Erectile function preservation after salvage radiation therapy for biochemically recurrent prostate cancer after prostatectomy: Five-year results of the SAKK 09/10 randomized phase 3 trial.

Objectives: To evaluate effects of dose intensified salvage radiotherapy (sRT) on erectile function in biochemically recurrent prostate cancer (PC) after radical prostatectomy (RP). Materials and methods: Eligible patients had evidence of biochemical failure after RP and a PSA at randomization of ≤ 2 ng/ml. Erectile dysfunction (ED) was investigated as secondary endpoint within the multicentre randomized trial (February 2011 to April 2014) in patients receiving either 64 Gy or 70 Gy sRT. ED and quality of life (QoL) were assessed using CTCAE v4.0 and the EORTC QoL questionnaires C30 and PR25 at baseline and up to 5 years after sRT. Results: 344 patients were evaluable. After RP 197 (57.3 %) patients had G0-2 ED while G3 ED was recorded in 147 (42.7 %) patients. Subsequently, sexual activity and functioning was impaired. 5 years after sRT, 101 (29.4 %) patients noted G0-2 ED. During follow-up, 44.2 % of patients with baseline G3 ED showed any improvement and 61.4 % of patients with baseline G0-2 ED showed worsening. Shorter time interval between RP and start of sRT (p = 0.007) and older age at randomization (p = 0.005) were significant predictors to more baseline ED and low sexual activity in the long-term. Age (p = 0.010) and RT technique (p = 0.031) had a significant impact on occurrence of long-term ED grade 3 and worse sexual functioning. During follow-up, no differences were found in erectile function, sexual activity, and sexual functioning between the 64 Gy and 70 Gy arm. Conclusion: ED after RP is a known long-term side effect with significant impact on patients' QoL. ED was further affected by sRT, but dose intensification of sRT showed no significant impact on erectile function recovery or prevalence of de novo ED after sRT. Age, tumor stage, prostatectomy and RT-techniques, nerve-sparing and observation time were associated with long-term erectile function outcome.ClinicalTrials.gov. Identifier: NCT01272050.

Current Evidence on Local Therapies in Advanced Adrenocortical Carcinoma.

International guidelines emphasise the role of local therapies (LT) for the treatment of advanced adrenocortical carcinoma (ACC). However, large studies are lacking in this field. Therefore, we performed a review of the literature to synthesise current evidence and develop clinical guidance. PubMed database was searched for systematic literature. We identified 119 potentially relevant articles, of which 21 could be included in our final analysis. All were retrospective and reported on 374 patients treated with LT for advanced ACC (12 studies on radiotherapy, 3 on transarterial chemoembolisation and radioembolisation, 4 on image-guided thermal ablation [radiofrequency, microwave ablation, and cryoablation, and two studies reporting treatment with several different LT]). Radiotherapy was frequently performed with palliative intention. However, in most patients, disease control and with higher dosage also partial responses could be achieved. Data for other LT were more limited, but also point towards local disease control in a significant percentage of patients. Very few studies tried to identify factors that are predictive on response. Patients with a disease-free interval after primary surgery of more than 9 months and lesions<5 cm might benefit most. Underreporting of toxicities may be prevalent, but LT appear to be relatively safe overall. Available evidence on LT for ACC is limited. LT appears to be safe and effective in cases with limited disease and should be considered depending on local expertise in a multidisciplinary team discussion.

Prediction models of incontinence and sexual function one year after radical prostatectomy based on data from 20 164 prostate cancer patients.

