Long-term neurocognitive function after whole-brain radiotherapy in patients with melanoma brain metastases in the era of immunotherapy.

BACKGROUND: Whole-brain radiotherapy (WBRT) used to be standard of care for patients suffering from melanoma brain metastases (MBM) and may still be applicable in selected cases. Deterioration of neurocognitive function (NCF) is commonly seen during and after WBRT. Knowledge on long-term effects in melanoma patients is limited due to short survival rates. With the introduction of immune checkpoint inhibitors, patients may experience ongoing disease control, emphasizing the need for paying more attention to potential long-term adverse effects. METHODS: In this single-center study, we identified in a period of 11 years all long-term survivors of MBM who received WBRT at least 1 year prior to inclusion. NCF was assessed by Neuropsychological Assessment Battery (NAB) screening and detailed neurological exam; confounders were documented. RESULTS: Eight patients (median age 55 years) could be identified with a median follow-up of 5.4 years after WBRT. Six patients reported no subjective neurological impairment. NAB screening revealed an average-range score in 5/8 patients. In 3/8 patients a NAB score below average was obtained, correlating with subjective memory deficits in 2 patients. In these patients, limited performance shown in modalities like memory function, attention, and spatial abilities may be considerably attributed to metastasis localization itself. Six out of 8 patients were able to return to their previous work. CONCLUSION: Five of 8 long-term survivors with MBM after WBRT experienced little to no restriction in everyday activities. In 3 out of 8 patients, cognitive decline was primarily explained by localization of the metastases in functionally relevant areas of the brain. The results of our small patient cohort do not support general avoidance of WBRT for treatment of brain metastases. However, long-term studies including pretreatment NCF tests are needed to fully analyze the long-term neurocognitive effects of WBRT.

Stereotactic radiosurgery for brain metastases from pelvic gynecological malignancies: oncologic outcomes, validation of prognostic scores, and dosimetric evaluation.

INTRODUCTION: Stereotactic radiosurgery is a well-established treatment option in the management of brain metastases. Multiple prognostic scores for prediction of survival following radiotherapy exist, but are not disease-specific or validated for radiosurgery in women with primary pelvic gynecologic malignancies metastatic to the brain. The aim of the present study is to evaluate the feasibility, safety, outcomes, and impact of established prognostic scores. METHODS: We retrospectively identified 52 patients treated with radiotherapy for brain metastases between 2008 and 2021. Stereotactic radiosurgery was utilized in 31 patients for an overall number of 75 lesions; the remaining 21 patients received whole-brain radiotherapy. Kaplan-Meier survival analysis and the log-rank test were used to calculate and compare survival curves and univariate and multivariate Cox regression to assess the influence of cofactors on recurrence, local control, and prognosis. RESULTS: With a median follow-up of 10.7 months, overall survival rates post radiosurgery were 65.3%, 51.3%, and 27.7% for 1, 2, and 5 years, respectively, which were significantly higher than post whole-brain radiotherapy (p=0.049). Five local failures (6.7%) were detected, resulting in 1 and 2 year local cerebral control rates of 97.4% and 94.0%, respectively. Univariate factors for prediction of superior overall survival were high performance status (p=0.030) and application of three prognostic scores, especially the Recursive Partitioning Analysis score (p=0.028). Uni- and multivariate analysis revealed that extracranial progression prior to radiosurgery was significant for inferior overall survival (p<0.0001). Radionecrosis was diagnosed in five women (16%); long-term neurotoxicity was significantly worse after whole-brain radiotherapy compared with radiosurgery (p=0.023). CONCLUSION: Stereotactic radiosurgery for brain metastases from pelvic gynecologic malignancies appears to be safe and well tolerated, achieving promising local cerebral control. Prognostic scores were shown to be transferable and radiosurgery should be recommended as primary intracranial treatment, especially in women with no prior extracranial progression and Recursive Partitioning Analysis class I.

Adenoid cystic Carcinoma and Carbon ion Only irradiation (ACCO): Study protocol for a prospective, open, randomized, two-armed, phase II study.

