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Purpose: The purpose of this review was to evaluate the current status of reporting prospectively assessed late morbidity after curative radiation therapy in large clinical studies., Methods and Materials: A descriptive review on publications from 10 high-impact journals with a primary or partial focus on radiation therapy published between December 1, 2015, and November 30, 2017, was conducted. Publications were considered eligible if they reported prospectively assessed late morbidity after curative radiation therapy and included ≥200 patients with cancer of any type. Full text publication and supplementary material were analyzed according to items based on extensions to the Consolidated Standards of Reporting Trials (CONSORT) statement regarding reporting of harms and patient reported outcomes., Results: Overall, 802 publications were identified in PubMed; of these, 69 met the eligibility criteria. Mild and moderate morbidity were reported in 40% and 57% of publications; aggregated endpoints instead of individual endpoints were reported in 23%. In 43% of publications, crude incidence of worst grade of morbidity was used as the only statistical method for summarizing physician-assessed morbidity. Duration of morbidity or recurrent events were not reported in any of the publications., Conclusions: Comprehensive, quantitative reporting of late morbidity after radiation therapy is challenging because of the high dimensionality and time evolution of the range of normal tissue effects. The following suggestions and recommendations are proposed: (1) report on individual severity grades, including moderate and mild; (2) use patient reported outcomes in complement to physician-assessed morbidity; (3) report on individual symptoms/endpoints on top of aggregated endpoints; (4) report on duration of morbidity or recurrent events; (5) take steps toward a consensus on severity grading scales/patient questionnaires; (6) use time to event analysis and prevalence rates; (7) report or use statistical methods accounting for pretreatment morbidity when relevant., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Both preoperative short-course radiotherapy (SC-PRT) and preoperative long-course chemo radiotherapy (CRT) have shown to reduce local recurrence rates after total mesorectal excision (TME), but neither resulted in improved survival. This study compared the long-term health-related quality of life (HRQL) and symptoms between CRT and SC-PRT., Methods: Patients who were preoperatively treated with a total dose of 50.0 to 50.4 Gy for locally advanced rectal cancers were identified from 2 hospital registries. Starting from 2011, all patients who were disease-free in the study population (n = 105) were sent a HRQL-questionnaire composed of the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and questions on bowel and urinary function. Patients who underwent SC-PRT in the TME trial were used as a reference group., Results: HRQL results from 85 patients receiving CRT (81.0%), with a median follow-up time of 58 months, were compared with the results of patients who underwent SC-PRT (n = 306). Apart from more nausea and vomiting reported by patients receiving CRT (mean score for CRT 5.9 vs. 1.3 for SC-PRT; P < .01; not clinically relevant) and less satisfaction with urinary function indicated by patients who received CRT (mean score for CRT 71.2 vs. 81.2 for SC-PRT; P < .01), no significant differences were found in HRQL and symptoms between patients who received CRT and SC-PRT., Conclusions: This analysis of HRQL in patients who received CRT shows no clinically relevant differences in long-term HRQL and symptoms between patients who received CRT and SC-PRT, apart from less satisfaction with urinary function reported by patients who received CRT. These results indicate that both approaches have a comparable impact on long-term HRQL., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: We investigated very long-term bowel function after total mesorectal excision (TME) with or without preoperative short-course radiotherapy (PRT) for rectal cancer, the risk factors for bowel dysfunction, and the association of bowel dysfunction with health-related quality of life (HRQL)., Patients and Methods: In the TME trial (1996-1999), 1530 Dutch patients with rectal cancer were randomized to TME preceded by 5 × 5 Gy PRT or TME alone. A set of questionnaires was sent to the surviving patients (n = 583) in 2012. The questionnaires included the Low Anterior Resection Syndrome Score (LARS score), European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core (EORTC QLQ-C30) and Colorectal Module (EORTC QLQ-CR29). The LARS score range was divided into "no LARS," "minor LARS," and "major LARS" categories in ascending severity of bowel dysfunction. The potential risk factors for major LARS were tested on multivariable analysis. The HRQL was compared between the LARS score categories., Results: Of the 478 respondents, 242 nonstoma patients were included in the present analysis. The median interval since treatment was 14.6 years, and the median age at the follow-up point was 75 years. Major LARS was reported by 46% of all patients (56% PRT plus TME vs. 35% TME). PRT (odds ratio [OR], 3.0; 99% confidence interval [CI], 1.3-6.9) and age ≤ 75 years at the follow-up point (OR, 2.4; 99% CI, 1.1-5.5) increased the risk of major LARS. Gender, tumor height, anastomotic leakage, type of anastomosis, interval since treatment, and comorbid diabetes were not significant. Patients with major LARS fared worse in many HRQL domains (P < .01; score difference > 5% of score range)., Conclusion: A considerable proportion of nonstoma patients endured major LARS years after TME. PRT and age ≤ 75 years at follow-up pose further risks of major LARS in addition to surgery. Major LARS is associated with reduced HRQL., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: This study investigated the long-term probability of developing a second cancer in a large pooled cohort of patients treated with surgery with or without radiotherapy (RT)., Patients and Methods: All second cancers diagnosed in patients included in the TME, PORTEC-1, and PORTEC-2 trials were analyzed. In the TME trial, patients with rectal cancer (n = 1,530) were randomly allocated to preoperative external-beam RT (EBRT; 25 Gy in five fractions) or no RT. In the PORTEC trials, patients with endometrial cancer were randomly assigned to postoperative EBRT (46 Gy in 2-Gy fractions) versus no RT (PORTEC-1; n = 714) or EBRT versus vaginal brachytherapy (VBT; PORTEC-2; n = 427)., Results: A total of 2,554 patients were analyzed (median follow-up, 13.0 years; range 1.8 to 21.2 years). No differences were found in second cancer probability between patients who were treated without RT (10- and 15-year rates, 15.8% and 26.5%, respectively) and those treated with EBRT (10- and 15-year rates, 15.4% and 25.6%, respectively) or VBT (10-year rate, 14.9%). In the individual trials, no significant differences were found between treatment arms. All cancer survivors had a higher risk of developing a second cancer compared with an age- and sex-matched general population. The standardized incidence ratio for any second cancer was 2.98 (95% CI, 2.82 to 3.14)., Conclusion: In this pooled trial cohort of > 2,500 patients with pelvic cancers, those who underwent EBRT or VBT had no higher probability of developing a second cancer than patients who were treated with surgery alone. However, patients with rectal or endometrial cancer had an increased probability of developing a second cancer compared with the general population., (© 2014 by American Society of Clinical Oncology.)

State of the art combined radiochemotherapy and image-guided brachytherapy for locally advanced cervical cancer (LACC) has shown improved disease control and survival as well as a significant reduction of organ related morbidity. However, LACC cancer survivors are still experiencing a spectrum of symptoms. The aim of this study was to identify co-occurring symptoms in cervix cancer survivors by using patient-reported outcome and physician assessed morbidity. EMBRACE I is a multicenter prospective observational study with 1416 LACC patients (2008–2015). Information on physician-assessed morbidity and patient-reported outcome was assessed at baseline and at regular follow-ups up with the CTCAE v.3 and EORTC-C30/CX24, respectively. Patients with at least 2 years of follow-up were included and data from 3 months to 2 years was used in the analysis. Factor analysis was used on both EORTC and CTCAE data with symptoms and follow-ups as observations. The extracted factors represent clusters of symptoms. Subsequently, regression models were built to investigate associations between the symptom clusters and QOL. The analysis included 742 patients. Despite the differences in the definition of physician-assessed and patient-reported symptoms, similar clusters are identified by the two assessment methods. Three main organ-related clusters are recognized for urinary, gastro-intestinal and vaginal morbidity. Furthermore, a general symptoms cluster where fatigue, pain, insomnia, neuropathy, and hot flashes have large weights is found. Lastly, a cluster with nausea, vomit and lack of appetite is also identified. The general, gastrointestinal and nausea clusters show significant associations with general QOL. This analysis on both PRO and physician-assessed morbidity found a cluster associated with general symptoms and organ-related symptom clusters (urinary, gastrointestinal, vaginal). This shows that LACC survivors experience a variety of co-occurring symptoms. Our analysis also shows that the cluster of general symptoms is associated with a decrease in QOL. [ABSTRACT FROM AUTHOR]

