LC, locoregional control, MFS, OS, and BCSS amounted to 97.2%, 96.5%, 86%, 85.7%, and 93.2 %, respectively. In multivariate analysis, HER2+ and triple-negative breast cancer subtype (TN) turned out to be significant negative predictors for IBRs (hazard ratios, 15.02 and 12.87, respectively; P <.05). Sorted by subtypes, 10-year LC rates were observed in 98.7% (range, 96.7%-99.5%) (luminal A), 98% (range, 94%-99.3%) (luminal B), 87.9% (range, 66.2%-96%) (HER2+), and 89% (range, 76.9%-94.9%) (TN), respectively. Conclusions: After 10 years, boost IOERT maintains high LC rates in any risk setting. (C) 2018 Elsevier Inc. All rights reserved.

To report acute and late toxicity with long-term follow-up, and to describe our experiences with pulmonary dose constraints.

The term IORT (intraoperative radiotherapy) is currently used for various techniques that show huge differences in dose delivery and coverage of the tissue at risk. The largest evidence for boost IORT preceding whole breast irradiation (WBI) originates from intraoperative electron treatments (IOERT) with single doses around 10 Gy. At median follow-up periods at 6 years, outstandingly low local recurrence rates of less than 1% are observed. Higher local relapse rates were described for G3 tumors and triple negative breast cancers as well as for IORT following primary systemic treatment for locally advanced tumors. Even there, long term (>5y) local tumor control rates mostly beyond 95% were maintained. Compared to other boost methods, an intraoperative treatment has evident advantages in terms of precision (by avoiding a "spatial and/or temporal miss"), cosmetic outcome and patient comfort. Direct visualisation of a tumor bed during surgery guarantees for an accurate dose delivery, which has additionally gained importance in times of primary reconstruction techniques after lumpectomy, since IORT is performed before breast tissue including parts of the tumor bed is mobilized for plastic purposes. As a consequence of direct tissue exposure without distension by hematoma/seroma, IORT allows for small treatment volumes and complete skin sparing, both having a positive effect on late tissue tolerance and, hence, cosmetic appearance. Boost IORT marginally prolongs the surgical procedure, while significantly shortening postoperative radiotherapy. Its combination with external beam radiotherapy to the whole breast (WBI) is currently tested in two multicentric prospective trials: as kV-IORT in the multicentric TARGIT-B (oost) study, and as IOERT in the HIOB trial (3 weeks hypofractionated WBI preceded by IORT electron boost).

AIM:The purpose of this work was to retrospectively evaluate survival and local control rates of triple-negative breast cancer subtypes classified as five marker negative (5NP) and core basal (CB), respectively, after breast-conserving surgery and intraoperative boost radiotherapy with electrons (IOERT) followed by whole breast irradiation.METHODS AND MATERIALS:A total of 71 patients with triple-negative breast cancer were enrolled, who were treated with lumpectomy, axillary lymph node dissection, and IOERT with 9.6 Gy (median Dmax) followed by normofractionated whole breast irradiation to median total doses of 54 Gy. Chemotherapy was applied in a neoadjuvant (12 %), adjuvant (75 %), or combinational setting (7 %).RESULTS:After a median follow-up of 97 months (range 4-170 months), 5 in-breast recurrences were detected (7.0 %). For all patients, 8-year actuarial rates for local control, metastases-free survival, disease-specific survival, and overall survival amounted to 89, 75, 80, and 69 %, respectively. All local recurrences occurred in grade 3 (G3) tumors irrespective of their specific immunohistochemical phenotype; thus, the local control rate for grades 1/2 (G1/2) was 100 % for both 5NP and CB, while for G3 it was 88 % for 5NP and 90 % for CB (p = 0.65 and 0.82, respectively, n.s.). For disease-specific survival, only the difference of the best-prognosis group 5-NP/G3 vs. the worst-prognosis cohort CB/G1/2 was statistically significant: 90 % vs. 54 % (p = 0.03).CONCLUSION:Boost-IOERT provides acceptable long-term in-breast control in triple negative breast cancer. The best subgroup in terms of disease-specific survival was represented by 5NP in combination with tumor grading G3.