BACKGROUND: Adenoid cystic carcinoma is a rare form of head and neck cancer with a slow, but aggressive growth pattern which remains a challenge for local tumor control. Based on phase II data, radiation treatment using partially high LET radiation results in a prolonged PFS and OS. There is a paucity of randomized clinical data examining the role of the use of high LET radiation only. Therefore, the purpose of this prospective clinical trial is to analyze local control rates in patients with node negative ACC treated with carbon ion radiotherapy alone compared to a combined modality approach. METHODS: This trial is conducted as a prospective, open-label, phase II, two-armed, investigator-initiated study comparing the local control rates in node negative ACCs of the head and neck treated either with sole carbon ion radiotherapy or a combination of carbon ions and photons. Secondary outcomes investigated are progression-free survival, overall survival, acute and late toxicity, and quality of life. A total of 314 patients will be randomly assigned to C12 treatment alone or bimodal treatment: Patients in the experimental group will receive a dose of 51 Gy (RBE) in 17 fractions and a boost of 15 Gy (RBE) in 5 fractions. Patients in the control group will receive 25 fractions photon IMRT 50Gy and a boost using 8 × 3 Gy (RBE) carbon ions. Local control will be assessed in regular follow up examinations until 5 years after the completion of treatment. DISCUSSION: The present trial aims to evaluate local control rates to compare sole carbon ion radiotherapy to bimodal radiotherapy with carbon ions and photons in patients with node negative ACCs of the head and neck region. Local control is selected as the primary endpoint due to its major clinical relevance because of slow but aggressive growth patterns. TRIAL REGISTRATION: The study was prospectively registered on 2nd January 2020: ClinicalTrials.gov, NCT04214366 . "Adenoid Cystic Carcinoma and Carbon Ion Only Irradiation (ACCO)". STUDY STATUS: Under recruitment, participant recruitment is not completed. Start of recruitment was January 2020. There are no results been published or submitted to any journal.

Sleep behavior of infants with infantile hemangioma treated with propranolol-a cohort study.

Sleep problems are frequently reported in infants treated with propranolol for infantile hemangiomas, possibly serving as a marker for a negative impact on central nervous system function. In this cohort study, we objectively investigate the sleep behavior of infants with infantile hemangiomas on propranolol compared to a healthy, untreated control group. Sleep of propranolol-treated infants and controls was investigated using ankle actigraphy and a 24-h diary for 7-10 days at ages 3 and 6 months. The main outcome measures were the Number of Nighttime Awakenings and Sleep Efficiency. The main secondary outcome measures included 24-hour Total Sleep, daytime sleep behavior, and parent-rated infant sleep quality and behavioral development based on the Brief Infant Sleep Questionnaire (BISQ) and the age-appropriate Ages-and-Stages Questionnaire (ASQ), respectively. Fifty-four term-born infants were included in each cohort. No group difference in any investigated parameter was seen at age 3 months. At age 6 months, the propranolol group exhibited a decrease in Sleep Efficiency and a trend towards an increased Number of Nighttime Awakenings compared to the control group. Treated infants at 6 months also had shorter daytime waking periods. 24-hour Total Sleep was unaffected by propranolol. No negative impact of propranolol on subjective sleep quality and behavioral development was noted.Conclusion: Propranolol exerts a measurable yet mild impact on objectively assessed infants' sleep measures. Behavioral developmental scores were unaffected. Our results support propranolol as first-line therapy for complicated infantile hemangiomas. What is Known: • Sleep disorders are frequently reported in infants with infantile hemangiomas treated with propranolol and often lead to treatment discontinuation. • Investigations of the sleep pattern in this patient group using objective measures are lacking. What is New: • The sleep pattern of propranolol-treated infants is assessed using actigraphy and a 24-h sleep diary and compared to healthy, untreated controls. • Propranolol leads to a decreased sleep efficiency at night and an increased demand of daytime sleep, yet effects are mild overall.

Intrafractional vaginal dilation in anal cancer patients undergoing pelvic radiotherapy (DILANA) - a prospective, randomized, 2-armed phase-II-trial.

