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For decades, the antineoplastic potential of hyperthermia alone or in combination with radiotherapy and/or chemotherapy has been subject of intensive preclinical and clinical research in various tumor entities. The clinical evidence on the beneficial effects of additional hyperthermia in combination with intravesical Mitomycin C for superficial non-muscle-invasive bladder cancer as well as for deep regional microwave hyperthermia techniques applied during an external beam radiotherapy or chemoradiation treatment for more advanced tumors are summarized. In some series, deep regional hyperthermia in combination with an initial transurethral resection and Cisplatin-based chemoradiation increased the 5-year overall survival rates up to 20%. The presented data justifies a fresh irrespective chance for mild regional hyperthermia in the context of new progressive prospective trials on multimodality treatment for bladder preservation.

In order to evaluate organ-at-risk (OAR) doses in external-beam-accelerated partial-breast irradiation (APBI) compared to standard whole-breast irradiation (WBI) after breast-conserving surgery. Between 2011 and 2021, 170 patients with early breast cancer received APBI within a prospective institutional single-arm trial. The prescribed dose to the planning treatment volume was 38 Gy in 10 fractions on 10 consecutive working days. OAR doses for the contralateral breast, the ipsilateral, contralateral, and whole lung, the whole heart, left ventricle (LV), and the left anterior descending coronary artery (LAD), and for the spinal cord and the skin were assessed and compared to a control group with real-world data from 116 patients who underwent WBI. The trial was registered at the German Clinical Trials Registry, DRKS-ID: DRKS00004417. Compared to WBI, APBI led to reduced OAR doses for the contralateral breast (0.4 ± 0.6 vs. 0.8 ± 0.9 Gy, p = 0.000), the ipsilateral (4.3 ± 1.4 vs. 9.2 ± 2.5 Gy, p = 0.000) and whole mean lung dose (2.5 ± 0.8 vs. 4.9 ± 1.5 Gy, p = 0.000), the mean heart dose (1.6 ± 1.6 vs. 1.7 ± 1.4 Gy, p = 0.007), the LV V23 (0.1 ± 0.4 vs. 1.4 ± 2.6%, p < 0.001), the mean LAD dose (2.5 ± 3.4 vs. 4.8 ± 5.5 Gy, p < 0.001), the maximum spinal cord dose (1.5 ± 1.1 vs. 4.5 ± 5.7 Gy, p = 0.016), and the maximum skin dose (39.6 ± 1.8 vs. 49.1 ± 5.8 Gy, p = 0.000). APBI should be recommended to suitable patients to minimize the risk of secondary tumor induction and the incidence of consecutive major cardiac events.

Purpose A markerless workflow for the treatment of breast cancer patients has been introduced and evaluated retrospectively. It includes surface-guided radiation therapy (SGRT)-only positioning for patients with small cone beam CT (CBCT) position corrections during the first five fractions. Prerequisites and the frequency of its clinical application were evaluated, as well as potential benefits in terms of treatment time and dose savings, the frequency of CBCT scans, and the accuracy of the positioning. Methods A group of 100 patients treated with the new workflow on two Versa HD linacs has been compared to a matched control group of patients treated with the former workflow, which included prepositioning with skin markings and lasers, SGRT and daily CBCT. The comparison was based on the evaluation of logfiles. Results Of the patients treated with the new workflow, 40% did not receive daily CBCT scans. This resulted in mean time savings of 97 s, 166 s and 239 s per fraction for the new workflow, for patients treated without daily CBCT and for SGRT-only fractions, respectively, when compared to the old workflow. Dose savings amounted to a weighted computed tomography dose index reduction of CTDIW = 2.56 cGy on average for normofractionated treatment and weekly CBCTs, while for patients not treated with daily CBCT, SGRT-based positioning accuracy was 5.2 mm for the mean translational magnitude, as evaluated by CBCT. Conclusion For 40% of the patients, after five fractions with small CBCT corrections, the workflow could be changed to SGRT-only positioning with weekly CBCT. This leads to imaging dose and time savings and thus also reduced intrafraction motion, potentially increased patient throughput and patient comfort, while assuring appropriate positioning accuracy.