BACKGROUND: Incontinence and sexual dysfunction are long-lasting side effects after surgical treatment (radical prostatectomy, RP) of prostate cancer (PC). For an informed treatment decision, physicians and patients should discuss expected impairments. Therefore, this paper firstly aims to develop and validate prognostic models that predict incontinence and sexual function of PC patients one year after RP and secondly to provide an online decision making tool. METHODS: Observational cohorts of PC patients treated between July 2016 and March 2021 in Germany were used. Models to predict functional outcomes one year after RP measured by the EPIC-26 questionnaire were developed using lasso regression, 80-20 splitting of the data set and 10-fold cross validation. To assess performance, R2, RMSE, analysis of residuals and calibration-in-the-large were applied. Final models were externally temporally validated. Additionally, percentages of functional impairment (pad use for incontinence and firmness of erection for sexual score) per score decile were calculated to be used together with the prediction models. RESULTS: For model development and internal as well as external validation, samples of 11 355 and 8 809 patients were analysed. Results from the internal validation (incontinence: R2 = 0.12, RMSE = 25.40, sexual function: R2 = 0.23, RMSE = 21.44) were comparable with those of the external validation. Residual analysis and calibration-in-the-large showed good results. The prediction tool is freely accessible: https://nora-tabea.shinyapps.io/EPIC-26-Prediction/. CONCLUSION: The final models showed appropriate predictive properties and can be used together with the calculated risks for specific functional impairments. Main strengths are the large study sample (> 20 000) and the inclusion of an external validation. The models incorporate meaningful and clinically available predictors ensuring an easy implementation. All predictions are displayed together with risks of frequent impairments such as pad use or erectile dysfunction such that the developed online tool provides a detailed and informative overview for clinicians as well as patients.

Impact of Radiotherapy on Malfunctions and Battery Life of Cardiac Implantable Electronic Devices in Cancer Patients.

PURPOSE: This study analyses a large number of cancer patients with CIEDs for device malfunction and premature battery depletion by device interrogation after each radiotherapy fraction and compares different guidelines in regard to patient safety. METHODS: From 2007 to 2022, a cohort of 255 patients was analyzed for CIED malfunctions via immediate device interrogation after every RT fraction. RESULTS: Out of 324 series of radiotherapy treatments, with a total number of 5742 CIED interrogations, nine device malfunctions (2.8%) occurred. Switching into back-up/safety mode and software errors occurred four times each. Once, automatic read-out could not be performed. The median prescribed cumulative dose at planning target volume (PTV) associated with CIED malfunction was 45.0 Gy (IQR 36.0-64.0 Gy), with a median dose per fraction of 2.31 Gy (IQR 2.0-3.0 Gy). The median maximum dose at the CIED at time of malfunction was 0.3 Gy (IQR 0.0-1.3 Gy). No correlation between CIED malfunction and maximum photon energy (p = 0.07), maximum dose at the CIED (p = 0.59) nor treatment localization (p = 0.41) could be detected. After excluding the nine malfunctions, premature battery depletion was only observed three times (1.2%). Depending on the national guidelines, 1-9 CIED malfunctions in this study would have been detected on the day of occurrence and in none of the cases would patient safety have been compromised. CONCLUSION: Radiation-induced malfunctions of CIEDs and premature battery depletion are rare. If recommendations of national safety guidelines are followed, only a portion of the malfunctions would be detected directly after occurrence. Nevertheless, patient safety would not be compromised.

Comparison of three different dosages of low-level laser therapy on expression of cell proliferation and inflammatory markers following ovariohysterectomy in rats.

The objective of the current study was to evaluate Low-level laser therapy (LLLT) on the healing of incisional wounds following ovariohysterectomy in rats, by means of subjective histopathological and immunohistochemical analysis. A total of 72 female Wistar rats were categorised into four treatment groups (Group I; sacrification 4 hours following only one LLLT application, Group II; sacrification 7 days following only one LLLT application, Group III; sacrification 4 hours after two LLLT applications, and Group IV; sacrification 7 days after two LLLT applications). Each group was further divided into four different doses subgroups (Group Control [C, off mode LLLT application], L1 [1 J/cm2], L3 [3 J/cm2], and L6 [6 J/cm2]), with equal representation in each subgroup. Ovariohysterectomy was employed using two 2-cm-length midline abdominal incisions in the left and right sides of line alba. The Group C was assigned to the left side incision to each rat in the study. After irradiation, the tissue was subjected to histopathological analysis to determine the extent of mononuclear cell infiltration, edoema, and epithelialization. Additionally, immunohistochemical analysis was performed to evaluate the expression of proliferating cell nuclear antigen (pCNA) and inducible nitric oxide synthase (iNOS). Group L1 and L3 significantly decreased mononuclear cell infiltration compared with Group C in all treatment groups (p < 0.05). Group L3 significantly decreased edoema compared with Group C in all groups except for treatment Group I (p < 0.05). Group L2 and L3 significantly increased epithelization in treatment Group IV (p < 0.05). Moreover, Group L2 and L3 significantly increased pCNA in all groups, while L2 and L3 significantly decreased iNOS expression in treatment Group II, III, and IV (p < 0.05). However, no statistical difference was found between subgroups of treatment Group I in iNOS expiration (p > 0.05). The results of the current examination demonstrated that LLLT can modulate mononuclear cell infiltration and edoema, and improve epithelization, as well as increase pCNA expression, whereas decrease iNOS expression during the wound healing process, therefore enhancing wound healing following ovariohysterectomy in rats.