A total of 124 Taylorella (T.) equigenitalis and five T. asinigenitalis field isolates collected between 2002 and 2014 were available for genotyping using REP- (repetitive extragenic palindromic) PCR and PFGE (pulsed-field gel electrophoresis). The study comprised 79 T. equigenitalis field isolates originating from ten defined breeds of German horses and revealed a spectrum of five REP (rep-E1-E4, rep-E3a) and 15 PFGE (TE-A1-A9, TE-B1-B3, TE-C, TE-E1, and TE-E2) genotypes. T. equigenitalis field isolates (n=40) obtained from Austrian Lipizzaner horses were differentiated into three REP (rep-E1, rep-E3a, and rep-E4) and three PFGE genotypes (TE-A2, TE-A5, and TE-D); those isolated from four Austrian Trotters belonged to the REP/PFGE genotype rep-E2/TE-A1. Interestingly, a T. equigenitalis isolate recovered from a Holsteiner stallion living in South Africa revealed the REP/PFGE genotype rep-E1/TE-A5 which was otherwise exclusively present in the majority of Austrian Lipizzaner horses in our study. The type strain included in this study revealed the genotype REP/PFGE rep-E1/TE-F. Six strains of T. asinigenitalis including the type strain were separated into three REP (rep-A1-A3) and six PFGE genotypes (TA-A1, TA-A2, TA-A3, TA-B, TA-C, TA-D). Overall, the generated REP and PFGE genotypes showed a good correlation, whereas REP-PCR proved to be a suitable method for molecular epidemiological screening of T. equigenitalis and T. asinigenitalis isolates that should be differentiated in detail by genotyping using PFGE.

To evaluate retrospectively rates of local (LCR) and locoregional tumor control (LRCR) in patients with locally advanced breast cancer (LABC) who were treated with preoperative chemotherapy (primary systemic treatment, PST) followed by breast‐conserving surgery (BCS) and either intraoperative radiotherapy with electrons (IOERT) preceding whole‐breast irradiation (WBI) (Group 1) or with WBI followed by an external tumor bed boost (electrons or photons) instead of IOERT (Group 2). From 2002 to 2007, 83 patients with clinical Stage II or III breast cancer were enrolled in Group 1 and 26 in Group 2. All patients received PST followed by BCS and axillary lymph node dissection. IOERT boosts were applied by single doses of 9 Gy (90% reference isodose) versus external boosts of 12 Gy (median dose range, 6–16) in 2 Gy/fraction (ICRU). WBI in both groups was performed up to total doses of 51–57 Gy (1.7–1.8 Gy/fraction). The respective median follow‐up times for Groups 1 and 2 amount 59 months (range, 3–115) and 67.5 months (range, 13–120). Corresponding 6‐year rates for LCR, LRCR, metastasis‐free survival, disease‐specific survival and overall survival were 98.5, 97.2, 84.7, 89.2 and 86.4% for Group 1 and 88.1, 88.1, 74, 92 and 92% for Group 2, respectively, without any statistical significances. IOERT as boost modality during BCS in LABC after PST shows a trend to be superior in terms of LCR and LRCR in comparison with conventional boosts.

While surgery is considered standard of care for early stage (I/II), non-small-cell lung cancer (NSCLC), radiotherapy is a widely accepted alternative for medically unfit patients or those who refuse surgery. International guidelines recommend several treatment options, comprising stereotactic body radiation therapy (SBRT) for small tumors, conventional radiotherapy ≥ 60 Gy for larger sized especially centrally located lesions or continuous hyperfractionated accelerated RT (CHART). This study presents clinical outcome and toxicity for patients treated with a dose-differentiated accelerated schedule using 1.8 Gy bid (DART-bid).