BACKGROUND Several randomised, phase 3 trials have investigated the value of different techniques of accelerated partial breast irradiation (APBI) for patients with early breast cancer after breast-conserving surgery compared with whole-breast irradiation. In a phase 3 randomised trial, we evaluated whether APBI using multicatheter brachytherapy is non-inferior compared with whole-breast irradiation. Here, we present the 10-year follow-up results. METHODS We did a randomised, phase 3, non-inferiority trial at 16 hospitals and medical centres in Austria, Czech Republic, Germany, Hungary, Poland, Spain, and Switzerland. Patients aged 40 years or older with early invasive breast cancer or ductal carcinoma in situ treated with breast-conserving surgery were centrally randomly assigned (1:1) to receive either whole-breast irradiation or APBI using multicatheter brachytherapy. Whole-breast irradiation was delivered in 25 daily fractions of 50 Gy over 5 weeks, with a supplemental boost of 10 Gy to the tumour bed, and APBI was delivered as 30·1 Gy (seven fractions) and 32·0 Gy (eight fractions) of high-dose-rate brachytherapy in 5 days or as 50 Gy of pulsed-dose-rate brachytherapy over 5 treatment days. Neither patients nor investigators were masked to treatment allocation. The primary endpoint was ipsilateral local recurrence, analysed in the as-treated population; the non-inferiority margin for the recurrence rate difference (defined for 5-year results) was 3 percentage points. The trial is registered with ClinicalTrials.gov, NCT00402519; the trial is complete. FINDINGS Between April 20, 2004, and July 30, 2009, 1328 female patients were randomly assigned to whole breast irradiation (n=673) or APBI (n=655), of whom 551 in the whole-breast irradiation group and 633 in the APBI group were eligible for analysis. At a median follow-up of 10·36 years (IQR 9·12-11·28), the 10-year local recurrence rates were 1·58% (95% CI 0·37 to 2·8) in the whole-breast irradiation group and 3·51% (1·99 to 5·03) in the APBI group. The difference in 10-year rates between the groups was 1·93% (95% CI -0·018 to 3·87; p=0·074). Adverse events were mostly grade 1 and 2, in 234 (60%) of 393 participants in the whole-breast irradiation group and 314 (67%) of 470 participants in the APBI group, at 7·5-year or 10-year follow-up, or both. Patients in the APBI group had a significantly lower incidence of treatment-related grade 3 late side-effects than those in the whole-breast irradiation group (17 [4%] of 393 for whole-breast irradiation vs seven [1%] of 470 for APBI; p=0·021; at 7·5-year or 10-year follow-up, or both). At 10 years, the most common type of grade 3 adverse event in both treatment groups was fibrosis (six [2%] of 313 patients for whole-breast irradiation and three [1%] of 375 patients for APBI, p=0·56). No grade 4 adverse events or treatment-related deaths have been observed. INTERPRETATION Postoperative APBI using multicatheter brachytherapy after breast-conserving surgery in patients with early breast cancer is a valuable alternative to whole-breast irradiation in terms of treatment efficacy and is associated with fewer late side-effects. FUNDING German Cancer Aid, Germany.

Background and Purpose Four-dimensional computed tomography (4DCT) has become an essential part of radiotherapy planning but is often affected by artifacts. A new breathing controlled 4DCT (i4DCT) algorithm has been introduced. This study aims to present the first clinical data and to evaluate the achieved image quality, projection data coverage and beam-on time. Material & Methods The analysis included i4DCT data for 129 scans of patients with thoracic tumors. Projection data coverage and beam-on time were evaluated. Additionally, image quality was exemplarily discussed and rated by ten clinical experts with a 5-score-scale for 30 patients with large variations in their breathing pattern (‘challenging subgroup’). Rated images were reconstructed amplitude- and phase-based. Results Expert scoring revealed that 78% (amplitude-based) and 63% (phase-based) of the challenging subgroup were artifact-free (rating ≥4). For the entire cohort, average beam-on time per couch position was 4.9 ± 1.6 s. For the challenging subgroup, time increased slightly but not significantly compared to the remaining patients (5.1 s vs. 4.9 s; p = 0.64). Median projection data coverage was 93% and 94% for inhalation and exhalation, respectively, for the entire cohort. The comparison for the subgroup and the remaining patients revealed a small but significant decrease of the median coverage values for the challenging cases (inhalation: 90% vs. 94%, p = 0.02; exhalation: 93% vs. 94%, p = 0.02). Conclusions This first clinical evaluation of i4DCT shows very promising results in terms of image quality and projection data coverage. The results agree with and support the results of previous i4DCT phantom studies.

Osteoarthritis (OA) is one of the most common and socioeconomically relevant diseases, with rising incidence and prevalence especially with regard to an ageing population in the Western world. Over the decades, the scientific perception of OA has shifted from a simple degeneration of cartilage and bone to a multifactorial disease involving various cell types and immunomodulatory factors. Despite a wide range of conventional treatment modalities available, a significant proportion of patients remain treatment refractory. Low-dose radiotherapy (LDRT) has been used for decades in the treatment of patients with inflammatory and/or degenerative diseases and has proven a viable option even in cohorts of patients with a rather poor prognosis. While its justification mainly derives from a vast body of empirical evidence, prospective randomized trials have until now failed to prove the effectiveness of LDRT. Nevertheless, over the decades, adaptions of LDRT treatment modalities have evolved using lower dosages with establishment of different treatment schedules for which definitive clinical proof is still pending. Preclinical research has revealed that the immune system is modulated by LDRT and very recently osteoimmunological mechanisms have been described. Future studies and investigations further elucidating the underlying mechanisms are an essential key to clarify the optimal patient stratification and treatment procedure, considering the patients’ inflammatory status, age, and sex. The present review aims not only to present clinical and preclinical knowledge about the mechanistic and beneficial effects of LDRT, but also to emphasize topics that will need to be addressed in future studies. Further, a concise overview of the current status of the underlying radiobiological knowledge of LDRT for clinicians is given, while seeking to stimulate further translational research.