BACKGROUND: The incidence of anal cancer is rising in the last decades and more women are affected than men. The prognosis after chemoradiation is very good with complete remission rates of 80-90%. Thus, reducing therapy-related toxicities and improving quality of life are of high importance. With the development of new radiotherapy techniques like IMRT (Intensity-modulated radiotherapy), the incidence of acute and chronic gastrointestinal toxicities has already been reduced. However, especially in female anal cancer patients genital toxicities like vaginal fibrosis and stenosis are of great relevance, too. Up to now, there are no prospective data reporting incidence rates, techniques of prevention or impact on quality of life. The aim of the DILANA trial is to evaluate the incidence and grade of vaginal fibrosis, to optimize radiotherapy by reducing dose to the vaginal wall to minimize genital toxicities and improve quality of life of anal cancer patients. METHODS: The study is designed as a prospective, randomized, two-armed, open, single-center phase-II-trial. Sixty patients will be randomized into one of two arms, which differ only in the diameter of a tampon used during treatment. All patients will receive standard (chemo) radiation with a total dose of 45-50.4 Gy to the pelvic and inguinal nodes with a boost to the anal canal up to 54-60 Gy. The primary objective is the assessment of the incidence and grade of vaginal fibrosis 12 months after (chemo) radiation depending on the extent of vaginal dilation. Secondary endpoints are toxicities according to the CTC AE version 5.0 criteria, assessment of clinical feasibility of daily use of a tampon, assessment of compliance for the use of a vaginal dilator and quality of life. DISCUSSION: Prospective studies are needed evaluating the incidence and grade of vaginal fibrosis after (chemo) radiation in female anal cancer patients. Furthermore, the assessment of techniques to reduce the incidence of vaginal fibrosis like intrafractional vaginal dilation as well as other radiotherapy-independent methods like using a vaginal dilator are essential. Additionally, implementation of a systematic assessment of vaginal stenosis is necessary to grant reproducibility and comparability of future data. TRIAL REGISTRATION: The trial is registered with clinicaltrials.gov (NCT04094454, 19.09.2019).

A matched-pair analysis comparing stereotactic radiosurgery with whole-brain radiotherapy for patients with multiple brain metastases.

INTRODUCTION: Stereotactic radiosurgery (SRS) is an emerging treatment for patients with multiple brain metastases (BM). The present work compares the SRS of multiple brain metastases with whole-brain radiotherapy (WBRT). METHODS: We performed a matched-pair analysis for 128 patients with multiple BM treated with either SRS or WBRT over a 5-year period. Patients were matched pairwise for seven potential prognostic factors. A mixed Cox Proportional Hazards model with univariate and multivariate analysis was fitted for overall survival (OS). Distant intracranial progression-free survival (icPFS) and local control were assessed using a Fine and Gray subdistribution hazard model and considering death as competing event. RESULTS: Patients undergoing SRS had a median of 4 BM (range 3-16). 1-year local control of individual BM following SRS was 91.7%. Median OS in the SRS subgroup was 15.7 months (IQR 9.7-36.4) versus 8.0 months (interquartile range, IQR 3.8-18.0) in the WBRT subgroup (HR 2.25, 95% CI [1.5; 3.5], p < 0.001). Median icPFS was 8.6 (IQR 3.4-18.0) versus 22.4 (IQR 5.6-28.6) months, respectively (HR for WBRT 0.41, 95% CI [0.24; 0.71], p = 0.001). Following SRS, synchronous BM diagnosis (HR 2.51, 95% CI [1.30; 4.70], p = 0.004), higher initial number of BM (HR 1.21, 95% CI [1.10; 1.40], p = 0.002) and lung cancer histology (HR 2.05, 95% CI [1.10; 3.80], p = 0.024) negatively impacted survival. Excellent clinical performance (KPI 90%) was a positive prognosticator (HR 0.38, 95% CI [0.20; 0.72], p = 0.003), as was extracerebral tumor control (HR 0.48, 95% CI [0.24; 0.97], p = 0.040). Higher initial (HR 1.19, 95% CI [1.00; 1.40], p < 0.013) and total number of BM (HR 1.23, 95% CI [1.10; 1.40], p < 0.001) were prognostic for shorter icPFS. CONCLUSION: This is the first matched-pair analysis to compare SRS alone versus WBRT alone for multiple BM. OS was prolonged in the SRS subgroup and generally favorable in the entire cohort. Our results suggest SRS as a feasible and effective treatment for patients with multiple BM.

