Impact of dose escalation on colostomy-free survival and treatment outcome in squamous cell anal carcinoma.

PURPOSE: Primary radiochemotherapy (RCT) constitutes the standard of care for early- and advanced-stage anal carcinoma. This retrospective study investigates the impact of dose escalation on colostomy-free survival (CFS), overall survival (OS), locoregional control (LRC), progression-free survival (PFS), and acute and late toxicities in patients with squamous cell anal cancer. METHODS: Considered were the outcomes of 87 patients with anal cancer treated with radiation/RCT between May 2004 and January 2020 at our institution. Toxicities were evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE version 5.0). RESULTS: The 87 patients received treatment with a median boost of 63 Gy to the primary tumor. With a median follow-up of 32 months, the 3­year CFS, OS, LRC, and PFS were 79.5%, 71.4%, 83.9%, and 78.5%, respectively. Tumor relapse occurred in 13 patients (14.9%). Dose escalation to > 63 Gy (maximum 66.6 Gy) to the primary tumor in 38/87 patients revealed a nonsignificant trend for improved 3­year CFS (82.4% vs. 97%, P = 0.092), a significantly improved CFS for T2/T3 tumors (72.6% vs. 100%, P = 0.008), and a significantly improved 3­year PFS for T1/T2 tumors (76.7% vs. 100%, P = 0.035). While acute toxicities did not differ, dose escalation > 63 Gy led to a higher rate of chronic skin toxicities (43.8% vs. 69%, P = 0.042). Treatment with intensity-modulated radiotherapy (IMRT) showed a significant improvement in 3­year OS (75.4% vs. 53.8%, P = 0.048). In multivariate analysis, significant improvements for T1/T2 tumors (CFS, OS, LRC, PFS), G1/2 tumors (PFS), and IMRT (OS) were shown. The nonsignificant trend for CFS improvement with dose escalation > 63 Gy was also apparent in multivariate analysis (P = 0.067). CONCLUSION: Dose escalation > 63 Gy (maximum 66.6 Gy) may improve CFS and PFS for certain subgroups, with a concomitant increase in chronic skin toxicities. Modern IMRT seems to be associated with an improvement in OS.

Evaluation of treatment-associated eye toxicity after irradiation in childhood and adolescence-results from the Registry of the Evaluation of Side Effects after Radiotherapy in Childhood and Adolescence (RiSK).

PURPOSE: The aim of the study is to evaluate treatment-related acute and late eye toxicity associated with radiation therapy in childhood and adolescence as correlated with RT (radiotherapy) doses. METHODS: From 2001 to 2016, a total of 1725 children and adolescents undergoing radiation therapy were prospectively documented in the Registry of the Evaluation of Side Effects after Radiotherapy in Childhood and Adolescence (RiSK). The RTOG/EORTC criteria were used to classify ocular acute and late effects. Uni- and multivariate analyses were carried out to evaluate the impact of patient age, pre-existing impairments, and radiation dose on ocular toxicity. RESULTS: Of all documented patients, 593 received dose to the eye and formed the basis of this analysis. In 435 patients, information on acute reaction was available and graded 1, 2, 3, and 4 in 49, 17, 0, and 2 patients, respectively. Information on late toxicity was available in 268 patients and graded 1, 2, 3, and 4 in 15, 11, 11, and 5 patients, respectively. The acute toxicity rate was significantly higher in children who received a maximum dose > 50 Gy to the eye (p < 0.001) and who had a pre-existing eye impairment (p < 0.001 in multivariate analysis). The development of late toxicity was significantly higher for patients experiencing acute toxicity and having received a radiation dose > 50 Gy. CONCLUSION: Acute and late toxicity both correlate with high radiation dose to the eye (> 50 Gy) and acute toxicity additionally with pre-existing eye impairments.

Diagnostic efficiency of hybrid imaging using PSMA ligands, PET/CT, PET/MRI and MRI in identifying malignant prostate lesions.