The effects of low-level laser therapy on polycystic ovarian syndrome in rats: three different dosages.

The main objective of this in vivo study was to investigate the effect of different low-level laser therapy (LLLT) doses on polycystic ovary syndrome (PCOS). In the present experimental study, a single dosage of estradiol valerate (EV) was administered to induce PCOS in female rats. After administration of the EV for induction of PCOS, rats were divided into 5 groups (n = 8/group): C group (animals that were not exposed to any form of procedure), PC group (no treatment following EV induction), L1 group (1 J/cm2 LLLT treatment following EV induction), L2 group (2 J/cm2 LLLT treatment following EV induction), L3 group (6 J/cm2 LLLT treatment following EV induction). The results indicated that no significant difference was found in the serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and progesterone (P4) between the C and L2 groups (p < 0.05). Although the serum levels of testosterone (T) were significantly higher in the C group compared with other groups (p < 0.05), the L2 group was determined to be the closest to the C group. Additionally, the LH, FSH, and T receptor level of the L2 group was closest to the C group. In conclusion, a 2 J/cm2 dosage of LLLT (L2 group) can be considered the most potentially effective treatment of PCOS in the rat. However, more studies are needed to determine the optimal dose of LLLT for the treatment of PCOS.

Second Conservative Treatment for Local Recurrence Breast Cancer: A GEC-ESTRO Oncological Outcome and Prognostic Factor Analysis.

PURPOSE: For second ipsilateral breast tumor event (2nd IBTE), second conservative treatment (2nd CT) combining lumpectomy plus accelerated partial breast reirradiation (APBrI) represents a curative option. The aim of this study was to analyze oncological prognostic factors for patients with a 2nd IBTE treated with 2nd CT. METHODS AND MATERIALS: An analysis of clinical practices was conducted across 7 academic hospitals/cancer centers in 6 European countries based on the GEC-ESTRO database. Patients presenting a 2nd IBTE occurring after conservative surgery (lumpectomy + axillary evaluation) and irradiation performed for the primary tumor underwent a 2nd CT with brachytherapy-based APBrI. The main outcome was 5-year cumulative incidence (CI) rate of second local relapse. All analyzed patients were classified according to risk groups for Groupe Européen de Curiethérapie-European Society for Therapeutic Radiology and Oncology (GEC-ESTRO) accelerated partial breast irradiation (APBI) and molecular classification and time interval between first and second breast surgery (TIS1S2). Finally, we combined GEC-ESTRO APBI, molecular, and TIS1S2 risk groups, leading to the definition of a new score (named TAM: score based on the combination of time interval [T] between first and second surgery and APBI [A] and molecular [M] classifications) specifically designed for 2nd IBTE oncological outcome analysis. RESULTS: From July 1994 to January 2021, a total of 508 patients received a 2nd CT. At the time of 2nd IBTE, median age was 64.6 years (range, 56.2-72.6). With a median follow-up of 60.9 months (56.2-72.6), the 5-year second local relapse CI rate was 4% (95% confidence interval [95% CI], 2%-6%). The 5-year distant metastasis disease CI rate was 7% (95% CI, 4%-10%). Five-year disease-free and overall survival rates were 89% (95% CI, 86%-93%) and 91% (95% CI, 88%-94%), respectively. In multivariate analysis, TAM score was an independent prognostic factor for all the oncological items (P < .001) except disease-specific survival (P = .07) and overall survival (P = .09). The grade ≥3 late toxicity rate was 12.1%. CONCLUSIONS: This analysis of 2nd CT combining lumpectomy with APBrI for 2nd IBTE confirmed the excellent oncological results obtained after 2nd CT. Furthermore, the GEC-ESTRO TAM score appears to be an important prognostic factor, assisting patients and physicians in the decision-making process.