Simple Summary Accelerated partial breast irradiation represents a well-established and safe treatment alternative for selected patients with early stage breast cancer after breast-conserving surgery. In a prospective trial on external beam partial breast irradiation, the risk for radiogenic pneumonitis is analyzed. After a median follow-up of 56 (1–129) months, radiogenic pneumonitis grade 2 appeared in only 1/170 (0.6%) patients. Compared to standard whole breast irradiation, the radiation doses applied to the lungs were very low. The patient with the radiogenic pneumonitis was found to have a generally increased radiation susceptibility. Using accelerated partial breast irradiation, the risk of radiogenic pneumonitis appeared quite low and may be limited to very exceptional cases associated with innate risk factors with an increased radiation susceptibility. Abstract In order to evaluate the risk for radiation-associated symptomatic pneumonitis in a prospective external beam accelerated partial breast irradiation (APBI) trial, between 2011 and 2021, 170 patients with early stage breast cancer were enclosed in the trial. Patients were eligible for study participation if they had a histologically confirmed breast cancer or an exclusive ductal carcinoma in situ (DCIS), a tumor size ≤3 cm, free safety margins ≥2 mm, no involved axillary lymph nodes, tumor bed clips, and were ≥50 years old. Patients received APBI with 38 Gy with 10 fractions in 10 consecutive working days. The trial was registered at the German Clinical Trials Registry, DRKS-ID: DRKS00004417. Median follow-up was 56 (1–129) months. Ipsilateral lung MLD, V20, and V30 were 4.3 ± 1.4 Gy, 3.0 ± 2.0%, and 1.0 ± 1.0%, respectively. Radiogenic pneumonitis grade 2 appeared in 1/170 (0.6%) patients two months after radiotherapy. Ipsilateral MLD, V20, and V30 were 6.1 Gy, 7, and 3% in this patient. Additionally, individual radiosensitivity was increased in this specific patient. Compared to WBI, APBI leads to lower lung doses. Using APBI, the risk of symptomatic radiogenic pneumonitis is very low and may be limited, with an ipsilateral V20 < 3% to very exceptional cases associated with innate risk factors with an increased radiation susceptibility.

Purpose of Review This review focuses on the opposing effects on the immune system of radiotherapy (RT) and the consequences for combined cancer treatment strategies of RT with immunotherapies, including hyperthermia (HT). How RT and HT might affect cancer stem cell populations is also briefly outlined in this context. Recent Findings RT is one of the crucial standard cancer therapies. Most patients with solid tumors receive RT for curative and palliative purposes in the course of their disease. RT achieves a local tumor control by inducing DNA damage which can lead to tumor cell death. In recent years, it has become evident that RT does not only have local effects, but also systemic effects which involves induction of anti-tumor immunity and possible alteration of the immunosuppressive properties of the tumor microenvironment. Though, often RT alone is not able to induce potent anti-tumor immune responses since the effects of RT on the immune system can be both immunostimulatory and immunosuppressive. Summary RT with additional therapies such as HT and immune checkpoint inhibitors (ICI) are promising approaches to induce anti-tumor immunity effectively. HT is not only a potent sensitizer for RT, but it might also improve the efficacy of RT and certain chemotherapeutic agents (CT) by additionally sensitizing resistant cancer stem cells (CSCs). Graphical abstract

Simple Summary Hyperthermia (HT) is a promising therapeutic option for multiple cancer entities as it has the potential to increase the cytotoxicity of radiotherapy (RT) and chemotherapy (CT). Thermometric parameters of HT are considered to have potential as predictive factors of treatment response. So far, only limited data about the prognostic and predictive role of thermometric parameters are available. In this review, we investigate the existing clinical evidence regarding the correlation of thermometric parameters and cancer response in clinical studies in which patients were treated with HT in combination with RT and/or CT. Some studies show that thermometric parameters correlate with treatment response, indicating their potential significance for treatment guidance. Thus, the establishment of specific thermometric parameters might pave the way towards a better standardization of HT treatment protocols. Abstract Hyperthermia (HT) is a cancer treatment modality which targets malignant tissues by heating to 40–43 °C. In addition to its direct antitumor effects, HT potently sensitizes the tumor to radiotherapy (RT) and chemotherapy (CT), thereby enabling complete eradication of some tumor entities as shown in randomized clinical trials. Despite the proven efficacy of HT in combination with classic cancer treatments, there are limited international standards for the delivery of HT in the clinical setting. Consequently, there is a large variability in reported data on thermometric parameters, including the temperature obtained from multiple reference points, heating duration, thermal dose, time interval, and sequence between HT and other treatment modalities. Evidence from some clinical trials indicates that thermal dose, which correlates with heating time and temperature achieved, could be used as a predictive marker for treatment efficacy in future studies. Similarly, other thermometric parameters when chosen optimally are associated with increased antitumor efficacy. This review summarizes the existing clinical evidence for the prognostic and predictive role of the most important thermometric parameters to guide the combined treatment of RT and CT with HT. In conclusion, we call for the standardization of thermometric parameters and stress the importance for their validation in future prospective clinical studies

Purpose Retroperitoneal (RPS) sarcomas are associated with poor local and abdominal tumor control. However, the benefit of preoperative radio- or chemotherapy alone for these entities is currently unclear. Moreover, as intermediate- and high-grade sarcomas have a tendency toward early metastasis, exploration of neoadjuvant strategies is of high importance. This analysis reports the results of our 20-year single-institution experience with preoperative neoadjuvant concurrent chemoradiation. Methods From 2000–2019, 27 patients with intermediate- or high-grade RPS (12 dedifferentiated liposarcoma, 10 leiomyosarcoma, 5 others) were treated with radiotherapy (median dose: 50.4 Gy; range 45–75 Gy) and two cycles of chemotherapy (doxorubicin 50 mg/m2 BSA/d3 q28 and ifosfamide 1.5 g/m2 BSA/d1‑5 q28) in neoadjuvant intent. Chemotherapy consisted of doxorubicin alone in two cases and ifosfamide alone in one case. Fifteen patients (56%) additionally received deep regional hyperthermia. Results The median follow-up time was 53 months (±56.7 months). 92% of patients received two cycles of chemotherapy as planned and 92% underwent surgery. At 5 and 10 years, abdominal-recurrence-free survival was 74.6% (±10.1%) and 66.3% (±11.9%), distant metastasis-free survival was 67.2% (±9.7%) and 59.7% (±11.1%), and overall survival was 60.3% (±10.5%) and 60.3% (±10.5%), respectively. CTC grade III and IV toxicities were leukocytopenia (85%), thrombocytopenia (33%), and anemia (11%). There were no treatment-related deaths. Conclusion Neoadjuvant chemoradiotherapy with and without hyperthermia for retroperitoneal sarcomas is feasible and provided high local control of intermediate- and high-grade sarcoma.

