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.

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.

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.

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.

Comorbidity in limited disease small-cell lung cancer: Age-adjusted Charlson comorbidity index and its association with overall survival following chemoradiotherapy.

Background: Combined, platinum-based thoracic chemoradiotherapy (TCR) is the current state-of-the-art treatment for patients with limited disease (LD) small-cell lung cancer (SCLC). There is only limited data available regarding the effect of comorbidities on survival following TRC. The purpose of this study is to assess the age-adjusted Charlson comorbidity index (ACCI) as a predictor of overall survival in LD-SCLC patients undergoing TCR. Patients and methods: We retrospectively analyzed 367 SCLC patients diagnosed with LD-SCLC who received TCR between 2003 and 2017. We evaluated the ACCI (n = 348) as a predictor of overall survival (OS). In this cohort, 322 patients (88%) received platinum-based TCR (either cisplatin or carboplatin), and 37 (10%) patients received vincristine based TCR. Median radiation dose was 60 Gy (range 24-66 Gy). Additionally, 83% of patients (n = 303) received prophylactic cranial irradiation (PCI, 30 Gy in 2 Gy fractions). Kaplan-Meier survival analysis was performed for OS. For comparison of survival curves, Log-rank (Mantel-Cox) test was used. Univariate and multivariate Cox proportional-hazards ratios (HRs) were used to assess the influence of cofactors on OS. Results: Patients with an ACCI > 6 had a significantly shorter OS compared with patients with an ACCI ≤ 6 (median 11 vs. 20 months; p = 0.005). Univariate analysis for OS revealed a statistically significant effect for ACCI > 6 (HR 1.7; 95% CI 1.2-2.4; p = 0.003), PCI (HR 0.5; 95% CI 0.3-0.7; p < 0.001), and Karnofsky performance status ≤ 70% (KPS) (HR 1.4; 95% CI 1.1-1.90; p = 0.015). In multivariate analysis, OS was significantly associated with PCI (HR 0.6; 95% CI 0.4-0.9; p = 0.022) and ACCI > 6 (HR 1.5; 95% CI 1.0-2.1; p = 0.049). Conclusion: Comorbidity is significantly associated with survival in patients with LD-SCLC undergoing TCR. The ACCI may be a valuable tool to identify patients with a shorter survival and thus might be used for risk stratification and oncological decision making.

Long-Term Clinical Results of MR-Guided Stereotactic Body Radiotherapy of Liver Metastases.

(1) Background: Magnetic-resonance (MR)-guided stereotactic body radiotherapy (SBRT) allows for ablative, non-invasive treatment of liver metastases. However, long-term clinical outcome data are missing. (2) Methods: Patients received MR-guided SBRT with a MRIdian Linac between January 2019 and October 2021 and were part of an ongoing prospective observational registry. Local hepatic control (LHC), distant hepatic control (DHC), progression free survival (PFS) and overall survival (OS) were estimated with the Kaplan-Meier method. Toxicity was documented according to CTCAE (v.5.0). (3) Results: Forty patients were treated for a total of 54 liver metastases (56% with online plan adaptation). Median prescribed dose was 50 Gy in five fractions equal to a biologically effective dose (BED) (alpha/beta = 10 Gy) of 100 Gy. At 1 and 2 years, LHC was 98% and 75%, DHC was 34% and 15%, PFS was 21% and 5% and OS was 83% and 57%. Two-year LHC was higher in case of BED > 100 Gy (100% vs. 57%; log-rank p = 0.04). Acute grade 1 and 2 toxicity (mostly nausea) occurred in 26% and 7% of the patients, with no grade ≥ 3 event. (4) Conclusions: To our knowledge, this is the largest cohort of MR-guided liver SBRT. Long-term local control was promising and underscores the aim of achieving >100 Gy BED. Nonetheless, distant tumor control remains challenging.

Analysis of recurrence probability following radiotherapy in patients with CNS WHO grade 2 meningioma using integrated molecular-morphologic classification.