The term IORT (intraoperative radiotherapy) is currently used for various techniques that show decisive differences in dose delivery. The largest evidence for boost IORT preceding whole breast irradiation (WBI) originates from intraoperative electron treatments with single doses around 10 Gy, providing outstandingly low local recurrence rates in any risk constellation also at long term analyses. Compared to other boost methods, an intraoperative treatment has evident advantages as follows. Precision. Direct visualisation of the tumour bed during surgery guarantees an accurate dose delivery. This fact has additionally gained importance in times of primary reconstruction techniques after lumpectomy to optimise cosmetic outcome. IORT is performed before breast tissue is mobilised for plastic purposes. Cosmesis. As a consequence of direct tissue exposure without distension by hematoma/seroma, IORT allows for small treatment volumes and complete skin sparing, both having a positive effect on late tissue tolerance and, hence, cosmetic appearance. Patient Comfort. Boost IORT marginally prolongs the surgical procedure, while significantly shortening postoperative radiotherapy. Its combination with a 3-week hypofractionated external beam radiotherapy to the whole breast (WBI) is presently tested in the HIOB trial (hypofractionated WBI preceded by IORT electron boost), a prospective multicenter trial of the International Society of Intraoperative Radiotherapy (ISIORT).

BACKGROUND:Sequential chemo-radiotherapies with intensive radiation components deliver promising results in non-resected non-small cell lung cancer (NSCLC). In general, radiation doses are determined by dose constraints for normal tissues, not by features relevant for tumor control. DART-bid targets directly the doses required for tumor control, correlating doses to tumor volume in a differentiated mode. MATERIALS/METHODS:Radiation doses to primary tumors were aligned along increasing tumor size within 4 groups (<2.5 cm/2.5-4.5 cm/4.5-6.0 cm/>6.0 cm; mean number of three perpendicular diameters). ICRU-doses of 73.8 Gy/79.2 Gy/84.6 Gy/90.0 Gy, respectively, were applied. Macroscopically involved nodes were treated with a median dose of 59.4 Gy, nodal sites about 6 cm cranial to involved nodes electively with 45 Gy. Fractional doses were 1.8 Gy twice daily (bid).2 cycles chemotherapy were given before radiotherapy.Between 2004 and 2009, 160 not selected patients with 164 histologically/cytologically proven NSCLC were enrolled; Stage I: 38 patients; II: 6 pts.; IIIA: 69 pts.; IIIB: 47 pts. Weight loss >5%/3 months: 38 patients (24%).Primary endpoints are local and regional tumor control rates at 2 years (as >90% of locoregional failures occur within 2 years). Secondary endpoints are survival and toxicity. With a minimum follow-up time of 2 years for patients alive, the final results are presented. RESULTS:32 local and 10 regional recurrences occurred. The local and regional tumor control rates at 2 years are 77% and 93%, respectively.The median overall survival (OS) time is 28.0 months, the 2- and 5-year OS rates are 57% and 19%, respectively. For stage III patients, median OS amounts to 24.3 months, 2- /5-year OS rates to 51% and 18%, respectively.2 treatment-related deaths (progressive pulmonary fibrosis) occurred in patients with pre-existing pulmonary fibrosis. Further acute and late toxicity was mild. CONCLUSIONS:This novel approach yields a high level of locoregional tumor control and survival times. In general it is well tolerated. In all outcome parameters it seems to compare favourably with simultaneous chemo-radiotherapies, at present considered 'state of the art'; and is additionally amenable for an unselected patient population.

To investigate therapeutic outcome of dose escalation ≥ 80 Gy in nonresected non-small cell lung cancer (NSCLC).

Purpose: Our purpose was to investigate the tolerability of accelerated, twice-daily, high-dose radiotherapy. The secondary endpoints were survival and locoregional tumor control.Methods and Materials: Thirty consecutive patients with histologically/cytologically proven non small-cell lung cancer were enrolled. Tumor Stage I, II, III, and IIIB was found in 7, 3, 12, and 8 patients, respectively. We applied a median of 84.6 Gy (range, 75.6-90.0 Gy) to the primary tumors, 63.0 Gy (range, 59.4-72.0 Gy) to lymph nodes, and 45 Gy to nodes electively (within a region of about 6 cm cranial to macroscopically involved sites). Fractional doses of 1.8 Gy twice daily, with an interval of 11 hours, were given, resulting in a median treatment time of 35 days. In the majority of patients the conformal target-splitting technique was used. In 19 patients (63%) two cycles of induction chemotherapy were given. The median follow-up time of survivors is 72 months (range, 62-74 months).Results: We found Grade 1, 2 and 3 acute esophageal toxicity in 11 patients (37%), 2 patients (7%), and 2 patients (7%), respectively. Grade 2 acute pneumonitis was seen in 2 patients (7%). No late toxicity greater than Grade 1 was observed. The actual overall survival rates at 2 and 5 years are 63% and 23%, respectively; the median overall survival, 27.7 months. In 9 patients a local failure occurred, 7 of them presenting initially with an atelectasis without availability of 18-fluorodeoxyglucose-positron emission tomography staging at that time. In 4 patients recurrence occurred regionally.Conclusions: This Phase I/II trial with long-term follow-up shows low toxicity with promising results for survival and locoregional tumor control. (C) 2010 Elsevier Inc.