Background: Neoadjuvant treatment modalities in soft tissue sarcoma (STS) of the extremities have become more popular in recent years, but because of the rarity and heterogeneity of STS, there are yet few studies on the long-term impact of neoadjuvant treatment modalities, especially in terms of neoadjuvant radiochemotherapy. Methods: The study enrolled 136 patients with primary STS of the extremities who underwent surgery with curative intent or neoadjuvant therapy, followed by surgery in a 15-year period. Neoadjuvant treatment consisted of radiotherapy (RT) with 60 Gy and in most cases simultaneous chemotherapy (CTx) with ifosfamide (1.5 g/m2/d, d1–5, q28) and doxorubicine (50 mg/m2/d, d3, q28). We investigated the clinical, (post)-operative and histopathological data and the oncological follow-up as well. The median follow-up period was 82 months (range 6–202). Results: A total of 136 patients (M:F = 73:63) with a mean age of 62 years (range, 21–93) was observed. Seventy-four patients (54.4%) received neoadjuvant therapy (NT), 62 patients (45.6%) received primary surgery (PS). When receiving NT, patients with high-risk STS had a lower risk to develop distant metastasis (p = 0.025). Age, histological type, tumor size and surgical margins (R0 vs. R1) had no influence on any survival rates. There was an association between NT and the occurrence of postoperative complications (p = 0.001). The 5-year local recurrence free survival (LRFS), metastasis free survival (MFS), disease free survival (DFS) and overall survival (OS) rate of the whole cohort was 89.9%, 77.0%, 70.6% and 72.6%, whereas the 5-year LRFS, MFS, DFS and OS rate was 90.5%, 67.2%, 64.1% and 62.8% for the NT group and 89.5%, 88.3%. 78.4% and 83.8% for the PS group. Conclusion: Multimodal treatment strategies in patients with STS of extremities lead to excellent oncological outcomes. Patients with high-risk STS had a significantly better MFS when receiving NT than patients with low-risk STS. NT was associated with a higher probability of postoperative but well-manageable complications.

Purpose Radiotherapy represents an effective treatment option in Graves’ ophthalmopathy (GO), leading to palliation of clinical symptoms. However, there are only a limited number of trials comparing the effectiveness of low- vs. high-dose radiotherapy. Methods We analyzed 127 patients treated with radiotherapy for stage 3/4 GO (NOSPECS classification). Patients were treated with single doses of 2.0 Gy (cumulative dose 20 Gy) until 2007, afterwards a single dose of 0.8 Gy (cumulative dose 4.8 Gy) was applied. With a median follow-up-time of 9.0 years, the treatment efficacy (overall improvement, sense of eye pressure, lid edema, ocular motility, exophthalmos, subjective vision, and diplopia) and adverse effects were analyzed by a standardized survey. Results Overall, 63.8% described improvement of symptoms after radiotherapy. No significant differences in overall treatment response and improvement of main outcome measures between low- or high-dose radiotherapy treatments are detectable, while low-dose radiotherapy leads significantly more often to retreatment (13.1% vs. 1.7%, p = 0.016). The main independent predictor of treatment response is the presence of lid edema (odds ratio, OR, 3.53; p = 0.006). Conclusion At long-term follow-up, the majority of patients reported palliation of symptoms with limited adverse effects, suggesting clinical effectiveness of radiotherapy for amelioration of GO symptoms independent of low- or high-dose radiotherapy.

Purpose The goal of this study was to investigate how the choice of the region of interest (ROI) affects the registration results of surface imaging for daily positioning of breast cancer patients. Methods The AlignRT system (VisionRT, London) and the XVI Cone beam CT (CBCT; Elekta, Stockholm) installed on two Versa HD linacs (Elekta) were used in this study, which included 28 patients (160 fractions). In the clinical workflow, patients were prepositioned with AlignRT and then shifted in 6 degrees of freedom (DOF) according to the CBCT. A new reference capture was taken immediately afterward. Retrospectively, the surface capture resulting from prepositioning was registered to the latest reference capture. By varying the ROI used for registration, the surface‐based results were optimized in terms of minimizing the deviation to the clinically applied CBCT shifts. Two sets of ROIs were used: one obtained by applying a variable margin to the breast surface, another by combining ROIs of anatomical structures, including the sternum and contralateral breast. Results Registration results showed significant differences from one ROI to another. Generally, the results improved with increasing ROI size, especially for rotational DOFs. ROIs, including the axilla or supraclavicular lymph drainage region, did not yield an improved registration result. On the other hand, an ROI comprising the breast surface, sternum, and a belt caudal to the breasts decreased the average magnitude of the translational and rotational deviations by 6.6% and 30.8% (p

Background: To prospectively analyze feasibility and pathological complete response (pCR) rates of neoadjuvant chemoradiotherapy combined with regional hyperthermia (RHT) in patients with locally advanced (LARC) or recurrent (LRRC) rectal cancer. Methods: between 2012 and 2018, 111 patients with UICC stage IIB-IV or any locally recurrent rectal cancer were included (HyRec-Trial, ClinicalTrials.gov Identifier: NCT01716949). Patients received radiotherapy with concurrent 5-Fluororuracil (5-FU)/Capecitabine and Oxaliplatin, and RHT. Stage 1 feasibility analysis evaluated dose-limiting toxicities (DLT) after 19 patients, stage 2 after 59 evaluable patients. Analysis of the pCR rate was based on histopathological reports. Results: the feasibility rates for stages 1 and 2 were 90% (17/19) and 73% (43/59), respectively. In the intention-to-treat population the pCR rate was 19% (20/105, 90% confidence interval (CI) 13.0–26.5). In the per-protocol-analysis, complete tumor regression was seen in 28% (18/64) and 38% (3/8) of the patients with LARC and LRRC, respectively. Complete resection rates (R0) among patients with LARC and LRRC who received surgery were 99% (78/84) and 67% (8/12). Conclusions: the intensified neoadjuvant and multimodality treatment schedule was feasible and led to comparable early toxicity rates as described by other trials that used the similar chemoradiation protocol. The presented treatment regimen resulted in a very high pCR rate and appears as a promising option for patients with LRRC.