Post radiation mucosal ulcers (PRMU) after treatment for oropharyngeal squamous cell carcinoma (OPSCC) can have a huge negative impact on patients' quality of life, but little is known concerning risk factors and the impact of fraction size. Therefore, the goal of this study was to determine the pattern of PRMU development and to identify risk factors after a hypofractionated stereotactic body radiotherapy boost (SBRT) compared to conventionally fractionated radiotherapy for OPSCC. We performed a retrospective cohort study (N = 332) of OPSCC patients with ≥ 1-year disease-free survival, treated with 46 Gy Intensity Modulated Radiotherapy (IMRT) (2 Gy fractions) followed by either an SBRT boost of 16.5 Gy (5.5 Gy fractions) (N = 180), or 24 Gy IMRT (2 Gy fractions) (N = 152). PRMU (grade ≥ 2) was scored when observed > three months after the last radiotherapy (RT) fraction (CTCAE v5.0). Potential risk factors were analyzed with Cox regression models using death as competing risk. Dose at the PRMU site was calculated by projecting delineated PRMU on the planning CT. All cases of PRMU (N = 64) occurred within 24 months; all were grade 2. The cumulative incidence at 2 years in the SBRT boost group was 26% (N = 46) vs. 12% (N = 18) for conventional fractionation (p = 0.003). Most PRMU developed within nine months (N = 48). PRMU occurring > nine months (N = 16) were mainly observed in the SBRT boost group (N = 15). Sex (p = 0.048), acute tube feeding (p = < 0.001), tumor subsite tonsil (p = 0.001), and N stage (p = 0.017) were associated with PRMU risk at multivariable regression in the hypofractionated SBRT boost group. All 25 delineated PRMU were located within the high dose regions. The risk of PRMU should be included in the cost benefit analysis when considering future research using a hypofractionated SBRT boost for OPSCC patients. [ABSTRACT FROM AUTHOR]

Simple Summary: With the introduction of better-quality imaging for tumor visualization and treatment planning, a new conformed radiation treatment was introduced with high-dose-rate endorectal brachytherapy (HDREBT). The advantage of this treatment is allowing for better sparing of normal tissues surrounding the tumor during treatment while delivering higher dose to the tumor. This diminishes the number and severity of side effects and results in more effective treatment. This manuscript summarizes two decades of technological evolution and progress in clinical studies to validate this treatment concept from the pre-operative setting to prevent tumor recurrence and, more recently, the introduction of the objective of cure without surgery; i.e., non-operative management (NOM) for patients with curable rectal cancer. HDREBT is a conformed radiation modality, shown to be safe and efficient both in the pre-operative setting and is presently being explored with interest in NOM in a multicenter study. (1) Background: The introduction of total mesorectal excision (TME) for rectal cancer has led to improvement in local recurrence (LR) outcomes. Furthermore, the addition of preoperative external beam radiotherapy to TME reduces LR to less than 6%. As a trade-off to these gradual improvements in local therapies, the oncology community's work is now focusing on mitigating treatment-related toxicities. In other words, if a small proportion of 4–6% of rectal cancer patients benefit from additional local therapy beyond TME, the burden of acute and long-term side effects must be considered with care. (2) Methods: With the introduction of better-quality imaging for tumor visualization and treatment planning, a new conformed radiation treatment was introduced with high-dose-rate endorectal brachytherapy. The treatment concept was tested in phase I and II studies: first in the pre-operative setting, and then as a boost after external beam radiation therapy, as a dose-escalation study, to achieve higher local tumor control. (3) Results: HDREBT is safe and effective in achieving a high tumor regression rate and was well tolerated in a phase II multicenter and two matched-pair studies. (4) Conclusions: HDREBT is a conformed radiation therapy that is safe and effective, and is presently explored in a phase III dose-escalation study in the NOM of patients with operable rectal cancer. [ABSTRACT FROM AUTHOR]

Objective The aim of this study was to assess the impact of the evolving role of the addition of chemotherapy to postoperative radiotherapy on oncological outcomes and toxicity in patients with early-stage cervical cancer after radical hysterectomy. Methods Retrospective cohort study of patients with stage IB1--IIB FIGO 2009 cervical cancer treated from November 1999 to May 2015 by primary surgery and radiotherapy (46--50.4 Gy in 1.8--2.0 Gy fractions) with or without concurrent cisplatin (40 mg/m2, 5--6 weekly cycles) with or without a brachytherapy boost. Chemotherapy was allocated depending on the risk factors for recurrence. Incidences of all outcomes were calculated using Kaplan--Meier's methodology and compared by log-rank tests. Risk factors for recurrence and survival were identified using Cox's proportional hazards models. results A total of 154 patients were included, median follow-up was 9.6 years (IQR: 6.1--12.8). Five-year pelvic recurrence-free survival was 75.3%; 74.7% in patients with high-risk factors treated with radiotherapy; and 77.3% in those treated with chemoradiation (P=0.43). Distant metastasis-free survival at 5 years was 63.4%; 63.6% in high-risk patients after radiotherapy; and 57.1% after chemoradiation (P=0.36). Five-year overall survival was 63.9%: 66.8% and 51.6% after radiotherapy and after chemoradiation in patients with high-risk factors (P=0.37), respectively. Large tumor size was a risk factor for vaginal and pelvic recurrence, ≥2 involved lymph nodes was a significant risk factor for para-aortic recurrence and death. Mild treatment-related late toxicity was observed in 53.9% of the patients. Five-year severe (grade 3--5) late rectal, bladder, bowel, and vaginal toxicities were, respectively, 1.3%, 0%, 3.4%, and 0.9%. Any late severe toxicity was observed in 5.5% of patients treated with radiotherapy and in 15.3% of those treated with chemoradiation (P=0.07). Conclusion Postoperative (chemo)radiation for earlystage cervical cancer patients with risk factors for recurrence yields adequate pelvic tumor control, but overall survival is limited due to distant metastasis. [ABSTRACT FROM AUTHOR]

Introduction: Although the majority of women with endometrial cancer have a favorable prognosis due to early symptoms, 15-20% have high-risk disease features and are at increased risk of recurrence. In order to improve prognosis for these patients, several trials have compared chemotherapy (CT), radiotherapy (RT) or the combination of CTRT. Areas covered: This review focuses on the current evidence on adjuvant treatment for women with high-risk endometrial cancer and future perspectives. Expert commentary: For stage I-II high-risk endometrial cancer, external beam radiotherapy ensured good local control and no significant benefit in progression-free or overall survival was found with the addition of chemotherapy in 2 recent randomized trials. For women with stage III disease, the combination of chemotherapy and radiotherapy improved progression-free survival with a non-significant improvement of overall survival. Adjuvant chemotherapy alone resulted in higher rates of pelvic and para-aortic recurrence. More toxicity and reduced quality of life were found during and after adjuvant CTRT. It is essential to discuss the benefits and disadvantages of chemotherapy and radiotherapy with individual patients for shared decision-making. Translational research is ongoing to further characterize individual tumors, identify sensitivity to (immuno)therapies and find new treatment targets to improve outcomes. [ABSTRACT FROM AUTHOR]

Background/purpose To identify risk factors for vaginal stenosis and to establish a dose–effect relationship for image-guided brachytherapy in locally advanced cervical cancer. Materials/Methods Patients from the ongoing EMBRACE study with prospectively assessed morbidity (CTCAEv3.0) at baseline and at least one follow-up were selected. Patient-, disease- and treatment characteristics were tested as risk factors for vaginal stenosis G ⩾ 2 in univariate and multivariable analyses (Cox proportional hazards model) and a dose–effect curve was deduced from the estimates. The ICRU rectum point was used to derive the recto-vaginal reference point dose. Results In 630 patients included (median follow-up 24 months), 2-year actuarial estimate for vaginal stenosis G ⩾ 2 was 21%. Recto-vaginal reference point dose (HR = 1.025, p = 0.029), external beam radiotherapy (EBRT) dose >45 Gy/25 fractions (HR = 1.770, p = 0.056) and tumor extension in the vagina (HR = 2.259, p ⩽ 0.001) were risk factors for vaginal stenosis, adjusted for center reporting effects. Based on the model curve, the risk was 20% at 65 Gy, 27% at 75 Gy and 34% at 85 Gy (recto-vaginal reference point dose). Conclusion Keeping the EBRT dose at 45 Gy/25 fractions and decreasing the dose contribution of brachytherapy to the vagina decrease the risk of stenosis. A planning aim of ⩽65 Gy EQD2 (EBRT + brachytherapy dose) to the recto-vaginal reference point is therefore proposed. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the long-term health-related quality of life (HRQL) after external beam radiation therapy (EBRT) or vaginal brachytherapy (VBT) among PORTEC-2 trial patients, evaluate long-term bowel and bladder symptoms, and assess the impact of cancer on these endometrial cancer (EC) survivors. Patients and Methods: In the PORTEC-2 trial, 427 patients with stage I high-intermediate-risk EC were randomly allocated to EBRT or VBT. The 7- and 10-year HRQL questionnaires consisted of EORTC QLQ-C30; subscales for bowel and bladder symptoms; the Impact of Cancer Questionnaire; and 14 questions on comorbidities, walking aids, and incontinence pads. Analysis was done using linear mixed models for subscales and (ordinal) logistic regression with random effects for single items. A two-sided P value <.01 was considered statistically significant. Results: Longitudinal HRQL analysis showed persisting higher rates of bowel symptoms with EBRT, without significant differences in global health or any of the functioning scales. At 7 years, clinically relevant fecal leakage was reported by 10.6% in the EBRT group, versus 1.8% for VBT (P=.03), diarrhea by 8.4% versus 0.9% (P=.04), limitations due to bowel symptoms by 10.5% versus 1.8% (P=.001), and bowel urgency by 23.3% versus 6.6% (P<.001). Urinary urgency was reported by 39.3% of EBRT patients, 25.5% for VBT, P=.05. No difference in sexual activity was seen between treatment arms. Long-term impact of cancer scores was higher among the patients who had an EC recurrence or second cancer. Conclusions: More than 7 years after treatment, EBRT patients reported more bowel symptoms with impact on daily activities, and a trend for more urinary symptoms, without impact on overall quality of life or difference in cancer survivorship issues. [ABSTRACT FROM AUTHOR]