Definitive radiotherapy vs. postoperative radiotherapy for lower gingival carcinomas of the mandible : A single-center report about outcome and toxicity.

PURPOSE: To assess radiotherapy (RT) outcomes in patients with gingival carcinoma and growth up to or involvement of the lower jaw bone. METHODS: This was a retrospective analysis of 51 patients with squamous cell carcinomas of the gingiva. Patients received definitive (group 1, 31.4%) or postoperative (group 2, 66.7%) RT between 2005 and 2017 at the Department of Radiation Oncology, University Hospital Heidelberg. The primary endpoint was overall survival (OS) in both treatment groups. Other endpoints were local-disease-free survival (LDFS), progression-free survival (PFS) and treatment-related toxicity (Common Terminology Criteria for Adverse Events, CTCAE, Version 4.03). RESULTS: Median age at first diagnosis was 63 years. All patients had a local advanced disease (American Joint Commission on Cancer [AJCC] stage III-IV). After a median follow-up of 22 months (range 3-145 months), 20 patients (39.2%) were still alive. At 5 years, OS rate was 36.6%. No significant differences in OS (p = 0.773), PFS (p = 0.350) and LDFS (p = 0.399) were observed between the two groups. Most common higher-grade acute RT-related complications (≥ grade 3) were dermatitis (78.2%), oral mucositis (61.7%), xerostomia (51.5%), and loss of taste (74.6%). Three cases (5.8%) of osteoradionecrosis (ORN) of the lower jaw were detected after 15-31 months. CONCLUSIONS: Definitive and postoperative RT have similar treatment outcomes for patients with lower gingiva carcinomas of the lower jaw. The most common acute complications (grade ≥3) were dermatitis, oral mucositis, xerostomia and loss of taste.

Neoadjuvant versus definitive chemoradiotherapy for locally advanced esophageal cancer : Outcomes and patterns of failure.

PURPOSE: Randomized trials examining neoadjuvant chemoradiotherapy followed by surgical resection (nCRT-S) and definitive CRT (dCRT) for esophageal cancer (EC) patients are hampered by use of nonstandard treatment paradigms. Outcomes of nCRT-S versus dCRT in a more common patient population are lacking. We investigated local control and survival, evaluated clinical factors associated with endpoints, and assessed patterns of failure between these cohorts. METHODS: We retrospectively analyzed 130 patients with locally advanced EC receiving either dCRT or nCRT-S at our institution from 2000-2012. Inclusion criteria were curatively treated nonmetastatic EC, Karnofsky performance status ≥70%, and receipt of concomitant CRT. Patients were excluded if receiving <41 Gy neoadjuvantly or <50 Gy definitively. Kaplan-Meier analysis was used to evaluate local recurrence (LR), progression-free survival (PFS), and overall survival (OS). Univariate and multivariate Cox proportional hazards modeling addressed factors associated with outcomes. Patterns of failure were enumerated as local, regional, or distant. RESULTS: Mean follow-up was 34.2 months. The 3­year LR was 10.8% in the nCRT-S group and 21.5% in the dCRT group (p = 0.266). Median PFS were 15.6 and 14.9 months, respectively (p = 0.549). Median OS were 20.6 and 25.9 months, respectively (p = 0.81). On univariate and multivariate analysis, none of the investigated factors was associated with outcomes, although node-positive disease showed a trend for worse OS and PFS. Most common failures in both groups were distant (dCRT 31.2% vs. nCRT-S 21.6%) followed by local in-field recurrences (dCRT 26.9% vs. nCRT-S 10.8%). CONCLUSIONS: In this institutional analysis, no significant differences regarding outcomes and patterns of failure were observed between nCRT-S and dCRT.

Mutation in exon 1a of PLEC, leading to disruption of plectin isoform 1a, causes autosomal-recessive skin-only epidermolysis bullosa simplex.