Background Retroperitoneal (RPS) and intra-abdominal sarcomas (IAS) are associated with poor local and abdominal tumor control. Yet, the benefit of preoperative radio- or chemotherapy alone for these entities currently is unclear. Moreover, as intermediate- and high-grade sarcomas have a tendency for early metastasis, exploration of neoadjuvant strategies is of high importance. This analysis reports the results of our 20-year single-institution experience with preoperative neoadjuvant concurrent chemoradiation.Methods From 2000-2019, 27 patients with intermediate- or high-grade RPS or IAS (12 dedifferentiated liposarcoma, 10 leiomyosarcoma, 5 others) were treated with radiotherapy (median dose: 50.4 Gy; range 45-75 Gy) and two cycles of chemotherapy (doxorubicin 50mg/m² BSA/d3 q28 and ifosfamide 1.5g/m2 BSA/d1-5 q28) in neoadjuvant intention. Chemotherapy consisted of doxorubicin alone in two cases and ifosfamide alone in one case. Fifteen patients (56%) received deep regional hyperthermia additionally.Results The median follow-up time was 53 months (± 56.7 months). 92% of patients received two cycles of chemotherapy as planned and 92% underwent surgery. At 5 and 10 years, abdominal-recurrence-free-survival was 74.6% (± 10.1%) and 66.3% (± 11.9%), distant-metastasis-free-survival was 67.2% (± 9.7%) and 59.7% (± 11.1%), and overall-survival was 60.3% (± 10.5%) and 60.3% (± 10.5%), respectively. CTC grade III and IV toxicities were leukocytopenia (85%), thrombocytopenia (33%) and anemia (11%). There were no treatment-related deaths.Conclusions Neoadjuvant chemoradiotherapy with and without hyperthermia for retroperitoneal and intra-abdominal sarcoma is feasible and provided high local control of intermediate - and high-grade sarcoma.

To evaluate the value of interstitial brachytherapy (iBT) alone in the treatment of low-risk breast cancer patients with regard to local control, side effects, and cosmesis.From November 2000 to January 2004, 176 patients with low-risk breast cancer were treated with iBT only. Patients were eligible for entering the study if: the tumor size was3 cm; resection margins were clear by at least 2 mm; there were no lymph node metastases or only one micrometastasis (pNo, pNmi); age was35 years; steroid hormone receptor was positive; and histologic grade was 1 or 2. Seventy-five percent of patients received pulsed-dose-rate brachytherapy (D(ref) = 50 Gy); 25% of patients received high-dose-rate brachytherapy (D(ref) = 32.0 Gy). An interim analysis is presented for all patients after an interim follow-up of 12 months, and for half the patient population with an interim follow-up of 21 months.All patients remained disease-free on the date of analysis. A perioperative complication breast infection was recorded for 1/176 (0.6%) patients. Late toxicity i.e., hypersensation, hyperpigmentation, fibrosis, or teleangiectasia was observed in 1-12% of all patients. Grade I Fibrosis was registered in 7.6% (13/172) and grade II in 7.0% (12/172) of evaluable patients. Similarly, grade I teleangiectasia was observed in 4.7% (8/172), grade II in 0.6% (1/172), and grade III also in 0.6% (1/172) of evaluable patients. Excellent or good cosmetic results have been observed in 92-95% of patients.Brachytherapy as monotherapy in low-risk breast cancer patients after breast-conserving surgery is an effective, precise treatment modality without perioperative morbidity, low acute, mild late toxicity, and yields good to excellent cosmetic results.

Low-dose radiation therapy (LDRT) has been successfully established for decades as an alternative analgesic treatment option for patients suffering from chronic degenerative and inflammatory diseases. In this study, 483 patients were undergoing LDRT for degenerative joint disease of the fingers and thumb at the University Hospital Erlangen between 2004 and 2019. Radiotherapy was applied according to the German guidelines for LDRT. Several impact factors on therapeutic success, such as the age and gender, the number of affected fingers, the single and cumulative dose, as well as the number of series, were investigated. In summary, 70% of the patients showed an improvement of their pain following LDRT. No significant impact was found for the factors age, gender, the number of series or the cumulative dosage. Patients with an involvement of the thumb showed a significantly worse outcome compared to patients with an isolated affection of the fingers. In this cohort, patients receiving a single dose of 0.5 Gy reported a significantly better outcome than patients receiving 1.0 Gy, strongly suggesting a reduction in the total dose. In summary, LDRT is a good alternative treatment option for patients suffering from degenerative and inflammatory joint disease of the fingers.