Accumulating evidence suggests significant synergism combining radiotherapy (RT) with angiogenesis targeted therapies. This multicenter prospective phase I clinical trial established the safety profile and recommended dose for further studies of pazopanib concurrent with preoperative RT in patients with extremity soft tissue sarcomas (ESTS) in curative setting. Methods.Patients with deep seated intermediate and high grade sarcomas, ≥ 5 cm, received once daily pazopanib (dose-escalation cohorts 400 mg, 600 mg and 800 mg) for 6 weeks and 50 Gy preoperative RT starting Day 8. Surgery was performed 5–7 weeks later. Toxicity was scored according to CTC criteria 4.0. Dose limiting toxicities (DLT) were divided into two separate sets; DLT-I being toxicities occurring during the 6-week chemoradiotherapy period within the radiation portals until day of surgery (designated as DLT-I) and those occurring perioperatively until Day 21 after surgery (DLT-II). Results.A total of 12 patients were enrolled, 11 were evaluable (3 females and 8 males, median age 58 years, range 24–78 years, median tumor size 9 cm, range 5–15 cm). Ten underwent surgery. No increased toxicity inside the radiation fields was seen, but two of 10 patients (one each in the 400 mg and 600 mg cohorts) showed delayed wound healing after surgery. None of the patients showed significant volume reductions after RT. Evaluation of the resection specimen showed pathological (near) complete responses (≥ 95% necrosis rate) in four of 10 cases. Unexpectedly, grade 3 + hepatotoxicity led to premature pazopanib interruption in three of 11 (27%) of cases. Conclusion.Apart from hepatotoxicity, neoadjuvant pazopanib 800 mg daily in combination with 50 Gy seems tolerable; the regimen appears to demonstrate promising activity in ESTS and is the recommended dose for further studies. [ABSTRACT FROM AUTHOR]

BACKGROUND For patients who have chondrosarcoma with unresectable disease, because of tumor location, tumor size, or extensive metastatic disease, treatment options are very limited because of their relative resistance to radiotherapy and chemotherapy. The overall survival of this patient population is poor; however, specific studies are lacking, and large series have not been published. Therefore, the authors conducted this retrospective, 2-center study to gain insight into the outcome of patients with advanced, unresectable, conventional central chondrosarcoma. METHODS All patients with unresectable conventional central chondrosarcoma who were diagnosed between January 1, 1980 and December 31, 2011 in 2 major European bone sarcoma centers (Rizzoli Institute, Bologna, Italy and Leiden University Medical Center, Leiden, the Netherlands) were selected. Relevant information was collected from the medical records at both centers. RESULTS In total, 171 patients met the selection criteria. The overall survival rate for all patients was 48% at 1 year, 24% at 2 years, 12% at 3 years, 6% at 4 years, and 2% at 5 years. Patients with unresectable, locally advanced disease without distant metastases had a significantly better survival than patients with metastatic disease ( P = .0014). Systemic treatment, consisting of either doxorubicin-based chemotherapy or the noncytotoxic drugs imatinib and sirolimus, improved survival significantly compared with no treatment ( P = .0487). For patients who had locally advanced disease without metastases, radiotherapy was associated with a survival benefit ( P = .0032). CONCLUSIONS This study provides a standard for overall survival rates after a diagnosis of unresectable conventional central chondrosarcoma. Systemic treatment and radiotherapy may improve survival, although selection bias because of the retrospective nature of this study may have influenced the outcome. The poor survival underlines the need for new therapeutic options for this patient population. Cancer 2014;120:3159-3164. © 2014 American Cancer Society. [ABSTRACT FROM AUTHOR]

We provide an overview of imaging, histopathology, genetics, and multidisciplinary treatment of giant cell tumor of bone (GCTB), an intermediate, locally aggressive but rarely metastasizing tumor. Overexpression of receptor activator of nuclear factor κB ligand (RANKL) by mononuclear neoplastic stromal cells promotes recruitment of numerous reactive multinucleated giant cells. Conventional radiographs show a typical eccentric lytic lesion, mostly located in the meta-epiphyseal area of long bones. GCTB may also arise in the axial skeleton and very occasionally in the small bones of hands and feet. Magnetic resonance imaging is necessary to evaluate the extent of GCTB within bone and surrounding soft tissues to plan a surgical approach. Curettage with local adjuvants is the preferred treatment. Recurrence rates after curettage with phenol and polymethylmethacrylate (PMMA; 8%-27%) or cryosurgery and PMMA (0%-20%) are comparable. Resection is indicated when joint salvage is not feasible (e.g., intra-articular fracture with soft tissue component). Denosumab (RANKL inhibitor) blocks and bisphosphonates inhibit GCTB-derived osteoclast resorption. With bisphosphonates, stabilization of local and metastatic disease has been reported, although level of evidence was low. Denosumab has been studied to a larger extent and seems to be effective in facilitating intralesional surgery after therapy. Denosumab was recently registered for unresectable disease. Moderate-dose radiotherapy (40-55 Gy) is restricted to rare cases in which surgery would lead to unacceptable morbidity and RANKL inhibitors are contraindicated or unavailable. [ABSTRACT FROM AUTHOR]

Simple Summary: There are various society-specific guidelines addressing adjuvant brachytherapy (BT) after surgery for endometrial cancer (EC). However, these recommendations are not uniform. Against this background, clinicians need to make decisions despite gaps between best scientific evidence and clinical practice. We analysed decision criteria influencing the selection for adjuvant radiotherapy among European radiation oncology experts. For this, GEC-ESTRO provided 19 European radiation oncology experts on gynaecological brachytherapy for decision-making analyses. The manuscript presents patterns in decision-making among these experts and demonstrates areas of consensus/discrepancies. We also analysed dose prescription and techniques of brachytherapy. This analysis is of special value as the objective approach enabled us to obtain an unbiased description of decision-making among the specialists (the study was not aimed to create or enforce a consensus). The manuscript provides valuable insight into clinical decision-making with a high impact on treatment selection, as expected differences between experts were observed. With this manuscript we are able to visualize and quantify these. This information is relevant for interdisciplinary discussions. Background: There are various society-specific guidelines addressing adjuvant brachytherapy (BT) after surgery for endometrial cancer (EC). However, these recommendations are not uniform. Against this background, clinicians need to make decisions despite gaps between best scientific evidence and clinical practice. We explored factors influencing decision-making for adjuvant BT in clinical routine among experienced European radiation oncologists in the field of gynaecological radiotherapy (RT). We also investigated the dose and technique of BT. Methods: Nineteen European experts for gynaecological BT selected by the Groupe Européen de Curiethérapie and the European Society for Radiotherapy & Oncology provided their decision criteria and technique for postoperative RT in EC. The decision criteria were captured and converted into decision trees, and consensus and dissent were evaluated based on the objective consensus methodology. Results: The decision criteria used by the experts were tumour extension, grading, nodal status, lymphovascular invasion, and cervical stroma/vaginal invasion (yes/no). No expert recommended adjuvant BT for pT1a G1-2 EC without substantial LVSI. Eighty-four percent of experts recommended BT for pT1a G3 EC without substantial LVSI. Up to 74% of experts used adjuvant BT for pT1b LVSI-negative and pT2 G1–2 LVSI-negative disease. For 74–84% of experts, EBRT + BT was the treatment of choice for nodal-positive pT2 disease and for pT3 EC with cervical/vaginal invasion. For all other tumour stages, there was no clear consensus for adjuvant treatment. Four experts already used molecular markers for decision-making. Sixty-five percent of experts recommended fractionation regimens of 3 × 7 Gy or 4 × 5 Gy for BT as monotherapy and 2 × 5 Gy for combination with EBRT. The most commonly used applicator for BT was a vaginal cylinder; 82% recommended image-guided BT. Conclusions: There was a clear trend towards adjuvant BT for stage IA G3, stage IB, and stage II G1–2 LVSI-negative EC. Likewise, there was a non-uniform pattern for BT dose prescription but a clear trend towards 3D image-based BT. Finally, molecular characteristics were already used in daily decision-making by some experts under the pretext that upcoming trials will bring more clarity to this topic. [ABSTRACT FROM AUTHOR]