PLEC, the gene encoding the cytolinker protein plectin, has eight tissue-specific isoforms in humans, arising by alternate splicing of the first exon. To date, all PLEC mutations that cause epidermolysis bullosa simplex (EBS) were found in exons common to all isoforms. Due to the ubiquitous presence of plectin in mammalian tissues, EBS from recessive plectin mutations is always associated with extracutaneous involvement including muscular dystrophy, pyloric atresia and cardiomyopathy. We studied a consanguineous family with sisters having isolated blistering suggesting EBS. Skin disease started with foot blisters at walking age and became generalized at puberty while sparing mucous membranes. DNA sequencing revealed a homozygous nonsense mutation (c.46C>T; p.Arg16X) in the first exon of the plectin variant encoding plectin isoform 1a (P1a). Immunofluorescence antigen mapping, transmission electron microscopy, western blot analysis and qRT-PCR were performed on patient skin and cultured keratinocytes, control myocardium and striated muscle samples. We found hypoplastic hemidesmosomes and intra-epidermal 'pseudo-junctional' cleavage fitting EBS. Screening for cardiomyopathy and muscle dystrophy showed no abnormalities. We report the first cases of autosomal-recessive EBS from P1a deficiency affecting skin, while mucous membranes, heart and muscle are spared. The dominant expression of the P1a isoform in epidermal basal cell layer and cultured keratinocytes suggests that mutations in the first exon of isoform 1a cause skin-only EBS without extracutaneous involvement. Our study characterizes yet another of the eight isoforms of plectin and adds a tissue-specific phenotype to the spectrum of 'plectinopathies' produced by mutations of unique first exons of this gene.

Monogenic human skin disorders.

Human genodermatoses represent a broad and partly confusing spectrum of countless rare diseases with confluent and overlapping phenotypes often impeding a precise diagnosis in an affected individual. High-throughput sequencing techniques have expedited the identification of novel genes and have dramatically simplified the establishment of genetic diagnoses in such heterogeneous disorders. The precise genetic diagnosis of a skin disorder is crucial for the appropriate counselling of patients and their relatives regarding the course of the disease, prognosis and recurrence risks. Understanding the underlying pathophysiology is a prerequisite to understanding the disease and developing specific, targeted or individualized therapeutic approaches. We aimed to create a comprehensive overview of human genodermatoses and their respective genetic aetiology known to date. We hope this may represent a useful tool in guiding dermatologists towards genetic diagnoses, providing patients with individual knowledge on the respective disorder and applying novel research findings to clinical practice.

Effects of Ionizing Radiation on Cardiac Implantable Electronic Devices (CIEDs) in Patients with Esophageal Cancer Undergoing Radiotherapy: A Pilot Study.

(1) Background: The prevalence of cancer patients relying on cardiac implantable electronic device (CIED) is steadily rising. The aim of this study was to evaluate RT-related malfunctions of CIEDs. (2) Methods: We retrospectively analyze sixteen patients with esophageal cancer who were treated with radiotherapy between 2012 and 2022 at the University Hospital Heidelberg. All patients underwent systemic evaluation including pre-therapeutic cardiological examinations of the CIED functionality and after every single irradiation. (3) Results: Sixteen patients, predominantly male (14) with a mean age of 77 (range: 56-85) years were enrolled. All patients received 28 fractions of radiotherapy with a cumulative total dose 58.8 Gy. The mean maximum dose at the CIEDs was 1.8 Gy. Following radiotherapy and during the one-year post-radiation follow-up period, there were no registered events associated with the treatment in this evaluation. (4) Conclusion: The study did not observe any severe CIED malfunctions following each radiation fraction or after completion of RT. Strict selection of photon energy and alignment with manufacturer-recommended dose limits appear to be important. Our study showed no major differences in the measured values of the pacing threshold, sensing threshold and lead impedance after RT.

Oral Cavity Squamous Cell Carcinoma: Impact of Clear Margin Distance on Locoregional Control in Patients Undergoing Postoperative Radiotherapy.