Strahlentherapie und Onkologie 196(8), 679 - 682 (2020). doi:10.1007/s00066-020-01635-7, Published by Springer Medizin, Heidelberg

Standardbehandlung des muskelinvasiven Karzinoms ist die Zystektomie mit pelviner Lymphadenektomie. Die primar organerhaltende, multimodale Therapie gilt als Alternative zur radikalen Operation. Konzept und Ergebnisse der multimodalen Therapie, bestehend aus initialer transurethraler Resektion des Blasentumors (TURB), gefolgt von der simultanen Radiochemotherapie (RCT), werden vorgestellt. Auswertung retrospektiver Fallserien und prospektiver Therapieoptimierungsstudien zu primar organerhaltenden Behandlungskonzepten. Komparative Metaanalysen zum Vergleich der Zystektomie mit der trimodalen Behandlung werden vorgestellt. Eine komplette TURB samt Blasenmapping und Tumorgrundbiopsie sollte vor RCT angestrebt werden. Die Radiosensibilisierung sollte mit einer Cisplatin-basierten Chemotherapie oder mit einer Kombination von 5‑Fluorouracil und Mitomycin C erfolgen. Komplette Remissionsraten nach TURB plus RCT werden stadienabhangig bei 60–90 % der Patienten sowie 5‑Jahres-Uberlebensraten zwischen 40–75 % mit einem Erhalt der Blase bei ca. 80 % der uberlebenden Patienten erreicht. Die multimodale Therapie stellt eine Alternative zur radikalen Zystektomie mit kurativer Zielsetzung fur Patienten mit muskelinvasivem Harnblasenkarzinom dar. Besonders eignen sich Patienten mit fruhen Tumoren (cT2/3N0), bei denen die initiale TURB zur moglichst kompletten Tumorentfernung (R0) fuhrt.

BACKGROUND We previously confirmed the non-inferiority of accelerated partial breast irradiation (APBI) with interstitial brachytherapy in terms of local control and overall survival compared with whole-breast irradiation for patients with early-stage breast cancer who underwent breast-conserving surgery in a phase 3 randomised trial. Here, we present the 5-year late side-effects and cosmetic results of the trial. METHODS We did this randomised, controlled, phase 3 trial at 16 centres in seven European countries. Women aged 40 years or older with stage 0-IIA breast cancer who underwent breast-conserving surgery with microscopically clear resection margins of at least 2 mm were randomly assigned 1:1, via an online interface, to receive either whole-breast irradiation of 50 Gy with a tumour-bed boost of 10 Gy or APBI with interstitial brachytherapy. Randomisation was stratified by study centre, menopausal status, and tumour type (invasive carcinoma vs ductal carcinoma in situ), with a block size of ten, according to an automated dynamic algorithm. Patients and investigators were not masked to treatment allocation. The primary endpoint of our initial analysis was ipsilateral local recurrence; here, we report the secondary endpoints of late side-effects and cosmesis. We analysed physician-scored late toxicities and patient-scored and physician-scored cosmetic results from the date of breast-conserving surgery to the date of onset of event. Analysis was done according to treatment received (as-treated population). This trial is registered with ClinicalTrials.gov, number NCT00402519. FINDINGS Between April 20, 2004, and July 30, 2009, we randomly assigned 1328 women to receive either whole-breast irradiation (n=673) or APBI with interstitial brachytherapy (n=655); 1184 patients comprised the as-treated population (551 in the whole-breast irradiation group and 633 in the APBI group). At a median follow-up of 6·6 years (IQR 5·8-7·6), no patients had any grade 4 toxities, and three (

Studies have demonstrated correlations between accumulations of tumour-associated macrophages (TAMs), especially of M2-like phenotype, and increased mortality in advanced breast cancer. We investigated the prognostic potential of both main macrophage phenotypes in early hormone receptor-positive (HR+) breast cancer. The studied cohort of 136 patients participated in an institutional APBI phase II trial. Patient selection was characterized by HR+, small tumour size and no metastasis. Tissue microarrays from pre-RT resection samples were double stained for CD68/CD163 using immunohistochemistry. CD68+/CD163&minus, cells were considered M1-like macrophages and CD68+/CD163+ was representative of M2-like macrophages. M1 and M2 macrophage densities were analysed semi-automatically in the stromal and intraepithelial tumour compartment. Low M1 and high M2 densities were strongly associated with decreased disease-free survival (DFS). Combined TAM phenotype densities were studied after defining a macrophage shift classification: M1-shifted (M1 high, M2 low) and non-shifted (M1 low, M2 low, M1 high, M2 high) tumours entailed a favourable outcome. In contrast, M2-shifted (M1 low, M2 high) TAM populations were associated with extremely reduced DFS. Thus, the full predictive potential of TAMs was revealed in a combined analysis of both phenotypes. The M2-shifted subgroup of tumours is classified as high-risk and probably not suitable for partial breast irradiation.

The role of tumour-infiltrating inflammatory cells (TIICs) in the disease progression of hormone-receptor-positive breast cancer (HR+ BC) is largely unclear since it is generally regarded as the least immunogenic BC subtype. This study investigated the prognostic significance of CD1a+ dendritic cells, CD20+ B cells, CD45RO+ memory T cells and CD4+ T-helper cells in HR+ BC. One hundred and forty-six patients were treated for early stage, distant-metastases-free HR+ BC in an accelerated partial breast irradiation (APBI) phase II trial. Immunohistochemistry was used to double-stain two adjoining sets of tissue microarrays from pre-RT (radiotherapy) tumour resection samples for CD1a/CD20 and CD45RO/CD4. Cell densities of CD1a+, CD20+, CD45RO+ and CD4+ TIICs in the stromal and intraepithelial compartment were registered semiautomatically. High densities of CD20+ and CD4+ TIICs were strongly associated with reduced disease-free survival (DFS), while high stromal CD45RO+ TIIC densities were indicators of subsequent successful treatment. An immunoscore based on CD20+ and CD45RO+ TIIC densities identified three different risk groups (p &lt, 0.001). Thus, contrary to current assumptions, intratumoural immune cell composition might be an important prognostic indicator and a possible contributing factor in the outcome of HR+ BC and should be the subject of further research. Specifically, B-cell infiltration entailed an increased relapse rate and could play an important role in disease progression.