Background. To evaluate long-term local control, survival, radiation side effects and functional outcome after limb-sparing surgery followed by postoperative radiotherapy (RT) for soft tissue sarcoma (STS). Material and methods. Between 1995 and 2010, 118 patients with STS of an extremity were treated with limb-sparing surgery and postoperative RT. Follow-up was complete for all patients. Acute and late radiation related toxicities were scored using CTCAE v4.0. Results. Median follow-up was 93 months. RT dose was 60 Gy in 92.4% of the patients; 5.1% received 66 Gy; 2.5% 50-56 Gy. Actuarial local recurrence rates at five and 10 years were 9% and 12%. Five- and 10-year overall survival rates were 69% and 51%. Acute radiation toxicities occurred in 91% of the patients; 19% were grade 3, 2% grade 4. Late radiation toxicities were reported in 71% of the patients: 50% grade 1, 18% grade 2, and 3% grade 3. Limb and joint function after treatment were good, 19% having mild limitation of motion, 1.5% moderate, and 2.5% severe limitations. Conclusion. Limb-sparing surgery with 60 Gy postoperative radiotherapy for patients with STS provides excellent local control and high survival rates with acceptable toxicity and functional outcomes. [ABSTRACT FROM AUTHOR]

Abstract: Background: The PORTEC-2 trial showed efficacy and reduced side-effects of vaginal brachytherapy (VBT) compared with external beam pelvic radiotherapy (EBRT) for patients with high-intermediate risk endometrial cancer. The current analysis was done to evaluate long-term health related quality of life (HRQL), and compare HRQL of patients to an age-matched norm population. Methods: Patients were randomly allocated to EBRT (n =214) or VBT (n =213). HRQL was assessed using EORTC QLQ-C30 and subscales from PR25 and OV28 (bladder, bowel, sexual symptoms); and compared to norm data. Findings: Median follow-up was 65 months; 348 (81%) patients were evaluable for HRQL (EBRT n =166, VBT n =182). At baseline, patient functioning was at lowest level, increasing during and after radiotherapy to reach a plateau after 12 months, within range of scores of the norm population. VBT patients reported better social functioning (p =0.005) and lower symptom scores for diarrhoea, faecal leakage, need to stay close to a toilet and limitation in daily activities due to bowel symptoms (p ⩽0.001), compared to EBRT. There were no differences in sexual functioning or symptoms between the treatment groups; however, sexual functioning was lower and sexual symptoms more frequent in both treatment groups compared to the norm population. Interpretation: Patients who received EBRT reported clinically relevant higher levels of bowel symptoms and related limitations in daily activities with lower social functioning, 5 years after treatment. VBT provides a better HRQL, which remained similar to that of an age-matched norm population, except for sexual symptoms which were more frequent in both treatment groups. [Copyright &y& Elsevier]

Simple Summary: Chemoradiation with photon radiotherapy is very effective as a locally advanced cervical cancer (LACC) treatment. However, the majority of women with LACC experience treatment-related toxicity involving the gastrointestinal and urogenital tracts and the immune system. Compared to that of photon therapy, proton therapy substantially reduces undesired dose to the organs around the tumor, leading to a decrease in radiotherapy-related side-effects. At present, few studies on proton therapy in patients with LACC will be conducted. The PROTECT trial aims to evaluate the differences in side effects between photon therapy and proton therapy, both combined with chemotherapy, for LACC. Fifteen patients will be enrolled per treatment group. Information will be collected on the differences in dose to the organs around the tumor, treatment-related side effects, and the impact on the immune system. This information will be used to assess the potential of proton therapy as an innovative treatment for LACC. External beam radiation therapy (EBRT) with concurrent chemotherapy followed by brachytherapy is a very effective treatment for locally advanced cervical cancer (LACC). However, treatment-related toxicity is common and reduces the patient's quality of life (QoL) and ability to complete treatment or undergo adjuvant therapies. Intensity modulated proton therapy (IMPT) enables a significant dose reduction in organs at risk (OAR), when compared to that of standard intensity-modulated radiation therapy (IMRT) or volumetric-modulated arc therapy (VMAT). However, clinical studies evaluating whether IMPT consequently reduces side effects for LACC are lacking. The PROTECT trial is a nonrandomized prospective multicenter phase-II-trial comparing clinical outcomes after IMPT or IMRT/VMAT in LACC. Thirty women aged >18 years with a histological diagnosis of LACC will be included in either the IMPT or IMRT/VMAT group. Treatment includes EBRT (45 Gy in 25 fractions of 1.8 Gy), concurrent five weekly cisplatin (40 mg/m2), and 3D image (MRI)-guided adaptive brachytherapy. The primary endpoint is pelvic bones Dmean and mean bowel V15Gy. Secondary endpoints include dosimetric parameters, oncological outcomes, health-related QoL, immune response, safety, and tolerability. This study provides the first data on the potential of IMPT to reduce OAR dose in clinical practice and improve toxicity and QoL for patients with LACC. [ABSTRACT FROM AUTHOR]

Simple Summary: Primary vaginal cancer is a rare disease and, consequently, evidence about the outcome of treatment is scarce. The aim of our retrospective, observational multicenter study was to assess the oncological outcome of the nowadays standing treatment for vaginal cancer, namely radio(chemo)therapy, followed by image-guided adaptive brachytherapy (IGABT). Our study confirms the results of the earlier published small monocentric IGABT studies, showing a high local control with acceptable morbidity. Notably, patients with large (T3/T4) tumors especially seem to benefit from volumetric (3D) image-guided brachytherapy, as compared to two-dimensional-based radiotherapy. In addition, although interpreted with caution, as for cervical cancer, a higher dose seems to lead to better local control. These results should, however, be further investigated in a prospective trial. Purpose: This study assessed outcomes following the nowadays standing treatment for primary vaginal cancer with radio(chemo)therapy and image-guided adaptive brachytherapy (IGABT) in a multicenter patient cohort. Methods: Patients treated with computer tomography (CT)–MRI-assisted-based IGABT were included. Retrospective data collection included patient, tumor and treatment characteristics. Late morbidity was assessed by using the CTCAE 3.0 scale. Results: Five European centers included 148 consecutive patients, with a median age of 63 years. At a median follow-up of 29 months (IQR 25–57), two- and five-year local control were 86% and 83%; disease-free survival (DFS) was 73% and 66%, and overall survival (OS) was 79% and 68%, respectively. Crude incidences of ≥ grade-three urogenital, gastro-intestinal and vaginal morbidity was 8%, 3% and 8%, respectively. Lymph node metastasis was an independent prognostic factor for disease-free survival (DFS). Univariate analysis showed improved local control in patients with T2–T4 tumors if >80 Gy EQD2α/β10 was delivered to the clinical target volume (CTV) at the time of brachytherapy. Conclusions: In this large retrospective multicenter study, IGABT for primary vaginal cancer resulted in a high local control with acceptable morbidity. These results compared favorably with two-dimensional (2D) radiograph-based brachytherapy and illustrate that IGABT plays an important role in the treatment of vaginal cancer. [ABSTRACT FROM AUTHOR]

• Doses to the vaginal dose points predicts well the risk of vaginal morbidity. • Higher doses to the vaginal PIBS points are associated with vaginal stenosis. • A shorter vaginal reference length is associated with ≥grade 2 vaginal stenosis. To evaluate dose–effect relationships between vaginal dose points and vaginal stenosis in patients treated for locally advanced cervical cancer with radio(chemo)therapy and image-guided adaptive brachytherapy. Patients from six centres participating in the EMBRACE-I study were included. Information on doses to different vaginal dose points, including the Posterior-Inferior Border of Symphysis (PIBS) points and recto-vaginal reference (RV-RP) point, were retrieved from the treatment planning system. In addition, the vaginal reference length (VRL) was evaluated. Vaginal stenosis was prospectively assessed according to the CTCAEv3.0 system at baseline and follow-up. Primary endpoint was grade 2 or higher (G ≥ 2) vaginal stenosis. Impact of dose to the vaginal dose points, and impact of VRL, age, vaginal involvement and applicator on vaginal stenosis G ≥ 2 was evaluated with a Cox proportional-hazard regression model. 301 patients were included. Median follow-up was 49 months. During follow-up, the incidence of G0, G1, G2, and G3 vaginal stenosis was 25% (76), 52% (158), 20% (59) and 3% (8), respectively. Median total doses to PIBS+2 cm, PIBS, PIBS-2 cm and the RV-RP were 52.9 (IQR 49.3–64.7), 41.0 (IQR 15.4–49.0), 4.1 (IQR 2.9–7.0) and 64.6 (IQR 60.0–70.6) Gy EQD2 3 , respectively. Higher doses to the PIBS, PIBS + 2 cm and RV-RP points were significantly associated with increased risk for vaginal stenosis G ≥ 2. Other risk factors for vaginal stenosis were: vaginal involvement at diagnosis, higher age, shorter VRL and use of a tandem-ovoid applicator. Higher doses to the PIBS+2 cm, PIBS and RV-RP dose points are associated with vaginal stenosis G ≥ 2. [ABSTRACT FROM AUTHOR]