OBJECTIVE: The objective of this study was to assess the accuracy of 68Ga-PSMA-11 PET/MRI, 18F-PSMA-1007 PET/CT, 68Ga-PSMA-11 PET/CT, and multiparametric (mp)MRI for the delineating of dominant intraprostatic lesions (IPL). MATERIALS AND METHODS: 35 patients with organ-confined prostate cancer who were assigned to definitive radiotherapy (RT) were divided into three groups based on imaging techniques: 68Ga-PSMA-PET/MRI (n = 9), 18F-PSMA-PET/CT (n = 16) and 68Ga-PSMA-PET/CT (n = 10). All patients without PSMA-PET/MRI received an additional mpMRI. PSMA-PET-based automatic isocontours and manual contours of the dominant IPLs were generated for each modality. The biopsy results were then used to validate whether any of the prostate biopsies were positive in the marked lesion using Dice similarity coefficient (DSC), Youden index (YI), sensitivity and specificity. Factors that can predict the accuracy of IPLs contouring were analysed. RESULTS: Diagnostic performance was significantly superior both for manual and automatic IPLs contouring using 68Ga-PSMA-PET/MRI (DSC/YI SUV70%-0.62/0.51), 18F-PSMA-PET/CT (DSC/YI SUV70%-0.67/0.53) or 68Ga-PSMA-PET/CT (DSC/YI SUV70%-0.63/0.51) compared to mpMRI (DSC/YI-0.47/0.41; p < 0.001). The accuracy for delineating IPLs was not improved by combination of PET/CT and mpMRI images compared to PET/CT alone. Significantly superior diagnostic accuracy was found for large prostate lesions (at least 15% from the prostate volume) and higher Gleason score (at least 7b) comparing to smaller lesions with lower GS. CONCLUSION: IPL localization was significantly improved when using PSMA-imaging procedures compared to mpMRI. No significant difference for delineating IPLs was found between hybrid method PSMA-PET/MRI and PSMA-PET/CT. PSMA-based imaging technique should be considered for the diagnostics of IPLs and focal treatment modality.

Impact of Whole Lung Irradiation on Survival Outcome in Patients With Lung Relapsed Ewing Sarcoma.

PURPOSE: There is no standard treatment procedure for relapsed Ewing sarcoma (EwS). This retrospective analysis evaluates the survival outcome in patients with an isolated pulmonary relapse of EwS treated with whole lung irradiation (WLI) in addition to second line chemotherapy (Ctx). METHODS AND MATERIALS: In our study, 136 patients with pulmonary relapsed EwS who were registered in the relapse register of the Cooperative Ewing Sarcoma Study group or the Sarcoma Relapse Registry for relapsed sarcoma of bone and soft tissues were analyzed. All patients received relapse Ctx or an additional total resection of lung metastasis. Of these patients, 88 (median age, 21 years; range, 7-52 years) achieved a second remission by the relapse treatment. Of these 88 patients, 48 patients received an additional WLI. The 3-year progression-free survival (PFS) and 3-year overall survival (OS) were analyzed (median follow-up, 3 years; range, 7 months to 11 years and 9 months). Additional prognostic factors for survival outcomes, including the response of lung metastases to Ctx, were also estimated. RESULTS: The survival outcome was significantly improved after WLI when analyzing the entire group of pulmonary relapsed patients: 3-year PFS 36% (+WLI) versus 14% (-WLI) (P = .001); 3- year OS 47% (+WLI) versus 33% (-WLI) (P = .007). The 3-year PFS in patients with complete remission of lung relapse receiving WLI (n = 48) compared with those without WLI (n = 40), was 37% (+WLI) versus 21% (-WLI) (P = .18). The site of the primary tumor and the response of pulmonary lesions to Ctx were significant prognostic indicators for survival in patients treated with WLI. No severe pulmonary function disorders or lung toxicities were observed after WLI treatment in both pediatric and adult patients. CONCLUSIONS: The WLI does not correlate with improved OS in patients with pulmonary relapsed EwS. However, a marginal trend toward superior PFS and improved local control of pulmonary disease suggests the application of WLI in patients with EwS with isolated lung relapse and second clinical remission.

A treatment planning study of prone vs. supine positions for locally advanced rectal carcinoma : Comparison of 3­dimensional conformal radiotherapy, tomotherapy, volumetric modulated arc therapy, and intensity-modulated radiotherapy.

PURPOSE: To ascertain the optimal radiation technique and radiation position for the neoadjuvant radiotherapy of patients with rectal cancer. MATERIALS AND METHODS: Treatment plans with similar dose objectives were generated for 20 selected patients. Dosimetric comparison was performed between prone and supine positions and between different radiation techniques. Dosimetric indices for the target volume and organs at risk (OAR) as well as normal tissue complication probability (NTCP) of late small bowel toxicity were analyzed. RESULTS: The helical tomotherapy (HT) in the prone position provided the optimal dose homogeneity in the target volume with the value of 0. Superior conformity values were obtained for Sliding Window (SW), Rapid Arc (RA) and HT compared to three-dimensional conformal radiotherapy (3D-CRT) techniques. All of the techniques showed dose reduction to OAR in the high-dose area in prone position versus supine position. Pairwise comparison revealed significantly higher small bowel protection by RA in the prone position in the high-dose area (V75, V45Gy). Similarly, superior bladder sparing was found for 3D-CRT in the prone position at higher doses (V50, V75). More healthy tissue in the radiation volume was involved by application of 3D-CRT with no relevant difference between positions. The mean values of NTCP for the small bowel did not show clinically meaningful variation between the techniques. CONCLUSION: All techniques provided superior sparing of OAR in the prone position. At higher radiation doses, treatment in prone position resulted in significant OAR protection, especially concerning small bowel sparing by RA and bladder sparing by 3D CRT.

Impact of radiation technique, radiation fraction dose, and total cisplatin dose on hearing : Retrospective analysis of 29 medulloblastoma patients.