Accelerated partial breast irradiation using sole interstitial multicatheter brachytherapy compared with whole-breast irradiation with boost for early breast cancer: 10-year results of a GEC-ESTRO randomised, phase 3, non-inferiority trial.

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.

Efficacy and safety of radiation therapy in advanced adrenocortical carcinoma.

BACKGROUND: International guidelines emphasise the role of radiotherapy (RT) for the management of advanced adrenocortical carcinoma (ACC). However, the evidence for this recommendation is very low. METHODS: We retrospectively analysed all patients who received RT for advanced ACC in five European centres since 2000. PRIMARY ENDPOINT: time to progression of the treated lesion (tTTP). Secondary endpoints: best objective response, progression-free survival (PFS), overall survival (OS), adverse events, and the establishment of predictive factors by Cox analyses. RESULTS: In total, 132 tumoural lesions of 80 patients were treated with conventional RT (cRT) of 50-60 Gy (n = 20) or 20-49 Gy (n = 69), stereotactic body RT of 35-50 Gy (SBRT) (n = 36), or brachytherapy of 12-25 Gy (BT) (n = 7). Best objective lesional response was complete (n = 6), partial (n = 52), stable disease (n = 60), progressive disease (n = 14). Median tTTP was 7.6 months (1.0-148.6). In comparison to cRT20-49Gy, tTTP was significantly longer for cRT50-60Gy (multivariate adjusted HR 0.10; 95% CI 0.03-0.33; p < 0.001) and SBRT (HR 0.31; 95% CI 0.12-0.80; p = 0.016), but not for BT (HR 0.66; 95% CI 0.22-1.99; p = 0.46). Toxicity was generally mild and moderate with three grade 3 events. No convincing predictive factors could be established. CONCLUSIONS: This largest published study on RT in advanced ACC provides clear evidence that RT is effective in ACC.

Acute toxicities of patients with locally advanced rectal cancer treated with intensified chemoradiotherapy within the CAO/ARO/AIO-12 trial: comparing conventional versus VMAT planning at a single center.

In locally advanced rectal cancer (LARC) neoadjuvant chemoradiotherapy is regarded as standard treatment. We assessed acute toxicities in patients receiving conventional 3D-conformal radiotherapy (3D-RT) and correlated them with dosimetric parameters after re-planning with volumetric modulated arc therapy (VMAT). Patients were randomized within the multicenter CAO/ARO/AIO-12 trial and received 50.4 Gy in 28 fractions and simultaneous chemotherapy with fluorouracil and oxaliplatin. Organs at risk (OAR) were contoured in a standardized approach. Acute toxicities and dose volume histogram parameters of 3D-RT plans were compared to retrospectively calculated VMAT plans. From 08/2015 to 01/2018, 35 patients with LARC were treated at one study center. Thirty-four patients were analyzed of whom 1 (3%) was UICC stage II and 33 (97%) patients were UICC stage III. Grade 3 acute toxicities occurred in 5 patients (15%). Patients with acute grade 1 cystitis (n = 9) had significantly higher Dmean values for bladder (29.4 Gy vs. 25.2 Gy, p < 0.01) compared to patients without bladder toxicities. Acute diarrhea was associated with small bowel volume (grade 2: 870.1 ccm vs. grade 0-1: 647.3 ccm; p < 0.01) and with the irradiated volumes V5 to V50. Using VMAT planning, we could reduce mean doses and irradiated volumes for all OAR: Dmean bladder (21.9 Gy vs. 26.3 Gy, p < 0.01), small bowel volumes V5-V45 (p < 0.01), Dmean anal sphincter (34.6 Gy vs. 35.6 Gy, p < 0.01) and Dmean femoral heads (right 11.4 Gy vs. 25.9 Gy, left 12.5 Gy vs. 26.6 Gy, p < 0.01). Acute small bowel and bladder toxicities were dose and volume dependent. Dose and volume sparing for all OAR could be achieved through VMAT planning and might result in less acute toxicities.