Background: The current World Health Organization (WHO) classification of brain tumors distinguishes 3 malignancy grades in meningiomas, with increasing risk of recurrence from CNS WHO grades 1 to 3. Radiotherapy is recommended by current EANO guidelines for patients not safely amenable to surgery or after incomplete resection in higher grades. Despite adequately predicting recurrence probability for the majority of CNS WHO grade 2 meningioma patients, a considerable subset of patients demonstrates an unexpectedly early tumor recurrence following radiotherapy. Methods: A retrospective cohort of 44 patients with CNS WHO grade 2 meningiomas were stratified into 3 risk groups (low, intermediate, and high) using an integrated morphological, CNV- and methylation family-based classification. Local progression-free survival (lPFS) following radiotherapy (RT) was analyzed and total dose of radiation was correlated with survival outcome. Radiotherapy treatment plans were correlated with follow-up images to characterize the pattern of relapse. Treatment toxicities were further assessed. Results: Risk stratification of CNS WHO grade 2 meningioma into integrated risk groups demonstrated a significant difference in 3-year lPFS following radiotherapy between the molecular low- and high-risk groups. Recurrence pattern analysis revealed that 87.5 % of initial relapses occurred within the RT planning target volume or resection cavity. Conclusions: Integrated risk scoring can identify CNS WHO grade 2 meningioma patients at risk or relapse and dissemination following radiotherapy. Therapeutic management of CNS WHO grade 2 meningiomas and future clinical trials should be adjusted according to the molecular risk-groups, and not rely on conventional CNS WHO grading alone.

Comparison of different dose accumulation strategies to estimate organ doses after stereotactic magnetic resonance-guided adaptive radiotherapy.

INTRODUCTION: Re-irradiation is frequently performed in the era of precision oncology, but previous doses to organs-at-risk (OAR) must be assessed to avoid cumulative overdoses. Stereotactic magnetic resonance-guided online adaptive radiotherapy (SMART) enables highly precise ablation of tumors close to OAR. However, OAR doses may change considerably during adaptive treatment, which complicates potential re-irradiation. We aimed to compare the baseline plan with different dose accumulation techniques to inform re-irradiation. PATIENTS & METHODS: We analyzed 18 patients who received SMART to lung or liver tumors inside prospective databases. Cumulative doses were calculated inside the planning target volumes (PTV) and OAR for the adapted plans and theoretical non-adapted plans via (1) cumulative dose volume histograms (DVH sum plan) and (2) deformable image registration (DIR)-based dose accumulation to planning images (DIR sum plan). We compared cumulative dose parameters between the baseline plan, DVH sum plan and DIR sum plan using equivalent doses in 2 Gy fractions (EQD2). RESULTS: Individual patients presented relevant increases of near-maximum doses inside the proximal bronchial tree, spinal cord, heart and gastrointestinal OAR when comparing adaptive treatment to the baseline plans. The spinal cord near-maximum doses were significantly increased in the liver patients (D2% median: baseline 6.1 Gy, DIR sum 8.1 Gy, DVH sum 8.4 Gy, p = 0.04; D0.1 cm³ median: baseline 6.1 Gy, DIR sum 8.1 Gy, DVH sum 8.5 Gy, p = 0.04). Three OAR overdoses occurred during adaptive treatment (DIR sum: 1, DVH sum: 2), and four more intense OAR overdoses would have occurred during non-adaptive treatment (DIR sum: 4, DVH sum: 3). Adaptive treatment maintained similar PTV coverages to the baseline plans, while non-adaptive treatment yielded significantly worse PTV coverages in the lung (D95% median: baseline 86.4 Gy, DIR sum 82.4 Gy, DVH sum 82.2 Gy, p = 0.006) and liver patients (D95% median: baseline 87.4 Gy, DIR sum 82.1 Gy, DVH sum 81.1 Gy, p = 0.04). CONCLUSION: OAR doses can increase during SMART, so that re-irradiation should be planned based on dose accumulations of the adapted plans instead of the baseline plan. Cumulative dose volume histograms represent a simple and conservative dose accumulation strategy.

Noninferiority of Local Control and Comparable Toxicity of Intensity Modulated Radiation Therapy With Simultaneous Integrated Boost in Breast Cancer: 5-Year Results of the IMRT-MC2 Phase III Trial.