Background The aim of this study was to evaluate the efficacy and safety of chemoradiotherapy (RCT) combined with regional deep hyperthermia (RHT) of high-risk bladder cancer after transurethral resection of bladder tumor (TUR-BT). Materials and methods Between 1982 and 2016, 369 patients with pTa, pTis, pT1, and pT2 cN0–1 cM0 bladder cancer were treated with a multimodal treatment after TUR-BT. All patients received radiotherapy (RT) of the bladder and regional lymph nodes. RCT was administered to 215 patients, RCT + RHT was administered to 79 patients, and RT was used in 75 patients. Treatment response was evaluated 4–6 weeks after treatment with TUR-BT. Results Complete response (CR) overall was 83% (290/351), and in treatment groups was RT 68% (45/66), RCT 86% (178/208), and RCT + RHT 87% (67/77). CR was significantly improved by concurrent RCT compared with RT (odds ratio [OR], 2.32; 95% confidence interval [CI], 1.05–5.12; p = .037), less influenced by hyperthermia (OR, 2.56; 95% CI, 0.88–8.00; p = .092). Overall survival (OS) after RCT was superior to RT (hazard ratio [HR], 0.7; 95% CI, 0.50–0.99; p = .045). Five-year OS from unadjusted Kaplan-Meier estimates was RCT 64% versus RT 45%. Additional RHT increased 5-year OS to 87% (HR, 0.32; 95% CI, 0.18–0.58; p = .0001). RCT + RHT compared with RCT showed a significantly better bladder-preservation rate (HR, 0.13; 95% CI, 0.03–0.56; p = .006). Median follow-up was 71 months. The median number of RHT sessions was five. Conclusion The multimodal treatment consisted of a maximal TUR-BT followed by RT; concomitant platinum-based chemotherapy combined with RHT in patients with high-grade bladder cancer improves local control, bladder-preservation rate, and OS. It offers a promising alternative to surgical therapies like radical cystectomy. Implications for Practice Radical cystectomy with appropriate lymph node dissection has long represented the standard of care for muscle-invasive bladder cancer in medically fit patients, despite many centers reporting excellent long-term results for bladder preserving strategies. This retrospective analysis compares different therapeutic modalities in bladder-preservation therapy. The results of this study show that multimodal treatment consisting of maximal transurethral resection of bladder tumor followed by radiotherapy, concomitant platinum-based chemotherapy combined with regional deep hyperthermia in patients with Ta, Tis, T1–2 bladder carcinomas improves local control, bladder-preservation rate, and survival. More importantly, these findings offer a promising alternative to surgical therapies like radical cystectomy. The authors hope that, in the future, closer collaboration between urologists and radiotherapists will further improve treatments and therapies for the benefit of patients.

Career situation of first and presenting author Student for a master or a PhD. Introduction The treatment of chronic inflammatory and/or degenerative diseases by low dose radiation therapy (LDRT) is a successful alternative treatment option, especially for patients who were refractory for treatment with drugs. Generally, LDRT aims to reduce pain of patients and to increase their mobility. Although LDRT has successfully been applied since the late 19th century, the underlying immunological mechanisms are only fragmentarily analyzed. Objectives Therefore we have aimed to analyze the impact of locally delivered LDRT on systemic immune changes. Methods For this the IMMO-LDRT01 study (NCT02653079) was initiated in 2016. The study will include 150 patients suffering from chronic inflammatory and/or degenerative diseases, such as arthritis, arthrosis or benign calcaneodynia. The patients are treated with six local irradiations (single dose per fraction of 0.5Gy) in three weeks. If necessary, the serial irradiation can be repeated after 8–12 weeks, in order to achieve a further reduction of the pain. Blood samples are taken before and after every serial irradiation, as well as during follow-up appointments of the patients. For detailed immunophenotyping of whole blood, we established a multicolor flow cytometry assay, which allows the monitoring of seven main immune cell types, 26 immune cell subtypes, and the activation status of the immune cells. Results To date 80 patients have been included in the study. First evaluations showed a significant reduction of B cells and cytotoxic T cells in the peripheral blood of patients. In particular, LDRT impacted on activation markers of immune cells. One has to stress that the immunological effects of LDRT were dependent on the particular type of disease of the patients. Currently, the data of the immunophenotyping are correlated to pain perception and quality of life of the patients. Conclusions These analyses will be helpful to optimize LDRT. A better patient stratification based on pain- and immune-related biomarkers is envisaged for the future, alongside with initiation of deliberated randomized clinical trials. Acknowledgements This study has been in part funded by the Bundesministerium fur Bildung und Forschung (GREWIS and GREWIS-alpha, 02NUK017G and 02NUK050E). Disclosure of Interest None declared.