Health-related quality of life and clinical outcome after radiotherapy of patients with intracranial meningioma.

This retrospective, single-institutional study investigated long-term outcome, toxicity and health-related quality of life (HRQoL) in meningioma patients after radiotherapy. We analyzed the data of 119 patients who received radiotherapy at our department from 1997 to 2014 for intracranial WHO grade I-III meningioma. Fractionated stereotactic radiotherapy (FSRT), intensity modulated radiotherapy (IMRT) or radiosurgery radiation was applied. The EORTC QLQ-C30 and QLQ-BN20 questionnaires were completed for assessment of HRQoL. Overall survival (OS) for the entire study group was 89.6% at 5 years and 75.9% at 10 years. Local control (LC) at 5 and 10 years was 82.4% and 73.4%, respectively. Local recurrence was observed in 22 patients (18.5%). Higher grade acute and chronic toxicities were observed in seven patients (5.9%) and five patients (4.2%), respectively. Global health status was rated with a mean of 59.9 points (SD 22.3) on QLQ-C30. In conclusion, radiotherapy resulted in very good long-term survival and tumor control rates with low rates of severe toxicities but with a deterioration of long-term HRQoL.

Evaluation of the relationship between placentome perfusion, echotexture, and endocrine changes in cows at the end of pregnancy.

Although Doppler ultrasonography (USG) is frequently used in human medicine to evaluate placental function and fetal well-being, studies in veterinary medicine are limited. Thus, this study aimed to determine the relationship between placentome perfusion and echotexture and endocrine changes during the last stages of pregnancy in cows using B-mode/Doppler USG and reveal the effects of hormonal changes on placentome and uterine artery hemodynamics. The animals consisted of 12 pregnant Swiss Brown cows 3.8 ± 0.34 years old with at least one birth. Imaging with USG was continued for 1 month, thrice weekly, until delivery. To determine serum progesterone (P4), total estrogen, and cortisol levels, blood was drawn from the tail vein immediately after USG examinations. Contrast (CON), homogeneity (HOM), and mean gray value (MGV) were determined by placentome echotexture analysis. Color Doppler perfusion areas (A mix) and power Doppler perfusion areas (A red) of the placentome, pulse rate (PR), pulsatility index (PI), resistance index (RI), blood flow velocity (BFVe), blood flow volume (BFVo), and diameter (DM) in the spectral analysis of uterine artery values were collected. ImageJ was used to analyze the B-mode images, and PixelFlux (Chameleon® Software, Münster, Germany) was used to calculate the placentome perfusion values and hemodynamic parameters of the uterine artery in Doppler images. In the last month of pregnancy, there was no statistical difference in the placentome echotexture values CON and HOM. However, MGV increased close to birth (P < 0.001). Placentome perfusion level and area did not change significantly but were found to decrease numerically 2 days before delivery (P > 0.05). Uterine artery PR increased from 62.36 bpm on day 25 prepartum to 81.42 bpm at birth (P < 0.05). The P4 concentration decreased in the last month of pregnancy, whereas an increase was detected in estrogen and cortisol during this period (P < 0.05). In the uterine artery of pregnant cornu, RI and PI were negatively correlated with BFVe (P < 0.01). Based on this study, echotextural differences were observed in placentomes in the last stage of pregnancy in cows, and there were significant changes in placental and uterine artery blood flow. These changes may be related to placental maturation, especially on the days close to birth.

Dose-Escalated Salvage Radiotherapy for Macroscopic Local Recurrence of Prostate Cancer in the Prostate-Specific Membrane Antigen Positron Emission Tomography Era.