PURPOSE: The IMRT-MC2 trial was conducted to demonstrate the noninferiority of conventionally fractionated intensity modulated radiation therapy with a simultaneous integrated boost to 3-dimensional conformal radiation therapy with a sequential boost for adjuvant breast radiation therapy. METHODS AND MATERIALS: A total of 502 patients were randomized between 2011 and 2015 for the prospective, multicenter, phase III trial (NCT01322854). Five-year results of late toxicity (late effects normal tissue task force-subjective, objective, management, and analytical), overall survival, disease-free survival, distant disease-free survival, cosmesis (Harvard scale), and local control (noninferiority margin at hazard ratio [HR] of 3.5) were analyzed after a median follow-up of 62 months. RESULTS: The 5-year local control rate for the intensity modulated radiation therapy with simultaneous integrated boost arm was non-inferior to the control arm (98.7% vs 98.3%, respectively; HR, 0.582; 95% CI, 0.119-2.375; P = .4595). Furthermore, there was no significant difference in overall survival (97.1% vs 98.3%, respectively; HR, 1.235; 95% CI, 0.472-3.413; P = .6697), disease-free survival (95.8% vs 96.1%, respectively; HR, 1.130; 95% CI, 0.487-2.679; P = .7758), and distant disease-free survival (97.0% vs 97.8%, respectively; HR, 1.667; 95% CI, 0.575-5.434; P = .3601). After 5 years, late toxicity evaluation and cosmetic assessment further showed no significant differences between treatment arms. CONCLUSIONS: The 5-year results of the IMRT-MC2 trial provide strong evidence that the application of conventionally fractionated simultaneous integrated boost irradiation for patients with breast cancer is both safe and effective, with noninferior local control compared with 3-dimensional conformal radiation therapy with sequential boost.

Oral Sequelae after Head and Neck Radiotherapy: RCT Comparing 3D-Printed Tissue Retraction Devices with Conventional Dental Splints.

OBJECTIVES: To evaluate oral sequelae after head and neck radiotherapy (RT) when using two different types of intraoral appliances. Thermoplastic dental splints (active control) protect against backscattered radiation from dental structures. Semi-individualized, 3D-printed tissue retraction devices (TRDs, study group) additionally spare healthy tissue from irradiation. MATERIALS AND METHODS: A total of 29 patients with head and neck cancer were enrolled in a randomized controlled pilot trial and allocated to receive TRDs (n = 15) or conventional splints (n = 14). Saliva quality and quantity (Saliva-Check, GC), taste perception (Taste strips, Burghart-Messtechnik), and oral disability (JFLS-8, OHIP-14, maximum mouth opening) were recorded before and 3 months after RT start. Radiotherapy target volume, modality, total dose, fractionation, and imaging guidance were case-dependent. To evaluate intra-group developments between baseline and follow-up, nonparametric Wilcoxon tests were performed. Mann-Whitney-U tests were applied for inter-group comparisons. RESULTS: At follow-up, taste perception was unimpaired (median difference in the total score; TRDs: 0, control: 0). No significant changes were found regarding oral disability. Saliva quantity (stimulated flow) was significantly reduced with conventional splints (median -4 mL, p = 0.016), while it decreased insignificantly with TRDs (median -2 mL, p = 0.07). Follow-up was attended by 9/15 study group participants (control 13/14). Inter-group comparisons showed no significant differences but a tendency towards a better outcome for disability and saliva quality in the intervention group. CONCLUSION: Due to the small cohort size and the heterogeneity of the sample, the results must be interpreted with reservation. Further research must confirm the positive trends of TRD application. Negative side-effects of TRD application seem improbable.

Palliative Radiotherapy for Symptomatic Locally Advanced Breast Cancer.