PURPOSE: To analyze the incidence and degree of sensorineural hearing loss (SNHL) resulting from different radiation techniques, fractionation dose, mean cochlear radiation dose (Dmean), and total cisplatin dose. MATERIAL AND METHODS: In all, 29 children with medulloblastoma (58 ears) with subclinical pretreatment hearing thresholds participated. Radiotherapy (RT) and cisplatin had been applied sequentially according to the HIT MED Guidance. Audiological outcomes up to the latest follow-up (median 2.6 years) were compared. RESULTS: Bilateral high-frequency SNHL was observed in 26 patients (90%). No significant differences were found in mean hearing threshold between left and right ears at any frequency. A significantly better audiological outcome (p < 0.05) was found after tomotherapy at the 6 kHz bone-conduction threshold (BCT) and left-sided 8 kHz air-conduction threshold (ACT) than after a combined radiotherapy technique (CT). Fraction dose was not found to have any impact on the incidence, degree, and time-to-onset of SNHL. Patients treated with CT had a greater risk of SNHL at high frequencies than tomotherapy patients even though Dmean was similar. Increase in severity of SNHL was seen when the total cisplatin dose reached above 210 mg/m2, with the highest abnormal level found 8-12 months after RT regardless of radiation technique or fraction dose. CONCLUSION: The cochlear radiation dose should be kept as low as possible in patients who receive simultaneous cisplatin-based chemotherapy. The risk of clinically relevant HL was shown when Dmean exceeds 45 Gy independent of radiation technique or radiation regime. Cisplatin ototoxicity was shown to have a dose-dependent effect on bilateral SNHL, which was more pronounced in higher frequencies.

Primary Cardiac Angiosarcoma Treated With Positron Emission Tomography/Magnetic Resonance Imaging-Guided Adaptive Radiotherapy.

Radiotherapy (RT) for inoperable patients with primary cardiac sarcomas or residual tumor is often limited by the sensitivity of the heart and lung to radiation injury. We describe a novel treatment modality with adaptive radiotherapy (ART) using tumor volume tracking in a 37-year-old woman who presented with unresectable primary cardiac angiosarcoma. The patient was treated using positron emission tomography/magnetic resonance imaging-guided ART with 55.8 Gy concomitant with paclitaxel chemotherapy. In conclusion, the treatment was well tolerated, and a significant tumor volume reduction of ∼ 57% was achieved during radiotherapy, suggesting the effectiveness and tolerability of ART in combination with paclitaxel-based chemotherapy.

Auditory event-related potentials, bispectral index, and entropy for the discrimination of different levels of sedation in intensive care unit patients.

BACKGROUND: Sedation protocols, including the use of sedation scales and regular sedation stops, help to reduce the length of mechanical ventilation and intensive care unit stay. Because clinical assessment of depth of sedation is labor-intensive, performed only intermittently, and interferes with sedation and sleep, processed electrophysiological signals from the brain have gained interest as surrogates. We hypothesized that auditory event-related potentials (ERPs), Bispectral Index (BIS), and Entropy can discriminate among clinically relevant sedation levels. METHODS: We studied 10 patients after elective thoracic or abdominal surgery with general anesthesia. Electroencephalogram, BIS, state entropy (SE), response entropy (RE), and ERPs were recorded immediately after surgery in the intensive care unit at Richmond Agitation-Sedation Scale (RASS) scores of -5 (very deep sedation), -4 (deep sedation), -3 to -1 (moderate sedation), and 0 (awake) during decreasing target-controlled sedation with propofol and remifentanil. Reference measurements for baseline levels were performed before or several days after the operation. RESULTS: At baseline, RASS -5, RASS -4, RASS -3 to -1, and RASS 0, BIS was 94 [4] (median, IQR), 47 [15], 68 [9], 75 [10], and 88 [6]; SE was 87 [3], 46 [10], 60 [22], 74 [21], and 87 [5]; and RE was 97 [4], 48 [9], 71 [25], 81 [18], and 96 [3], respectively (all P < 0.05, Friedman Test). Both BIS and Entropy had high variabilities. When ERP N100 amplitudes were considered alone, ERPs did not differ significantly among sedation levels. Nevertheless, discriminant ERP analysis including two parameters of principal component analysis revealed a prediction probability PK value of 0.89 for differentiating deep sedation, moderate sedation, and awake state. The corresponding PK for RE, SE, and BIS was 0.88, 0.89, and 0.85, respectively. CONCLUSIONS: Neither ERPs nor BIS or Entropy can replace clinical sedation assessment with standard scoring systems. Discrimination among very deep, deep to moderate, and no sedation after general anesthesia can be provided by ERPs and processed electroencephalograms, with similar P(K)s. The high inter- and intraindividual variability of Entropy and BIS precludes defining a target range of values to predict the sedation level in critically ill patients using these parameters. The variability of ERPs is unknown.