BACKGROUND: The purpose of this study was to access the oncological outcome of prostate-specific membrane antigen positron emission tomography (PSMA PET/CT)-guided salvage radiotherapy (SRT) for localized macroscopic prostate cancer recurrence. METHODS: Between February 2010 and June 2021, 367 patients received SRT after radical prostatectomy. Out of the 367 screened patients, 111 patients were staged by PSMA PET/CT before SRT. A total of 59 out of these 111 (53.2%) patients were treated for PSMA PET-positive macroscopic prostatic fossa recurrence. Dose-escalated SRT was applied with a simultaneous integrated boost at a median prescribed dose of 69.3 Gy (IQR 69.3-72.6 Gy). The oncological outcome was investigated using Kaplan-Meier and Cox regression analyses. The genitourinary (GU)/gastrointestinal (GI) toxicity evaluation utilized Common Toxicity Criteria for Adverse Events (version 5.0). RESULTS: The median follow-up was 38.2 months. The three-year biochemical progression-free survival rate was 89.1% (95% CI: 81.1-97.8%) and the three-year metastasis-free survival rate reached 96.2% (95% CI: 91.2-100.0%). The cumulative three-year late grade 3 GU toxicity rate was 3.4%. No late grade 3 GI toxicity occurred. CONCLUSIONS: Dose-escalated PSMA PET/CT-guided salvage radiotherapy for macroscopic prostatic fossa recurrence resulted in favorable survival and toxicity rates.

Development and Validation of a Predictive Model for Toxicity of Neoadjuvant Chemoradiotherapy in Rectal Cancer in the CAO/ARO/AIO-04 Phase III Trial.

Background: There is a lack of predictive models to identify patients at risk of high neoadjuvant chemoradiotherapy (CRT)-related acute toxicity in rectal cancer. Patient and Methods: The CAO/ARO/AIO-04 trial was divided into a development (n = 831) and a validation (n = 405) cohort. Using a best subset selection approach, predictive models for grade 3−4 acute toxicity were calculated including clinicopathologic characteristics, pretreatment blood parameters, and baseline results of quality-of-life questionnaires and evaluated using the area under the ROC curve. The final model was internally and externally validated. Results: In the development cohort, 155 patients developed grade 3−4 toxicities due to CRT. In the final evaluation, 15 parameters were included in the logistic regression models using best-subset selection. BMI, gender, and emotional functioning remained significant for predicting toxicity, with a discrimination ability adjusted for overfitting of AUC 0.687. The odds of experiencing high-grade toxicity were 3.8 times higher in the intermediate and 6.4 times higher in the high-risk group (p < 0.001). Rates of toxicity (p = 0.001) and low treatment adherence (p = 0.007) remained significantly different in the validation cohort, whereas discrimination ability was not significantly worse (DeLong test 0.09). Conclusion: We developed and validated a predictive model for toxicity using gender, BMI, and emotional functioning. Such a model could help identify patients at risk for treatment-related high-grade toxicity to assist in treatment guidance and patient participation in shared decision making.

Salvage Nodal Radiotherapy as Metastasis-Directed Therapy for Oligorecurrent Prostate Cancer Detected by Positron Emission Tomography Shows Favorable Outcome in Long-Term Follow-Up.

BACKGROUND: The study aimed to access the long-term outcome of salvage nodal radiotherapy (SNRT) in oligorecurrent prostate cancer. METHODS: A total of 95 consecutive patients received SNRT for pelvic and/or extrapelvic nodal recurrence after prostate-specific membrane antigen (PSMA) or choline PET from 2010 to 2021. SNRT was applied as external beam radiotherapy with simultaneous integrated boost up to a median total dose of 62.9 Gy (EQD21.5Gy) to the recurrent lymph node metastases. The outcome was analyzed by cumulative incidence functions with death as the competing risk. Fine-Gray regression analyses were performed to estimate the relative hazards of the outcome parameters. Genitourinary (GU)/gastrointestinal (GI) toxicity evaluation utilized Common Toxicity Criteria for Adverse Events (v5.0). The results are as follows: the median follow-up was 47.1 months. The five-year biochemical progression rate (95% CI) was 50.1% (35.7-62.9%). Concomitant androgen deprivation therapy (ADT) was adminstered in 60.0% of the patients. The five-year biochemical progression rate was 75.0% (42.0-90.9%) without ADT versus 35.3% (19.6-51.4%) with ADT (p = 0.003). The cumulative five-year late grade 3 GU toxicity rate was 2.1%. No late grade 3 GI toxicity occured. CONCLUSIONS: Metastasis-directed therapy through SNRT for PET-staged oligorecurrent prostate cancer demonstrated a favorable long-term oncologic outcome. Omittance of ADT led to an increased biochemical progression.