Women with locally advanced cervical cancer (LACC) undergoing primary platinum-based chemoradiotherapy and brachytherapy often experience toxicities. Normal-tissue complication probability (NTCP) models quantify toxicity risk and aid in optimizing radiation therapy to minimize side effects. However, it is unclear which predictors to include in an NTCP model. The aim of this systematic review was to provide an overview of the identified predictors contributing to gastrointestinal (GI), genitourinary (GU), and vaginal toxicities and insufficiency fractures for LACC. A systematic search was performed and articles evaluating the relationship between predictors and toxicities in women with LACC treated with primary chemoradiation were included. The Quality In Prognosis Studies tool was used to assess risk of bias, with high-risk studies being excluded from further analysis. Relationships between dose-volume parameters, patient and treatment characteristics, and toxicity endpoints were analyzed. Seventy-three studies were identified. Twenty-six had a low or moderate risk of bias and were therefore included. Brachytherapy-related dose-volume parameters of the GI tract, including rectum and bowel equivalent dose in 2 Gy fractions (EQD2) D2 cm3, were frequently related to toxicities, unlike GU dose-volume parameters. Furthermore, (recto)vaginal point doses predicted toxicities. Few studies evaluated external beam radiation therapy dose-volume parameters and identified rectum EQD2 V30 Gy, V40 Gy, and V55 Gy, bowel and bladder EQD2 V40 Gy as toxicity predictors. Also, total reference air kerma and vaginal reference length were associated with toxicities. Relationships between patient characteristics and GI toxicity were inconsistent. The extent of vaginal involvement at diagnosis, baseline symptoms, and obesity predicted GU or vaginal toxicities. Only 1 study evaluated insufficiency fractures and demonstrated lower pretreatment bone densities to be associated. This review detected multiple candidate predictors of toxicity. Larger studies should consider insufficiency fractures, assess dose levels from external beam radiation therapy, and quantify the relationship between the predictors and treatment-related toxicities in women with LACC to further facilitate NTCP model development for clinical use. [ABSTRACT FROM AUTHOR]

Around 5-8 per cent of women diagnosed with cervical cancer present with metastatic disease at presentation and 16-25 per cent of patients fail at either within irradiated fields or at distant sites post-curative therapy in advanced cervical cancers. Conventionally, chemotherapy with palliative intent constituted the mainstay of treatment with modest survival outcomes and radiation therapy was reserved for symptomatic benefit only. While targeted therapies and immunotherapy have been added in therapeutic armamentarium, the impact on the outcomes is modest. In limited metastatic disease, radiation therapy to metastatic sites from different primary cancers has shown survival benefits; however, the data are scarce in cervical cancer. With a better understanding of the molecular biology of the metastases and recurrence pattern, emphasis is laid upon total eradication of the disease rather than offering relief from symptoms. This article summarizes the role of radiation therapy in limited metastatic disease and recurrent cervical cancer. [ABSTRACT FROM AUTHOR]

Highlights from the article: The aim of the trial was to determine the maximum tolerated brachytherapy boost dose after 13 × 3 Gy external beam radiotherapy. Four dose levels were tested: 5 Gy, 6 Gy, 7 Gy, and 8 Gy per brachytherapy fraction, and all patients received 3 weekly brachytherapy fractions. This is incorrect; the prescribed dose in EQD2 SB ( / = 3) sb ranges from 70.8 Gy for a patients in the dose level with 5 Gy per fraction to 99.6 Gy for a patient in the dose level with 8 Gy per fraction.

Purpose: Current incidence methods for reporting mild or moderate symptoms capture the (first) occurrence of an event and do not allow distinguishing between patients who suffer from long-lasting versus transient morbidity. This paper introduces a new methodological approach that identifies cancer survivors who have clinically relevant, long-lasting symptoms (patients with late, persistent, substantial and treatment-related symptoms, [LAPERS]).Methods and Materials: LAPERS can be evaluated in patients with baseline information and at least 3 late follow-up assessments after treatment. LAPERS identifies individual patients with a given symptom that is substantial (above a predefined clinically relevant threshold) and must be present in at least half of the follow-ups. Baseline morbidity is accounted for by requiring the median of the late symptom score to be worse than the baseline condition. The LAPERS approach was applied to 4 relevant patient-reported genito-urinary/gastrointestinal symptoms within the prospective, longitudinal EMBRACE study (An intErnational study on MRI-guided BRachytherapy in locally Advanced CErvical cancer, www.embracestudy.dk). LAPERS was compared with crude incidence and prevalence rates.Results: Within the EMBRACE cohort, 651/1044 patients (62%) had baseline and long-term follow-up available (median follow-up: 42 months). There was a considerable gap between LAPERS, crude incidence, and prevalence rates. The proportion of patients with LAPERS events was 3.8-4.8 times lower than crude incidences. The highest prevalence rates across follow-up times were 1.8-2.6 times lower than crude incidences.Conclusions: These findings indicate limitations of incidence methods for reporting substantial patient-reported symptoms because a considerable proportion of patients with symptoms do not experience them persistently over time, as they may fluctuate or get successfully treated. In contrast, the LAPERS method for longitudinal analysis identifies patients with clinically relevant, long-lasting symptoms. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the toxicity and efficacy of the combination of external beam radiation therapy (EBRT) followed by high-dose-rate endorectal brachytherapy (HDREBT) boost in elderly and medically inoperable patients with rectal cancer.Methods and Materials: A phase 1 dose-escalation study was performed. Treatment consisted of EBRT (13 × 3 Gy) followed by 3 weekly brachytherapy applications 6 weeks later. The HDREBT dose started at 5 Gy per fraction, increasing with 1 Gy per fraction if dose-limiting toxicity (DLT, defined as grade ≥3 proctitis <6 weeks after HDREBT) occurred in ≤2 patients per dose level. The primary endpoint was the maximum tolerated dose, defined as 1 dose level below the dose at which 3 patients experienced DLT. Secondary endpoints were toxicity, clinical tumor response, freedom from local progression, and local progression-free and overall survival (L-PFS and OS).Results: Thirty-eight patients with a median age of 83 years were included in the study. Thirty-two were evaluable for DLT and late toxicity and 33 for response evaluation. Maximum delivered dose was 8 Gy per fraction, resulting in a recommended dose of 7 Gy per fraction. Response occurred in 29 of 33 patients (87.9%), with 60.6% complete response (CR). The L-PFS and OS rates were 42% and 63%, respectively, at 2 years. Patients with CR showed a significantly improved L-PFS (60% at 2 years, P=.006) and a trend in improved OS (80% at 2 years, P=.11). Severe late toxicity occurred in 10 of 32 patients.Conclusion: We found that HDREBT after EBRT results in a high overall response rate, with improved L-PFS for patients with a CR. The high observed rate of severe late toxicity requires further evaluation of the risks and benefits of an HDREBT boost. [ABSTRACT FROM AUTHOR]

Purpose: Radiation therapy techniques have developed from 3-dimensional conformal radiation therapy (3DCRT) to intensity modulated radiation therapy (IMRT), with better sparing of the surrounding normal tissues. The current analysis aimed to investigate whether IMRT, compared to 3DCRT, resulted in fewer adverse events (AEs) and patient-reported symptoms in the randomized PORTEC-3 trial for high-risk endometrial cancer.Methods and Materials: Data on AEs and patient-reported quality of life (QoL) of the PORTEC-3 trial were available for analysis. Physician-reported AEs were graded using Common Terminology Criteria for Adverse Events v3.0. QoL was assessed by the European Organisation for Research and Treatment of Cancer QLQC30, CX24, and OV28 questionnaires. Data were compared between 3DCRT and IMRT. A P value of ≤ .01 was considered statistically significant due to the risk of multiple testing. For QoL, combined scores 1 to 2 ("not at all" and "a little") versus 3 to 4 ("quite a bit" and "very much") were compared between the techniques.Results: Of 658 evaluable patients, 559 received 3DCRT and 99 IMRT. Median follow-up was 74.6 months. During treatment no significant differences were observed, with a trend for more grade ≥3 AEs, mostly hematologic and gastrointestinal, after 3DCRT (37.7% vs 26.3%, P = .03). During follow-up, 15.4% (vs 4%) had grade ≥2 diarrhea, and 26.1% (vs 13.1%) had grade ≥2 hematologic AEs after 3DCRT (vs IMRT) (both P < .01). Among 574 (87%) patients evaluable for QoL, 494 received 3DCRT and 80 IMRT. During treatment, 37.5% (vs 28.6%) reported diarrhea after 3DCRT (vs IMRT) (P = .125); 22.1% (versus 10.0%) bowel urgency (P = 0039), and 18.2% and 8.6% abdominal cramps (P = .058). Other QoL scores showed no differences.Conclusions: IMRT resulted in fewer grade ≥3 AEs during treatment and significantly lower rates of grade ≥2 diarrhea and hematologic AEs during follow-up. Trends toward fewer patient-reported bowel urgency and abdominal cramps were observed after IMRT compared to 3DCRT. [ABSTRACT FROM AUTHOR]