INTRODUCTION: Postoperative radiotherapy can improve locoregional control (LC) in oral cavity squamous cell carcinoma (OCSCC) patients with positive resection margins. The present study aimed to evaluate the impact of surgical margin size on LC in this patient population. METHODS: This retrospective study involved 162 patients with OCSCC who underwent postoperative radiotherapy between 2000 and 2020 at the Department of Radiation Oncology, University Hospital Heidelberg and the German Cancer Research Center. The study aimed to determine the impact of different resection margins on LC, as well as overall survival (OS), progression-free survival (PFS), and treatment-related toxicity (CTCAE 4.03). RESULTS: Seventy-seven patients (47.5%) had involved (<1 mm) margins, 22 patients (13.6%) close (≤5 mm) margins, and 63 patients (38.9%) clear (>5 mm) margins. A surgical margin ≤ 5 mm was a significant predictor for worse LC (HR 2.6, 95% CI 1.2, 6.1), but not for OS (HR 1.2, CI 0.7, 1.9) or PFS (HR 1.2, 0.7, 2.0). CONCLUSION: Patients who have narrow resection margins (1-5 mm) experience poor local control and should receive postoperative radiotherapy. It is necessary to conduct further prospective studies to determine whether a narrower margin window could be achieved to better determine the appropriate indication for adjuvant radiotherapy.

Bone Marrow Sparing by Intensity Modulated Proton Beam Therapy in Postoperative Irradiation of Gynecologic Malignancies.

Purpose: The aim of this matched-pair cohort study was to evaluate the potential of intensity-modulated proton therapy (IMPT) for sparring of the pelvic bone marrow and thus reduction of hematotoxicity compared to intensity-modulated photon radiotherapy (IMRT) in the setting of postoperative irradiation of gynaecological malignancies. Secondary endpoint was the assessment of predictive parameters for the occurrence of sacral insufficiency fractures (SIF) when applying IMPT. Materials and Methods: Two cohorts were analyzed consisting of 25 patients each. Patients were treated with IMPT compared with IMRT and had uterine cervical (n = 8) or endometrial cancer (n = 17). Dose prescription, patient age, and diagnosis were matched. Dosimetric parameters delivered to the whole pelvic skeleton and subsites (ilium, lumbosacral, sacral, and lower pelvis) and hematological toxicity were evaluated. MRI follow-up for evaluation of SIF was only available for the IMPT group. Results: In the IMPT group, integral dose to the pelvic skeleton was significantly lower (23.4GyRBE vs 34.3Gy; p < 0.001), the average V5Gy, V10Gy, and V20Gy were reduced by 40%, 41%, and 28%, respectively, compared to the IMRT group (p < 0.001). In particular, for subsites ilium and lower pelvis, the low dose volume was significantly lower. Hematotoxicity was significantly more common in the IMRT group (80% vs 32%; p = 0009), especially hematotoxicity ≥ CTCAE II (36% vs 8%; p = 0.037). No patient in the IMPT group experienced hematotoxicity > CTCAE II. In the IMPT cohort, 32% of patients experienced SIF. Overall SIF occurred more frequently with a total dose of 50.4 GyRBE (37.5%) compared to 45 GyRBE (22%). No significant predictive dose parameters regarding SIF could be detected aside from a trend regarding V50Gy to the lumbosacral subsite. Conclusion: Low-dose exposure to the pelvic skeleton and thus hematotoxicity can be significantly reduced by using IMPT compared to a matched photon cohort. Sacral insufficiency fracture rates appear similar to reported rates for IMRT in the literature.

Impact of Radiotherapy on Endotracheal Intubation Quality Metrics in Patients with Esophageal Cancer: A Challenge for Advanced Airway Management?

(1) Background: Currently, no data are available in the literature investigating the influence of radiotherapy (RT) on endotracheal intubation success in patients with esophageal cancer. This study aims to evaluate the impact of RT on endotracheal intubation quality metrics in patients with esophageal cancer. (2) Methods: Patients with esophageal cancer who underwent RT followed by surgery between 2012 and 2023 at the University Hospital Heidelberg, Germany, were retrospectively analyzed. (3) Results: Fifty-five patients, predominantly males 65.5% with a mean age of 64 years, were enrolled. Overall, 81.8% of the patients had an ASA class of III, followed by 27.2% ASA II. The mean prescribed cumulative total dose to the primary tumor and lymph node metastasis was 48.2 Gy with a mean single dose of 1.8 Gy. The mean laryngeal total dose was 40.0 Gy. Direct laryngoscopy was performed in 80.0% of cases, followed by 12.1% videolaryngoscopy, and 7.2% required fiberoptic intubation. Overall, 96.4% of patients were successfully intubated on the first attempt. (4) Conclusions: It has been demonstrated that post-RT effects can increase the risk of airway management difficulties and complications. The results of our study did not indicate any evidence of impaired advanced airway management in patients with esophageal cancer who had undergone RT.