Objective: Women with locally advanced breast cancer (LABC) or inoperable local recurrence often suffer from a significantly reduced quality of life (QOL) due to local tumor-associated pain, bleeding, exulceration, or malodorous discharge. We aimed to further investigate the benefit of radiotherapy (RT) for symptom relief while weighing the side-effects. Materials and methods: Patients who received symptom-oriented RT for palliative therapy of their LABC or local recurrence in the Department of Radiation Oncology at Heidelberg University Hospital between 2012 and 2021 were recorded. Clinical, pathological, and therapeutic data were collected and the oncological and symptomatic responses as well as therapy-associated toxicities were analyzed. Results: We retrospectively identified 26 consecutive women who received palliative RT with a median total dose of 39 Gy or single dose of 3 Gy in 13 fractions due to (impending) exulceration, pain, local hemorrhage, and/or vascular or plexus compression. With a median follow-up of 6.5 months after initiation of RT, overall survival at 6 and 12 months was 60.0% and 31.7%, and local control was 75.0% and 47.6%, respectively. Radiation had to be discontinued in 4 patients due to oncological clinical deterioration or death. When completed as initially planned, symptom improvement was achieved in 95% and WHO level reduction of analgesics in 28.6% of patients. In 36% (16%) of patients, local RT had already been indicated >3 months (>6 months) before the actual start of RT, but was delayed or not initiated among others in favor of drug alternatives or systemic therapies. RT-associated toxicities included only low-grade side-effects (CTCAE I°-II°) with predominantly skin erythema and fatigue even in the context of re-RT. Conclusion: Palliative RT in symptomatic LABC or locoregional recurrence is an effective treatment option for controlling local symptoms with only mild toxicity. It may thus improve QOL and should be considered early in palliative patient care management.

To fly or not to fly: Stereotactic MR-guided adaptive radiotherapy effectively treats ultracentral lung tumors with favorable long-term outcomes.

BACKGROUND: Stereotactic radiotherapy of ultracentral lung tumors (ULT) is challenging as it may cause overdoses to sensitive mediastinal organs with severe complications. We aimed to describe long-term outcomes after stereotactic magnetic resonance (MR)-guided online adaptive radiotherapy (SMART) as an innovative treatment of ULT. PATIENTS & METHODS: We analyzed 36 patients that received SMART to 40 tumors between 02/2020 - 08/2021 inside prospective databases. ULT were defined by planning target volume (PTV) overlap with the proximal bronchial tree or esophagus. We calculated Kaplan Meier estimates for overall survival (OS) and progression-free survival (PFS), and competing risk estimates for the incidence of tumor progression and treatment-related toxicities. ULT patients (N = 16) were compared to non-ULT patients (N = 20). RESULTS: Baseline characteristics were similar between ULT and non-ULT, but ULT were larger (median PTV: ULT 54.7 cm3, non-ULT 19.2 cm3). Median follow-up was 23.6 months. ULT and non-ULT showed a similar OS (2-years: ULT 67%, non-ULT 60%, p = 0.7) and PFS (2-years: ULT 37%, non-ULT 34%, p = 0.73). Progressions occurred mainly at distant sites (2-year incidence of distant progression: ULT 63%, non-ULT 61%, p = 0.77), while local tumor control was favorable (2-year incidence of local progression: ULT 7%, non-ULT 0%, p = 0.22). Treatment of ULT led to significantly more toxicities ≥ grade (G) 2 (ULT: 9 (56%), non-ULT: 1 (5%), p = 0.002). Most toxicities were moderate (G2). Two ULT patients developed high-grade toxicities: 1) esophagitis G3 and bronchial bleeding G4 after VEGF treatment, 2) bronchial bleeding G3. Estimated incidence of high-grade toxicities was 19% (3-48%) in ULT, and no treatment-related death occurred. CONCLUSION: Our small series supports SMART as potentially effective treatment of ULT. SMART with careful fractionation could reduce severe complications, but treatment of ULT remains a high-risk procedure and needs careful benefit-risk-assessment.

Osteoradionecrosis of the Jaw-Comparison between Bone and Soft Tissue Injury and Their Influence on Surgical Outcomes-A Retrospective Cohort Study.

Surgical therapy of osteoradionecrosis of the jaw (ORN) is challenging and requires treatment of the affected hard and soft tissue. To understand how tissue injury after irradiation influences surgical outcomes, the objective of this study was to find out whether (a) bone-related, (b) soft tissue-related, and (c) treatment-related parameters influence the surgical success of patients with ORN. A total of 175 patients (324 lesions) were included in this retrospective, single-center study. All patients were diagnosed with ORN and underwent surgical therapy. The primary outcome was complete soft tissue recovery (mucosa/skin) and the absence of symptoms 3 months after surgery. At the time of follow-up, 58% of patients (189 of 324 lesions) had intact intraoral or extraoral soft tissue. The extent of bone destruction had no effect on treatment success, whereas soft tissue injury due to fibrosis (OR: 0.344; CI 0.142-0.834; p = 0.01818) and xerostomia (OR: 0.163; CI 0.064-0.419; p = 0.00016) increased the probability of treatment failure. Soft tissue reconstruction with a microvascular graft improved therapeutic success compared to local wound closure (OR: 2.998; CI 1.371-6.555; p = 0.006). Thus, for the treatment of ORN, it is extremely important to pay attention not only to the extent of bone destruction but especially to soft tissue defects. Because the extent of soft tissue injury is a predictor for therapeutic success, it should influence the choice of surgical treatment.