Background: The concept of the use of MRI for image-guided adaptive brachytherapy (IGABT) in locally advanced cervical cancer was introduced 20 years ago. Here, we report on EMBRACE-I, which aimed to evaluate local tumour control and morbidity after chemoradiotherapy and MRI-based IGABT.Methods: EMBRACE-I was a prospective, observational, multicentre cohort study. Data from patients from 24 centres in Europe, Asia, and North America were prospectively collected. The inclusion criteria were patients older than 18 years, with biopsy-proven squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the uterine cervix, The International Federation of Gynecology and Obstetrics (FIGO) stage IB-IVA disease or FIGO stage IVB disease restricted to paraaortic lymph metastasis below the L1-L2 interspace, suitable for curative treatment. Treatment consisted of chemoradiotherapy (weekly intravenous cisplatin 40 mg/m2, 5-6 cycles, 1 day per cycle, plus 45-50 Gy external-beam radiotherapy delivered in 1·8-2 Gy fractions) followed by MRI-based IGABT. The MRI-based IGABT target volume definition and dose reporting was according to Groupe Européen de Curiethérapie European Society for Radiation Oncology recommendations. IGABT dose prescription was open according to institutional practice. Local control and late morbidity were selected as primary endpoints in all patients available for analysis. The study was registered with ClinicalTrials.gov, NCT00920920.Findings: Patient accrual began on July 30, 2008, and closed on Dec 29, 2015. A total of 1416 patients were registered in the database. After exclusion for not meeting patient selection criteria before treatment, being registered but not entered in the database, meeting the exclusion criteria, and being falsely excluded, data from 1341 patients were available for analysis of disease and data from 1251 patients were available for assessment of morbidity outcome. MRI-based IGABT including dose optimisation was done in 1317 (98·2%) of 1341 patients. Median high-risk clinical target volume was 28 cm3 (IQR 20-40) and median minimal dose to 90% of the clinical target volume (D90%) was 90 Gy (IQR 85-94) equi-effective dose in 2 Gy per fraction. At a median follow-up of 51 months (IQR 20-64), actuarial overall 5-year local control was 92% (95% CI 90-93). Actuarial cumulative 5-year incidence of grade 3-5 morbidity was 6·8% (95% CI 5·4-8·6) for genitourinary events, 8·5% (6·9-10·6) for gastrointestinal events, 5·7% (4·3-7·6) for vaginal events, and 3·2% (2·2-4·5) for fistulae.Interpretation: Chemoradiotherapy and MRI-based IGABT result in effective and stable long-term local control across all stages of locally advanced cervical cancer, with a limited severe morbidity per organ. These results represent a positive breakthrough in the treatment of locally advanced cervical cancer, which might be used as a benchmark for clinical practice and all future studies.Funding: Medical University of Vienna, Aarhus University Hospital, Elekta AB, and Varian Medical Systems. [ABSTRACT FROM AUTHOR]

• The survey results described in the manuscript captures the heterogeneity in the clinical practice of oligometastatic and oligorecurrent cervical cancer. • This survey will help to define the role of radiation therapy in oligometastatic and oligorecurrent cervical cancer. • This survey highlights the desire of radiation oncologists over the globe to practice stereotactic radiation therapy in oligometastatic disease and will help to plan future clinical trials. In the metastatic or recurrent cervical cancer, systemic chemotherapy constitutes the main treatment. Though there is an increasing use of high dose external radiation and brachytherapy in the metastatic setting, no consensus exists. A 17-item survey was designed with additional case-based questions to explore present management of oligo-metastatic and oligo-recurrent cervix cancer within EMBRACE research group participating sites. The questions were designed to elicit prevailing practices in the management of de-novo oligo-metastasis and oligo-recurrent setting after completing the primary treatment of cervix cancer. The survey was sent electronically with two rounds of email reminders to respond over a 2-week survey period. The online survey was designed such that it was mandatory to complete all questions. The responses were recorded and results were summarized as proportions and summary statistics were generated. Twenty-two centers responded to this survey. A majority (90%) of respondents reported a low incidence of de-novo oligo-metastatic cervical cancer in their practice (<5%), with a higher proportion of patients with oligo-recurrence after completing primary treatment (5–10%). All responding sites preferred to treat pelvic disease in the de-novo oligo-metastatic setting albeit with different fractionation regimens. While 68.2% of respondents recommended chemo-radiation and brachytherapy, 31.8% considered additional systemic therapy. Overall 77.3% centers recommended the use of stereotactic ablative radiation therapy to oligo-metastasis. For out-of-field nodal recurrences, 63.7% of respondents considered treating with curative intent, while 59% preferred treating in-field recurrence with palliative intent. A vast majority of the participating centers (90%) have stereotactic radiation therapy capacity and would consider a clinical trial addressing oligo-metastatic and oligo-recurrent cervical cancer. Although contemporary practice is variable, a substantial proportion of EMBRACE centers consider high dose radiation in de-novo metastatic and oligo-recurrence settings. However, there is clear need for a joint clinical protocol and prospective studies to address the role of high dose radiation within oligo-recurrent and oligo-metastatic scenarios. [ABSTRACT FROM AUTHOR]

Purpose: This report describes the persistence of late substantial treatment-related patient-reported symptoms (LAPERS) in the multi-institutional EMBRACE study on magnetic resonance image guided adaptive brachytherapy in locally advanced cervical cancer (LACC).Methods and Materials: Patient-reported symptoms (European Organization for Research and Treatment of Cancer [EORTC]-C30/CX24) and physician-assessed morbidity (Common Terminology Criteria for Adverse Events [CTCAE], version 3.0) were assessed at baseline and regular timepoints during follow-up. Patients with sufficient EORTC follow-up (baseline and ≥3 late follow-up visits) were analyzed. LAPERS events were defined as the presence of substantial EORTC symptoms (quite a bit/very much) for at least half of the assessments (persistence) and progression beyond baseline condition (treatment-related). For each EORTC symptom, the ratio between LAPERS rates and crude incidence rates of substantial symptoms was calculated to represent the proportion of symptomatic patients with persisting symptoms. For 9 symptoms with a corresponding EORTC/CTCAE assessment, the overlap of LAPERS and severe morbidity events (grades 3-5) was evaluated.Results: Of 1047 patients with EORTC available, 741 had sufficient follow-up for the LAPERS analyses. The median follow-up was 59 months (interquartile range, 42-70 months). Across all symptoms, the proportion of patients with LAPERS events (LAPERS rates) was in median 4.6% (range, 0.0% vaginal bleeding to 20.4% tiredness). Urinary frequency, neuropathy, fatigue, insomnia, and menopausal symptoms revealed LAPERS rates of >10%. Vomiting, blood in stool, urinary pain/burning, and abnormal vaginal bleeding displayed LAPERS rates of <1%. A median of 19% of symptomatic patients (interquartile range, 8.0%-28.5%) showed persistent long-term symptoms (LAPERS events). In symptoms with a corresponding EORTC/CTCAE assessment, 12% of LAPERS events were accompanied by a severe CTCAE event.Conclusions: Within this large cohort of survivors of LACC, a subgroup of patients with persistent symptoms (LAPERS events) was identified. For symptoms with a corresponding EORTC/CTCAE assessment, the vast majority of LAPERS events occurred in patients without corresponding severe physician-assessed morbidity. These findings emphasize the importance of distinguishing between transient and persisting symptoms in the aftercare of LACC survivors. [ABSTRACT FROM AUTHOR]

• Quality assurance (QA) with phantoms was developed to test multicenter quantitative MRI (qMRI). • The QA framework was applied to the qMRI protocols of a trial for cervical cancer. • Consistent values for apparent diffusion coefficient and T2 were obtained between 15 institutes. • Dynamic contrast-enhanced MRI and T1 require institute-specific corrections of patient data. • Changes in qMRI protocols are allowed during a trial by repeating QA. A wide variation of MRI systems is a challenge in multicenter imaging biomarker studies as it adds variation in quantitative MRI values. The aim of this study was to design and test a quality assurance (QA) framework based on phantom measurements, for the quantitative MRI protocols of a multicenter imaging biomarker trial of locally advanced cervical cancer. Fifteen institutes participated (five 1.5 T and ten 3 T scanners). Each institute optimized protocols for T2, diffusion-weighted imaging, T1, and dynamic contrast-enhanced (DCE–)MRI according to system possibilities, institutional preferences and study-specific constraints. Calibration phantoms with known values were used for validation. Benchmark protocols, similar on all systems, were used to investigate whether differences resulted from variations in institutional protocols or from system variations. Bias, repeatability (%RC), and reproducibility (%RDC) were determined. Ratios were used for T2 and T1 values. The institutional protocols showed a range in bias of 0.88–0.98 for T2 (median %RC = 1%; %RDC = 12%), −0.007 to 0.029 × 10−3 mm2/s for the apparent diffusion coefficient (median %RC = 3%; %RDC = 18%), and 0.39–1.29 for T1 (median %RC = 1%; %RDC = 33%). For DCE a nonlinear vendor-specific relation was observed between measured and true concentrations with magnitude data, whereas the relation was linear when phase data was used. We designed a QA framework for quantitative MRI protocols and demonstrated for a multicenter trial for cervical cancer that measurement of consistent T2 and apparent diffusion coefficient values is feasible despite protocol differences. For DCE–MRI and T1 mapping with the variable flip angle method, this was more challenging. [ABSTRACT FROM AUTHOR]