Combined Photon and Carbon Ion Radiation Therapy for Sinonasal Malignancies: Results of the HIT-SNT Prospective Phase 2 Trial.

PURPOSE: Radiation treatment of sinonasal malignancies is a challenging task due to proximity to critical structures of the head and neck and skull base. Local tumor control is highly dose-dependent, but dose application is limited due to accompanying toxicity and dose constraints. To evaluate the toxicity and efficacy of combined radiation treatment with intensity-modulated radiation therapy (IMRT) and carbon ion boost, we conducted a prospective phase 2 IMRT-Heidelberg Ion-Beam Therapy Sinonasal Tumors (HIT-SNT) trial. METHODS AND MATERIALS: Between 2011 and 2019, we treated 35 patients with histologically proven, incompletely resected or inoperable adeno- (51%) or squamous cell carcinoma (49%) of the paranasal sinuses with combined IMRT (50 Gy) and carbon ion boost (24 Gy relative biologic effectiveness) to a total dose of 74 Gy. RESULTS: Acute mucositis Common Terminology Criteria for Adverse Events (CTCAE) grade 3 occurred in 12% of patients (n = 4) and was accompanied by odynophagia CTCAE grade 3. Except for 1 case of grade 3 weight loss, no other acute high-grade toxicity (grade 3-4) was observed. In a small patient cohort of 15 patients eligible for long-term follow-up we have seen no high-grade (grade ≥3) long-term side effects 2 years after radiation therapy. None of these patients suffered from therapy-associated vision or hearing loss. Secondary endpoints were 2-year overall survival, 2-year local progression-free survival, 2-year progression-free survival, and 2-year metastases-free survival with 79.4%, 61.8%, 61.8%, and 64.8%, respectively. CONCLUSIONS: To our knowledge, this is the first prospective data on toxicity and outcome of bimodal radiation therapy for the rare entity of sinonasal malignancies. Our study shows a low rate of CTCAE-reported acute toxicity with reasonable tumor control and survival rates after bimodal radiation therapy, which therefore remains a therapy approach to be further evaluated.

Incidence and Risk Assessment of Capsular Contracture in Breast Cancer Patients following Post-Mastectomy Radiotherapy and Implant-Based Reconstruction.

Our study aims to identify the risk factors and dosimetry characteristics associated with capsular contracture. METHODS: We retrospectively analyzed 118 women with breast cancer who underwent PMRT following an IBR between 2010 and 2022. Patients were treated with PMRT of 50.0-50.4 Gy in 25-28 fractions. Capsular contracture was categorized according to the Baker Classification for Reconstructed Breasts. RESULTS: After a median follow-up of 22 months, the incidence of clinically relevant capsular contracture (Baker III-IV) was 22.9%. Overall, capsular contracture (Baker I-IV) occurred in 56 patients (47.5%) after a median of 9 months after PMRT. The rate of reconstruction failure/implant loss was 25.4%. In the univariate analysis, postoperative complications (prolonged pain, prolonged wound healing, seroma and swelling) and regional nodal involvement were associated with higher rates of capsular contracture (p = 0.017, OR: 2.5, 95% CI: 1.2-5.3 and p = 0.031, respectively). None of the analyzed dosimetric factors or the implant position were associated with a higher risk for capsular contracture. CONCLUSION: Postoperative complications and regional nodal involvement were associated with an increased risk of capsular contracture following breast reconstruction and PMRT, while none of the analyzed dosimetric factors were linked to a higher incidence. Additional studies are needed to identify further potential risk factors.

Treatment Tolerability and Toxicity of Postoperative Proton Beam Therapy for Gynecologic Malignancies: Results of the Prospective Phase 2 APROVE Trial.