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).

Vaginal cancer treated with curative radiotherapy with or without concomitant chemotherapy: oncologic outcomes and prognostic factors.

BACKGROUND: Vaginal cancer is a rare disease for which prospective randomized trials do not exist. We aimed to assess survival outcomes, patterns of recurrence, prognostic factors, and toxicity in the curative treatment using image-guided radiotherapy (RT). METHODS: In this retrospective review, we identified 53 patients who were treated at a single center with external beam radiotherapy and brachytherapy with or without concomitant chemotherapy from 2000 to 2021. RESULTS: With a median follow-up of 64.5 months, the Kaplan-Meier 2-, 5-, and 7-year overall survival (OS) was found to be 74.8%, 62.8%, and 58.9%, respectively. Local and distant control were 67.8%, 65.0%, and 65.0% and 74.4%, 62.6%, and 62.6% at 2, 5, and 7 years, respectively. In univariate Cox proportional hazards ratio analysis, OS was significantly correlated to FIGO stage (hazard ratio [HR] 1.78, p = 0.042), postoperative RT (HR 0.41, p = 0.044), and concomitant chemotherapy (HR 0.31, p = 0.009). Local control rates were superior when an equivalent dose in 2-Gy fractions (EQD2) of ⩾65 Gy was delivered (HR 0.216, p = 0.028) and with the use of concurrent chemotherapy (HR 0.248, p = 0.011). Not surprisingly, local control was inferior for patients with a higher TNM stage (HR 3.303, p = 0.027). Minimal toxicity was observed with no patients having documentation of high-grade toxicity (CTCAE grade 3+). CONCLUSION: In treatment of vaginal cancer, high-dose RT in combination with brachytherapy is well tolerated and results in effective local control rates, which significantly improve with an EQD2(α/ß=10) ⩾65 Gy. Multivariate analyses revealed concomitant chemotherapy was a positive prognostic factor for overall and progression-free survival.

Outcome and prognostic factors in patients undergoing salvage therapy for recurrent esophagogastric cancer after multimodal treatment.

PURPOSE: Perioperative systemic treatment has significantly improved the outcome in locally advanced esophagogastric cancer. However, still the majority of patients relapse and die. Data on the optimal treatment after relapse are limited, and clinical and biological prognostic factors are lacking. METHODS: Patients with a relapse after neoadjuvant/perioperative treatment and surgery for esophagogastric cancer were analyzed using a prospective database. Applied treatment regimens, clinical prognostic factors and biomarkers were analyzed. RESULTS: Of 246 patients 119 relapsed. Among patients with a relapse event, those with an early relapse (< 6 months) had an inferior overall survival (OS 6.3 vs. 13.8 months, p < 0.001) after relapse than those with a late relapse (> 6 months). OS after relapse was longer in patients with a microsatellite-unstable (MSI) tumor. Systemic treatment was initiated in 87 patients (73% of relapsed pat.); among those OS from the start of first-line treatment was inferior in patients with an early relapse with 6.9 vs. 10.0 months (p = 0.037). In 27 patients (23% of relapsed pat.), local therapy (irradiation or surgical intervention) was performed due to oligometastatic relapse, resulting in a prolonged OS in comparison to patients without local therapy (median OS 35.2 months vs. 7.8 months, p < 0.0001). Multivariate analysis confirmed the prognostic benefit of the MSI status and a local intervention. CONCLUSION: Patients relapsing after multimodal treatment have a heterogeneous prognosis depending on the relapse-free interval (if systemic treatment applied), extent of metastatic disease as well as MSI status. The benefit of additional local intervention after relapse should be addressed in a randomized trial.

Pediatric cardiopulmonary resuscitation in infant and children with chronic diseases: A simple approach?