To evaluate the feasibility and efficacy of external beam three-dimensional (3D) conformal accelerated partial breast irradiation (APBI) for selected patients with early breast cancer. Between 2011 and 2016, 72 patients were recruited for this prospective phase 2 trial. Patients were eligible for APBI if they had histologically confirmed breast cancer or pure ductal carcinoma in situ (DCIS), a tumor diameter ≤3 cm, clear resection margins ≥2 mm, no axillary lymph node involvement, no distant metastases, tumor bed clips, and were aged ≥50 years. Patients were excluded if mammography showed a multicentric invasive growth pattern, or if they had residual diffuse microcalcifications postoperatively, an extensive intraductal component, or vessel invasion. Patients received 3D conformal external beam APBI with a total dose of 38 Gy in 10 fractions in 1–2 weeks. The trial had been registered at the German Clinical Trials Register, DRKS-ID: DRKS00004417. Median follow-up was 25.5 months (range 1–61 months). Local control was maintained in 71 of 72 patients. The 3‑year local recurrence rate was 2.1% (95% confidence interval, CI: 0–6.1%). Early toxicity (grade 1 radiodermatitis) was seen in 34.7% (25/72). Late side effects ≥ grade 3 did not occur. Cosmetic results were rated as excellent/good in 96.7% (59/61). APBI with external beam radiotherapy techniques is feasible with low toxicity and, according to the results of the present and other studies, on the way to becoming a standard treatment option for a selected subgroup of patients.

BACKGROUND AND PURPOSE To compare early side effects and patient compliance of accelerated partial breast irradiation (APBI) with multicatheter brachytherapy to external beam whole breast irradiation (WBI) in a low-risk group of patients with breast cancer. MATERIAL AND METHODS Between April 2004 and July 2009, 1328 patients with UICC stage 0-IIA breast cancer were randomized to receive WBI with 50Gy and a boost of 10Gy or APBI with either 32.0Gy/8 fractions, or 30.1Gy/7 fractions (HDR-brachytherapy), or 50Gy/0.60-0.80Gy per pulse (PDR-brachytherapy). This report focuses on early side-effects and patient compliance observed in 1186 analyzable patients. ClinicalTrials.gov identifier: NCT00402519. RESULTS Patient compliance was excellent in both arms. Both WBI and APBI were well tolerated with moderate early side-effects. No grade 4 toxicity had been observed. Grade 3 side effects were exclusively seen for early skin toxicity (radiation dermatitis) with 7% vs. 0.2% (p

To compare results after chemoradiotherapy with and without deep regional hyperthermia in patients with anal cancer. Between 2000 and 2015, a total of 112 consecutive patients with UICC stage I–IV anal cancer received chemoradiotherapy with 5‑fluororuracil and mitomycin C (CRT). In case of insufficient tumor response 4–6 weeks after chemoradiotherapy, patients received an interstitial pulsed-dose-rate brachytherapy boost. Additionally, 50/112 patients received hyperthermia treatments (HCRT). Median follow-up was 41 (2–165) months. After 5 years follow-up, overall (95.8 vs. 74.5%, P = 0.045), disease-free (89.1 vs. 70.4%, P = 0.027), local recurrence-free (97.7 vs. 78.7%, P = 0.006), and colostomy-free survival rates (87.7 vs. 69.0%, P = 0.016) were better for the HCRT group. Disease-specific, regional failure-free, and distant metastasis-free survival rates showed no significant differences. The adjusted hazard ratios for death were 0.25 (95% CI, 0.07 to 0.92; P = 0.036) and for local recurrence 0.14 (95% CI, 0.02 to 1.09; P = 0.06), respectively. Grades 3–4 early toxicities were comparable with the exception of hematotoxicity, which was higher in the HCRT group (66 vs. 43%, P = 0.032). Incidences of late side effects were similar with the exception of a higher telangiectasia rate in the HCRT group (38.0 vs. 16.1%, P = 0.009). Additional regional hyperthermia improved overall survival, local control, and colostomy rates. Its potential beneficial role has to be confirmed in a prospective randomized setting. Therefore, the HyCAN trial has already been established by our group and is currently recruiting patients (Clinicaltrials.gov identifier: NCT02369939).

Summary Background In a phase 3, randomised, non-inferiority trial, accelerated partial breast irradiation (APBI) for patients with stage 0, I, and IIA breast cancer who underwent breast-conserving treatment was compared with whole-breast irradiation. Here, we present 5-year follow-up results. Methods We did a phase 3, randomised, non-inferiority trial at 16 hospitals and medical centres in seven European countries. 1184 patients with low-risk invasive and ductal carcinoma in situ treated with breast-conserving surgery were centrally randomised to either whole-breast irradiation or APBI using multicatheter brachytherapy. The primary endpoint was local recurrence. Analysis was done according to treatment received. This trial is registered with ClinicalTrials.gov, number NCT00402519. Findings Between April 20, 2004, and July 30, 2009, 551 patients had whole-breast irradiation with tumour-bed boost and 633 patients received APBI using interstitial multicatheter brachytherapy. At 5-year follow-up, nine patients treated with APBI and five patients receiving whole-breast irradiation had a local recurrence; the cumulative incidence of local recurrence was 1·44% (95% CI 0·51–2·38) with APBI and 0·92% (0·12–1·73) with whole-breast irradiation (difference 0·52%, 95% CI −0·72 to 1·75; p=0·42). No grade 4 late side-effects were reported. The 5-year risk of grade 2–3 late side-effects to the skin was 3·2% with APBI versus 5·7% with whole-breast irradiation (p=0·08), and 5-year risk of grade 2–3 subcutaneous tissue late side-effects was 7·6% versus 6·3% (p=0·53). The risk of severe (grade 3) fibrosis at 5 years was 0·2% with whole-breast irradiation and 0% with APBI (p=0·46). Interpretation The difference between treatments was below the relevance margin of 3 percentage points. Therefore, adjuvant APBI using multicatheter brachytherapy after breast-conserving surgery in patients with early breast cancer is not inferior to adjuvant whole-breast irradiation with respect to 5-year local control, disease-free survival, and overall survival. Funding German Cancer Aid.