PURPOSE: The APROVE study is a prospective one-arm phase-2 study investigating the safety and treatment tolerability of postoperative proton beam therapy in women with uterine cervical or endometrial cancer. In this analysis, we report the primary study endpoint of safety and treatment tolerability as well as toxicity rates and progression-free survival (PFS). METHODS AND MATERIALS: 25 patients were treated with postoperative proton beam therapy with a total dose of 45 to 50.4 Gy (RBE) in 5 to 6 × 1.8 Gy (RBE) fractions weekly using active raster-scanning intensity modulated proton beam therapy (IMPT). Sequential or simultaneous platinum-based chemotherapy was administered if indicated. The primary endpoint was defined as the lack of any acute ≥grade 3 gastrointestinal (GI) or urogenital (GU) toxicity according to the Common Terminology Criteria for Adverse Events v 4.0 or premature treatment abortion. Secondary endpoints were clinical symptoms and toxicity, quality of life, and PFS. RESULTS: All patients completed IMPT according to the protocol, with a median treatment duration of 43 days (range, 33 to 51 days). No patient developed gastrointestinal or genitourinary toxicity ≥grade 3, and the treatment tolerability rate was 100%. Therefore, the null hypothesis H0: Tolerability Rate ≤80% could be rejected in favor of the alternative hypothesis H1: Tolerability rate >80% using an exact binomial test with a one-sided significance level of α = 10% (one-sided P value P = .0059). The median follow-up time after the end of IMPT was 25.1 months (range, 20.2 to 50.3 months). 18 of 25 (75%) patients completed the study follow-up of 24 months. 7 patients had progressive disease. Kaplan-Meier-estimated mean PFS was 39.9 months (95% confidence interval: 33.37 to 46.5 months). CONCLUSIONS: Postoperative IMPT is a safe treatment option for cervical and endometrial cancer patients, with only low-grade acute and late toxicities. Larger randomized trials are necessary to further assess the potential of IMPT and improve patient selection.

Health-related quality of life and patient-reported symptoms after postoperative proton beam radiotherapy of cervical and endometrial cancer: 2-year results of the prospective phase II APROVE-trial.

INTRODUCTION: The APROVE-trial investigated the tolerability of postoperative proton beam therapy in women with cervical or endometrial cancer. The present analysis evaluated the secondary endpoints of health-related quality of life (HRQOL) and patient-reported symptoms. METHODS: 25 patients were included in this prospective phase-II-trial and treated with postoperative radiotherapy using protons alone or in combination with chemotherapy. To attain general and gynecologic-specific HRQOL measures, the EORTC-QLQ-C30 questionnaires combined with -QLQ-CX24 for cervical and -QLQ-EN24 for endometrial cancer were assessed at baseline, at the end of RT and up to 2 years after radiotherapy. The results were compared to an age-matched norm reference population. Symptoms were assessed using Common Terminology Criteria for Adverse Events (CTCAE) and institutional patient-reported symptoms grading. RESULTS: Scores regarding global health status were markedly impaired at baseline (mean: 58.0 ± 20.1) compared to reference population data, but significantly (p = 0.036) improved and evened out to comparable norm values 2 years after proton therapy (mean: 69.9 ± 19.3). Treatment caused acute and long-term worsening of pain (p = 0.048) and gastrointestinal symptoms (p = 0.016) for women with endometrial cancer, but no higher-grade CTCAE ≥ 3° toxicity was observed. Dosimetric evaluation of rectum, sigmoid, large and small bowel showed no correlation with the reported gastrointestinal symptoms. After 2 years, fatigue had significantly improved (p = 0.030), whereas patients with cervical cancer experienced more often lymphedema (p = 0.017). Scores for endometrial cancer pertaining to sexual activity (p = 0.048) and body image (p = 0.022) had improved post treatment; in the latter this effect persisted after 2 years. CONCLUSION: Proton beam therapy in the adjuvant setting was well tolerated with only low-grade side effects concerning gastrointestinal symptoms, lymphedema and pain. Overall quality of life was impaired at baseline, but patients were able to recover to values comparable to norm population 2 years after proton therapy. Larger studies are needed to confirm whether the benefit of proton therapy translates into a clinical effect. Sexual dysfunction remains an important issue. TRIAL REGISTRATION: The trial was registered at https://clinicaltrials.gov (ClinicalTrials.gov Identifier: NCT03184350, 09th June 2017).