• Online RTQA with minimal data transfer is feasible and reduces manpower burden • Expert evaluation with qualitative feedback improved contouring compliance. • The Jaccard Conformity Index was not a reliable alternative to expert assessment. • Common delineation errors were identified which form the basis for ongoing education. • Strategies to improve engagement with educational content are needed. EMBRACE-II is an international prospective study of IMRT and MRI-guided adaptive brachytherapy (IGABT) in locally advanced cervix cancer. An online radiotherapy quality assurance (RTQA) programme with minimal data transfer and supporting continuing medical education (CME) was implemented for IMRT contouring. Participant contours for six volumes-of-interest (VOIs) on one benchmark case were scored (2 = excellent, 1 = fair, 0 = revision required) against a consensus reference contour. For contours receiving a 0 or 1 score, additional qualitative comments were provided. The Jaccard conformity index (JCI) was retrospectively calculated. User interaction with CME content (pre-accreditation questionnaire, contouring atlas, practice cases, quizzes, internal target volume (ITV-T) guide) was analysed. 78 clinicians submitted contours for evaluation. 41% passed at the first attempt, 44% after one revision and 6% after two or more revisions. 9% did not re-submit after failing. The lowest mean scores were for the elective nodal CTV (CTV-E) (1.01/2) and ITV-T (1.06/2). 60 different errors across the six VOIs were identified; five potentially had high impact on loco-regional control. A JCI cut-off of 0.7 would have identified 87% contours that failed expert assessment, but also excluded 54% of passing contours. 39 clinicians responded to the pre-accreditation questionnaire – 36% anticipated difficulties with the ITV-T and 13% with the CTV-E. 35% clinicians contoured on the practice cases, 17% answered a quiz, 96% used the atlas and 38% the ITV-T guide. Expert evaluation with qualitative feedback improved contouring compliance. The JCI is not a reliable alternative to expert assessment. Moderate uptake of optional CME content limited evaluation. [ABSTRACT FROM AUTHOR]

• Adaptive target volume concept for EBRT and brachytherapy in primary vaginal cancer. • MRI is the imaging modality of choice for target volume delineation in brachytherapy. • Common terminology will facilitate multicenter research. External beam radiotherapy (EBRT) combined with brachytherapy has an essential role in the curative treatment of primary vaginal cancer. EBRT is associated with significant tumour shrinkage, making primary vaginal cancer suitable for image guided adaptive brachytherapy (IGABT). The aim of these recommendations is to introduce an adaptive target volume concept for IGABT of primary vaginal cancer. In December 2013, a task group was initiated within GYN GEC-ESTRO with the purpose to introduce an IGABT target concept for primary vaginal cancer. All participants have broad experience in IGABT and vaginal cancer brachytherapy. The target concept was elaborated as consensus agreement based on an iterative process including target delineation and dose planning comparison, retrospective analysis of clinical data and expert opinions. Gynaecological examination and MR imaging are the modalities of choice for local tumour assessment. A specific template for standardised documentation with clinical drawings for vaginal cancer was developed. The adaptive target volume concept comprises different response-related target volumes. For EBRT these are related to the primary tumour and the lymph nodes, while for IGABT these are related to the primary tumour and are consisting of the residual gross tumour volume (GTV-T res) and the high-, and intermediate risk clinical target volumes (CTV-T HR , CTV-T IR). This target concept for IGABT of primary vaginal cancer defines adaptive target volumes for volumetric dose prescription and should improve comparability of different radiotherapy schedules of this rare disease. A prospective evaluation of the target volume concept within a multicentre study is planned. [ABSTRACT FROM AUTHOR]

Purpose: To describe the evolution of external beam radiation therapy (EBRT) from EMBRACE-I (general guidelines for EBRT) to the initial phase of the EMBRACE-II study (detailed protocol for EBRT).Methods and Materials: EMBRACE-I enrolled 1416 locally advanced cervical cancer patients treated with chemoradiation including image-guided adaptive brachytherapy during 2008 to 2015. From March 2016 until March 2018, 153 patients were enrolled in the ongoing EMBRACE-II study, which involves a comprehensive detailed strategy and accreditation procedure for EBRT target contouring, treatment planning, and image guidance. EBRT planning target volumes (PTVs), treated volumes (V43 Gy), and conformity index (CI; V43 Gy/PTV) were evaluated in both studies and compared.Results: For EMBRACE-I, conformal radiation therapy (60% of patients) or intensity-modulated radiation therapy (IMRT) and volumetric arc therapy (VMAT; 40%) was applied with 45 to 50 Gy over 25 to 30 fractions to the elective clinical target volume (CTV). For pelvic CTVs (82%), median PTV and V43 Gy volumes were 1549 and 2390 mL, respectively, and CI was 1.54. For pelvic plus paraortic nodal (PAN) CTVs (15%), median PTV and V43 Gy volumes were 1921 and 2895 mL, and CI was 1.51. For pelvic CTVs treated with 45 to 46 Gy, the use of conformal radiation therapy was associated with a median V43 Gy volume that was 546 mL larger than with IMRT/VMAT. For pelvic CTVs treated with IMRT, the use of a dose prescription ≥48 Gy was associated with a median V43 Gy volumes that was 428 mL larger than with a dose prescription of 45 to 46 Gy. For EMBRACE-II, all patients were treated with: IMRT/VMAT, daily IGRT, 45 Gy over 25 fractions for the elective CTV, and simultaneously integrated boost for pathologic lymph nodes. For pelvic CTVs (61%), median PTV and V43 Gy volumes were 1388 and 1418 mL, and CI was 1.02. For pelvic plus PAN CTVs (32%), median PTV and V43 Gy volumes were 1720 and 1765 mL, and CI was 1.03. From EMBRACE-I to initial II, median V43 Gy was decreased by 972 mL (41%) and 1130 mL (39%), and median CI decreased from 1.54 to 1.02 and 1.51 to 1.03 for pelvic and pelvic plus PAN irradiation, respectively.Conclusions: Application of IMRT/VMAT, IGRT, and a 45-Gy dose provides the potential of higher conformality inducing significant reduction of treated volume. Adherence to a detailed protocol including comprehensive accreditation, as in EMBRACE-II, reduces considerably V43 Gy and V50 Gy and improves conformality and interinstitutional consistency. [ABSTRACT FROM AUTHOR]

• In this cohort, the cumulative incidence of psPD increases from 13% in the first year to 28% at 10 years. • psPD is asymptomatic in 83% of patients. • 1p/19q codeletion and biopsy are associated with an increased risk of psPD. • When analyzed as a time-dependent covariate, psPD is not associated with overall survival. • An uniform definition and analysis method for psPD in diffuse glioma is needed for comparisons between photon - and proton beam radiotherapy. The interpretation of new enhancing lesions after radiotherapy for diffuse glioma remains a clinical challenge. We sought to characterize and classify new contrast enhancing lesions in a historical multicenter cohort of patients with IDH mutated grade 2 diffuse glioma treated with photon therapy. We reviewed all follow-up MRI's of all patients treated with radiotherapy for histologically confirmed, IDH mutated diffuse grade 2 glioma between 1–1-2007 and 31–12-2018 in two tertiary referral centers. Disease progression (PD) was defined in accordance with the RANO criteria for progressive disease in low grade glioma. Pseudoprogression (psPD) was defined as any transient contrast-enhancing lesion between the end of radiotherapy and PD, or any new contrast-enhancing lesion that remained stable over a period of 12 months in patients who did not exhibit PD. A total of 860 MRI's of 106 patients were reviewed. psPD was identified in 24 patients (23%) on 76 MRI's. The cumulative incidence of psPD was 13% at 1 year, 22% at 5 years, and 28% at 10 years. The mean of the observed maximal volume of psPD was 2.4 cc. The median Dmin in psPD lesions was 50.1 Gy. The presence of an 1p/19q codeletion was associated with an increased risk of psPD (subhazard ratio 2.34, p = 0.048). psPD was asymptomatic in 83% of patients. The cumulative incidence of psPD in grade 2 diffuse glioma increases over time. Consensus regarding event definition and statistical analysis is needed for comparisons between series investigating psPD. [ABSTRACT FROM AUTHOR]