BACKGROUND:Reporting further developments evolved since the first report about this conformal technique.METHODS:Technical progress focused on optimization of the quality assurance (QA) program, especially regarding the required work input; and on optimization of beam arrangements.RESULTS:Besides performing the regular QA program, additional time consuming dosimetric measurements and verifications no longer have to be accomplished.'Class solutions' of treatment plans for six patients with non-resected non-small cell lung cancer in locally advanced stages are presented. Target configurations comprise one central and five peripheral tumor sites with different topographic positions to hilus and mediastinum. The mean dose to the primary tumor is 81,9 Gy (range 79,2-90,0 Gy), to macroscopically involved nodes 61,2 Gy (range 55,8-63,0 Gy), to electively treated nodes 45,0 Gy. Treatments are performed twice daily, with fractional doses of 1,8 Gy at an interval of 11 hours. Median overall treatment time is 33 days. The set-up time at the linac does not exceed the average time for any other patient.CONCLUSION:Target splitting is a highly conformal and nonetheless non-expensive method with regard to linac and staff time. It enables secure accelerated high-dose treatments of patients with NSCLC.

BACKGROUND AND PURPOSE:In this study, a new method is introduced, which allows the overlay of three-dimensional structures, that have been delineated on transverse slices, onto the fluoroscopy from conventional simulators in real time.PATIENTS AND METHODS:Setup deviations between volumetric imaging and simulation were visualized, measured and corrected for 701 patient isocenters.RESULTS:Comparing the accuracy to mere virtual simulation lacking additional X-ray imaging, a clear benefit of the new method could be shown. On average, virtual prostate simulations had to be corrected by 0.48 cm (standard deviation [SD] 0.38), and those of the breast by 0.67 cm (SD 0.66).CONCLUSION:The presented method provides an easy way to determine entity-specific safety margins related to patient setup errors upon registration of bony anatomy (prostate 0.9 cm for 90% of cases, breast 1.3 cm). The important role of planar X-ray imaging was clearly demonstrated. The innovation can also be applied to adaptive image-guided radiotherapy (IGRT) protocols.

In external beam radiotherapy of prostate cancer, the consideration of various systematic error types leads to wide treatment margins compromising normal tissue tolerance. We investigated if systematic set-up errors can be reduced by a set of initial image-guided radiotherapy (IGRT) sessions. 27 patients received daily IGRT resulting in a set of 882 cone-beam computed tomographies (CBCTs). After matching to bony structures, we analyzed the dimensions of remaining systematic errors from zero up to six initial IGRT sessions and aimed at a restriction of daily IGRT for 10% of all patients. For threshold definition, we determined the standard deviations (SD) of the shift corrections and selected patients out of this range for daily image guidance. To calculate total treatment margins, we demanded for a cumulative clinical target volume (CTV) coverage of at least 95% of the specified dose in 90% of all patients. The gain of accuracy was largest during the first three IGRTs. In order to match precision and workload criteria, thresholds for the SD of the corrections of 3.5 mm, 2.0 mm and 4.5 mm in the left-right (L-R), cranial-caudal (C-C), and anterior-posterior (A-P) direction, respectively, were identified. Including all other error types, the total margins added to the CTV amounted to 8.6 mm in L-R, 10.4 mm in C-C, and 14.4 mm in A-P direction. Only initially performed IGRT might be helpful for eliminating gross systematic errors especially after virtual simulation. However, even with daily IGRT performance, a substantial PTV margin reduction is only achievable by matching internal markers instead of bony anatomical structures.