Propensity score-matched analysis comparing dose-escalated intensity-modulated radiation therapy versus external beam radiation therapy plus high-dose-rate brachytherapy for localized prostate cancer.

PURPOSE: Dose-escalated external beam radiation therapy (EBRT) and EBRT + high-dose-rate brachytherapy (HDR-BT) boost are guideline-recommended treatment options for localized prostate cancer. The purpose of this study was to compare long-term outcome and toxicity of dose-escalated EBRT versus EBRT + HDR-BT boost. METHODS: From 2002 to 2019, 744 consecutive patients received either EBRT or EBRT + HDR-BT boost, of whom 516 patients were propensity score matched. Median follow-up was 95.3 months. Cone beam CT image-guided EBRT consisted of 33 fractions of intensity-modulated radiation therapy with simultaneous integrated boost up to 76.23 Gy (DMean). Combined treatment was delivered as 46 Gy (DMean) EBRT, followed by two fractions HDR-BT boost with 9 Gy (D90%). Propensity score matching was applied before analysis of the primary endpoint, estimated 10-year biochemical relapse-free survival (bRFS), and the secondary endpoints metastasis-free survival (MFS) and overall survival (OS). Prognostic parameters were analyzed by Cox proportional hazard modelling. Genitourinary (GU)/gastrointestinal (GI) toxicity evaluation used the Common Toxicity Criteria for Adverse Events (v5.0). RESULTS: The estimated 10-year bRFS was 82.0% vs. 76.4% (p = 0.075) for EBRT alone versus combined treatment, respectively. The estimated 10-year MFS was 82.9% vs. 87.0% (p = 0.195) and the 10-year OS was 65.7% vs. 68.9% (p = 0.303), respectively. Cumulative 5­year late GU ≥ grade 2 toxicities were seen in 23.6% vs. 19.2% (p = 0.086) and 5­year late GI ≥ grade 2 toxicities in 11.1% vs. 5.0% of the patients (p = 0.002); cumulative 5­year late grade 3 GU toxicity occurred in 4.2% vs. 3.6% (p = 0.401) and GI toxicity in 1.0% vs. 0.3% (p = 0.249), respectively. CONCLUSION: Both treatment groups showed excellent long-term outcomes with low rates of severe toxicity.

PTEN mutant non-small cell lung cancer require ATM to suppress pro-apoptotic signalling and evade radiotherapy.

BACKGROUND: Despite advances in treatment of patients with non-small cell lung cancer, carriers of certain genetic alterations are prone to failure. One such factor frequently mutated, is the tumor suppressor PTEN. These tumors are supposed to be more resistant to radiation, chemo- and immunotherapy. RESULTS: We demonstrate that loss of PTEN led to altered expression of transcriptional programs which directly regulate therapy resistance, resulting in establishment of radiation resistance. While PTEN-deficient tumor cells were not dependent on DNA-PK for IR resistance nor activated ATR during IR, they showed a significant dependence for the DNA damage kinase ATM. Pharmacologic inhibition of ATM, via KU-60019 and AZD1390 at non-toxic doses, restored and even synergized with IR in PTEN-deficient human and murine NSCLC cells as well in a multicellular organotypic ex vivo tumor model. CONCLUSION: PTEN tumors are addicted to ATM to detect and repair radiation induced DNA damage. This creates an exploitable bottleneck. At least in cellulo and ex vivo we show that low concentration of ATM inhibitor is able to synergise with IR to treat PTEN-deficient tumors in genetically well-defined IR resistant lung cancer models.