Infants and children with complex chronic diseases have lifelong, life-threatening conditions and for many, early death is an unavoidable outcome of their disease process. But not all chronic diseases in children are fatal when treated well. Cardiopulmonary resuscitation is more common in children with chronic diseases than in healthy children. Resuscitation of infants and children presents significant challenges to physicians and healthcare providers. Primarily, these situations occur only rarely and are therefore not only medically demanding but also associated with emotional stress. In case of resuscitation in infants and children with chronic diseases these challenges become much more complex. The worldwide valid Pediatric Advanced Life Support Guidelines do not give clear recommendations how to deal with periarrest situations in chronically ill infants and children. For relevant life-limiting illnesses, a "do not resuscitate" order should be discussed early, taking into account medical, ethical, and emotional considerations. The decision to terminate resuscitative efforts in cardiopulmonary arrest in infants and children with chronic illnesses such as severe lung disease, heart disease, or even incurable cancer is complex and controversial among physicians and parents. Judging the "outcome" of resuscitation as a "good" outcome becomes complex because for some, life extension itself and for others, quality of life is a goal. Physicians often decide that a healthy child is more likely to have a reversible condition and thereby have a better outcome than a child with multiple comorbidities and chronic health care needs. Major challenges in resuscitation infants and children are that clinicians need to individualize resuscitation strategies in light of each chronic disease, anatomy and physiology. This review aims to highlight terms of resuscitation infants and children with complex chronic diseases, considering resuscitation-related factors, parent-related factors, patient-related factors, and physician-related factors.

Intensity modulated proton therapy for early-stage glottic cancer: high-precision approach to laryngeal function preservation with exceptional treatment tolerability.

BACKGROUND: Due to the increasing expertise in transoral laser surgery and image-guided radiation therapy, treatment outcomes have recently improved in patients with early-stage glottic cancer. The objective of the current study was to evaluate intensity-modulated proton therapy (IMPT) as novel treatment option. METHODS: A total of 15 patients with T1-2N0 glottic squamous cell carcinoma, treated between 2017 and 2020, were evaluated. Toxicity was recorded according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.03. RESULTS: The majority were T1a/b tumors (66.7%) and no patient had lymph node or distant metastases. The median total dose was 70 Gy relative biological effectiveness (RBE) (range 66-70 Gy RBE). The one- and two-year OS and metastases-free survival were 100%. One patient developed local failure and received salvage laryngectomy. No higher-grade acute or late toxicity was reported. The mean number of CTCAE grade I and II overall toxicity events per patient was 4.1 (95%-[confidence interval] CI 3.1-5.3) and 1.0 (95%-CI 0.5-1.5). CONCLUSION: High-precision proton therapy of T1-2N0 glottic cancer resulted in exceptional treatment tolerability with high rates of laryngeal function preservation and promising oncological outcome. IMPT has the potential to become a standard treatment option for patients with early-stage laryngeal cancer.

Dosimetric Benefit of Adaptive Magnetic Resonance-Guided Stereotactic Body Radiotherapy of Liver Metastases.

(1) Background: To assess dosimetry benefits of stereotactic magnetic resonance (MR)-guided online adaptive radiotherapy (SMART) of liver metastases. (2) Methods: This is a subgroup analysis of an ongoing prospective registry including patients with liver metastases. Patients were treated at the MRIdian Linac between February 2020 and April 2022. The baseline plan was recalculated based on the updated anatomy of the day to generate the predicted plan. This predicted plan could then be re-optimized to create an adapted plan. (3) Results: Twenty-three patients received 30 SMART treatment series of in total 36 liver metastases. Most common primary tumors were colorectal- and pancreatic carcinoma (26.1% respectively). Most frequent fractionation scheme (46.6%) was 50 Gy in five fractions. The adapted plan was significantly superior compared to the predicted plan in regard to planning-target-volume (PTV) coverage, PTV overdosing, and organs-at-risk (OAR) dose constraints violations (91.5 vs. 38.0%, 6 vs. 19% and 0.6 vs. 10.0%; each p < 0.001). Plan adaptation significantly increased median BEDD95 by 3.2 Gy (p < 0.001). Mean total duration of SMART was 72.4 min. (4) Conclusions: SMART offers individualized ablative irradiation of liver metastases tailored to the daily anatomy with significant superior tumor coverage and improved sparing of OAR.