Purpose To implement coverage probability (CovP) for dose planning of simultaneous integrated boost (SIB) of pathologic lymph nodes in locally advanced cervical cancer (LACC). Material and methods CovP constraints for SIB of the pathological nodal target (PTV-N) with a central dose peak and a relaxed coverage at the perimeter were generated for use with the treatment planning system Eclipse: PTV-N D98 >90%, CTV-N D98 >100% and CTV-N D50 >101.5% of prescribed dose. Dose of EBRT was 45 Gy/25 fx with a SIB of 55–57.5 Gy depending on expected dose from brachytherapy (BT). Twenty-five previously treated patients with 47 boosted nodes were analysed. Nodes were contoured on cone beam CT (CBCT) and the accumulated dose in GTV-N CBCT and volume of body, pelvic bones and bowel receiving >50 Gy (V50) were determined. Results Nearly all nodes (89%) were visible on CBCT and showed considerable concentric regression during EBRT. Total EBRT and BT D98 was >57 Gy EQD2 in 98% of the visible nodes. Compared to treatment plans aiming for full PTV-N coverage, CovP significantly reduced V50 of body, bones and bowel ( p < 0.001) Conclusion CovP is clinically feasible for SIB of pathological nodes and significantly decreases collateral SIB dose to nearby OAR. [ABSTRACT FROM AUTHOR]

Objective: Osteoradionecrosis (ORN) is a severe late complication after radiotherapy but current knowledge on ORN risks in the setting of postoperative radiotherapy (PORT) is limited. We studied the incidence and risk factors of ORN in patients with oral cavity cancers (OCC, treated with PORT.Patients and Methods: A retrospective cohort study was conducted including OCC patients (mainly squamous cell) treated with postoperative intensity modulated radiotherapy between 2010 and 2018 with > 1 year disease-free survival. Cumulative incidences of ORN were computed using the Kaplan Meier method. Clinical and dosimetric risk factors for mandibular ORN were evaluated using Cox regression models.Results: Within our cohort (N = 227, median follow-up 49 months) we observed 46 cases of ORN, mainly in the mandible (n = 41). The cumulative incidence of mandibular ORN was 15.9 % (SE 2.5 %) at three years and 19.8 % (SE 3.0 %) at five years. At univariable analysis, smoking, mandibular mandibulotomy or segment resection, mean dose to the mandible, and mandible volume (%) ≥ 60 Gy (V60) were significantly associated with increased ORN risks. At multivariable analysis, smoking (HR 2.13, 95 %CI 1.12-4.06) and V60 (HR 1.02 per 1 % increase, 95 %CI 1.01-1.04) remained predictive factors. For active smokers with a high V60 ≥ 40 % we observed rapid ORN development with a 1-year incidence of 29 % vs 6 % for others (p < 0.01).Conclusion: OCC Patients treated with PORT are at high risk for mandibular ORN. We identified the mandibular volume receiving ≥ 60 Gy as the dominant risk factor, especially in active smokers. Limiting high-dose volumes at treatment planning may decrease ORN risks. [ABSTRACT FROM AUTHOR]

Background: About 15% of patients with endometrial cancer have high-risk features and are at increased risk of distant metastases and endometrial cancer-related death. We designed the PORTEC-3 trial to investigate the benefit of adjuvant chemoradiotherapy compared with radiotherapy alone for women with high-risk endometrial cancer.Methods: PORTEC-3 was a multicentre, open-label, randomised, international trial. Women with high-risk endometrial cancer were randomly allocated (1:1) to radiotherapy alone (48·6 Gy) in 1·8 Gy fractions five times a week or chemoradiotherapy (two cycles concurrent cisplatin 50 mg/m(2) and four adjuvant cycles of carboplatin area under the curve [AUC] 5 and paclitaxel 175 mg/m(2)) using a biased coin minimisation procedure with stratification for participating centre, lymphadenectomy, stage of cancer, and histological type. The primary endpoints of the PORTEC-3 trial were overall survival and failure-free survival analysed in the intention-to-treat population. This analysis focuses on 2-year toxicity and health-related quality of life as secondary endpoints; analysis was done according to treatment received. Health-related quality of life was assessed with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) the cervix cancer module and chemotherapy and neuropathy subscales of the ovarian cancer module at baseline, after radiotherapy and at 6, 12, 24, 36, and 60 months after randomisation. Adverse events were graded with Common Terminology Criteria for Adverse Events version 3.0. The study was closed on Dec 20, 2013, after achieving complete accrual, and follow-up remains ongoing for the primary outcomes analysis. This trial is registered with ISRCTN.com, number ISRCTN14387080, and with ClinicalTrials.gov, number NCT00411138.Findings: Between Sept 15, 2006, and Dec 20, 2013, 686 women were randomly allocated in the PORTEC-3 trial. Of these, 660 met eligibility criteria, and 570 (86%) were evaluable for health-related quality of life. Median follow-up was 42·3 months (IQR 25·8-55·1). At completion of radiotherapy and at 6 months, EORTC QLQ-C30 functioning scales were significantly lower (worse functioning) and health-related quality of life symptom scores higher (worse symptoms) for the chemoradiotherapy group compared with radiotherapy alone, improving with time. At 12 and 24 months, global health or quality of life was similar between groups, whereas physical functioning scores remained slightly lower in patients who received chemoradiotherapy compared with patients who received radiotherapy alone. At 24 months, 48 (25%) of 194 patients in the chemoradiotherapy group reported severe tingling or numbness compared with 11 (6%) of 170 patients in the radiotherapy alone group (p<0·0001). Grade 2 or worse adverse events were found during treatment in 309 (94%) of 327 patients in the chemoradiotherapy group versus 145 (44%) of 326 patients in the radiotherapy alone group, and grade 3 or worse events were found in 198 (61%) of 327 patients in the chemoradiotherapy group versus 42 (13%) of 326 patients in the radiotherapy alone group (p<0·0001), with most of the grade 3 adverse events being haematological (45%). At 12 and 24 months, no significant differences in grade 3 or worse adverse events were found between groups; only grade 2 or higher sensory neuropathy adverse events persisted at 24 months (25 [10%] of 240 patients in the chemoradiotherapy group vs one [<1%] of 247 patients in the radiotherapy alone group; p<0·0001).Interpretation: Despite the increased physician and patient-reported toxicities, this schedule of adjuvant chemotherapy given during and after radiotherapy in patients with high-risk endometrial cancer is feasible, with rapid recovery after treatment, but with persistence of patient-reported sensory neurological symptoms in 25% of patients. We await the analysis of primary endpoints before final conclusions are made.Funding: Dutch Cancer Society, Cancer Research UK, National Health and Medical Research Council, Project Grant, Cancer Australia Grant, Italian Medicines Agency, and Canadian Cancer Society Research Institute. [ABSTRACT FROM AUTHOR]

Purpose: This study analyzed functioning and symptom scores for longitudinal quality of life (QoL) from patients with locally advanced cervical cancer who underwent definitive chemoradiation therapy with image guided adaptive brachytherapy in the EMBRACE study.Methods and Materials: In total, 744 patients at a median follow-up of 21 months were included. QoL was prospectively assessed using European Organization for Research and Treatment of Cancer Quality of Life core module 30 (EORTC QLQ-C30) and EORTC cervical cancer module 24 (CX24) questionnaires at baseline, then every 3 months during the first year, every 6 months in the second and third years, and finally yearly thereafter in patients with no evidence of disease. Outcomes were evaluated over time and compared to those from an age-matched female reference population.Results: General QoL and emotional and social functioning were impaired at baseline but improved during the first 6 months after treatment, to reach a level comparable to that of the reference population, whereas cognitive functioning remained impaired. Both social and role functioning showed the lowest scores at baseline but which increased after treatment to reach a plateau at 6 months and then declined slightly at 3 and 4 years. The overall symptom experience was elevated at baseline and decreased to a level within the range of that of the reference population. Similarly, tumor-related symptoms (eg, pain, appetite loss, and constipation), which were present before treatment, decreased substantially at the first follow-up after treatment. Several treatment-related symptoms developed either immediately after and persisted over time (diarrhea, menopausal symptoms, peripheral neuropathy, and sexual functioning problems) or developed gradually after treatment (lymphedema and dyspnea).Conclusions: This longitudinal prospective QoL analysis showed that patients' general QoL and functioning were impaired before treatment compared to those of reference data. Several tumor-related symptoms resolved after treatment, and functioning and general QoL returned to that of the level of the reference population, indicating a transient impact of diagnosis and treatment. However, several treatment-related symptoms and problems did develop and persist, either immediately or gradually after treatment. [ABSTRACT FROM AUTHOR]