Comparing Iridium-192 with Cobalt-60 sources in high-dose-rate brachytherapy boost for localized prostate cancer.

BACKGROUND: Dosimetric and clinical comparison of two cohorts of Iridium-192 (Ir-192) and Cobalt-60 (Co-60) high-dose-rate brachytherapy (DR-BT) boost for localized prostate cancer. MATERIAL AND METHODS: Patients with localized prostate cancer receiving either Ir-192 or Co-60 high-dose-rate brachytherapy (HDR-BT) boost in combination with external beam radiotherapy (EBRT) in the period of 2002-2019 were evaluated for dosimetric differences, side effects, biochemical relapse-free survival (bRFS), metastasis-free survival (MFS), and overall survival (OS). EBRT, delivered in 46 Gy (DMean) in conventional fractionation, was followed by two fractions HDR-BT boost with 9 Gy (D90%) 2 and 4 weeks after EBRT. Genitourinary (GU)/gastrointestinal (GI) toxicity were evaluated utilizing the Common Toxicity Criteria for Adverse Events version 5.0 and biochemical failure was defined according to the Phoenix definition. RESULTS: A total of 338 patients with a median follow-up of 101.8 (IQR 65.7-143.0) months were evaluated. At 10 years the estimated bRFS, MFS, and OS in our patient sample were 81.1%/71.2% (p=.073), 87.0%/85.7% (p=.862), and 70.1%/69.7% (p=.998) for Ir-192/Co-60, respectively. Cumulative 5-year late grade ≥2 GU toxicity was 20% for Ir-192 and 18.3% for Co-60 (p=.771). Cumulative 5-year late grade ≥2 GI toxicity was 5.8% for Ir-192 and 4.6% for Co-60 (p=.610). Grade 3 late GU side effects were pronounced in the Ir-192 cohort with 8.1% versus 1.4% in the Co-60 cohort (p=.01), which was associated with significantly lower dose to the organs at risk in the Co-60 cohort. PTV D90% was 9.3 ± 0.8 Gy versus 9.0 ± 1.1 Gy (p=.027) for Ir-192 versus Co-60. PTV V100% and PTV V150% were not significantly different between both cohorts. CONCLUSION: Co-60 brachytherapy sources are an effective alternative to Ir-192 in combined prostate HDR-BT boost + EBRT.

Differences in stem cell marker and osteopontin expression in primary and recurrent glioblastoma.

BACKGROUND: Despite of a multimodal approach, recurrences can hardly be prevented in glioblastoma. This may be in part due to so called glioma stem cells. However, there is no established marker to identify these stem cells. METHODS: Paired samples from glioma patients were analyzed by immunohistochemistry for expression of the following stem cell markers: CD133, Musashi, Nanog, Nestin, octamer-binding transcription factor 4 (Oct4), and sex determining region Y-box 2 (Sox2). In addition, the expression of osteopontin (OPN) was investigated. The relative number of positively stained cells was determined. By means of Kaplan-Meier analysis, a possible association with overall survival by marker expression was investigated. RESULTS: Sixty tissue samples from 30 patients (17 male, 13 female) were available for analysis. For Nestin, Musashi and OPN a significant increase was seen. There was also an increase (not significant) for CD133 and Oct4. Patients with mutated Isocitrate Dehydrogenase-1/2 (IDH-1/2) status had a reduced expression for CD133 and Nestin in their recurrent tumors. Significant correlations were seen for CD133 and Nanog between OPN in the primary and recurrent tumor and between CD133 and Nestin in recurrent tumors. By confocal imaging we could demonstrate a co-expression of CD133 and Nestin within recurrent glioma cells. Patients with high CD133 expression had a worse prognosis (22.6 vs 41.1 months, p = 0.013). A similar trend was seen for elevated Nestin levels (24.9 vs 41.1 months, p = 0.08). CONCLUSIONS: Most of the evaluated markers showed an increased expression in their recurrent tumor. CD133 and Nestin were associated with survival and are candidate markers for further clinical investigation.