Exclusion of non-Involved uterus from the target volume (EXIT-trial): An individualized treatment for locally advanced cervical cancer using modern radiotherapy and imaging techniques followed by completion surgery.

Background and purpose: Chemoradiotherapy followed by brachytherapy is the standard of care for locally advanced cervical cancer (LACC). In this study, we postulate that omitting an iconographical unaffected uterus (+12 mm distance from the tumour) from the treatment volume is safe and that no tumour will be found in the non-targeted uterus (NTU) leading to reduction of high-dose volumes of surrounding organs at risk (OARs). Material and Methods: In this single-arm phase 2 study, two sets of target volumes were delineated: one standard-volume (whole uterus) and an EXIT-volume (exclusion of non-tumour-bearing parts of the uterus with a minimum 12 mm margin from the tumour). All patients underwent chemoradiotherapy targeting the EXIT-volume, followed by completion hysterectomy. In 15 patients, a plan comparison between two treatment plans (PTV vs PTV_EXIT) was performed. The primary endpoint was the pathological absence of tumour involvement in the non-targeted uterus (NTU). Secondary endpoints included dosimetric impact of target volume reduction on OARs, acute and chronic toxicity, overall survival (OS), locoregional recurrence-free survival (LRFS), and progression-free survival (PFS). Results: In all 21 (FIGO stage I: 2; II: 14;III: 3; IV: 2) patients the NTU was pathologically negative. Ssignificant reductions in Dmean in bladder, sigmoid and rectum; V15Gy in sigmoid and rectum, V30Gy in bladder, sigmoid and rectum; V40Gy and V45Gy in bladder, bowel bag, sigmoid and rectum; V50Gy in rectum were achieved. Median follow-up was 54 months (range 7-79 months). Acute toxicity was mainly grade 2 and 5 % grade 3 urinary. The 3y- OS, PFS and LRFS were respectively 76,2%, 64,9% and 81 %. Conclusion: MRI-based exclusion of the non-tumour-bearing parts of the uterus at a minimum distance of 12 mm from the tumour out of the target volume in LACC can be done without risk of residual disease in the NTU, leading to a significant reduction of the volume of surrounding OARS treated to high doses.

Performance of MRI for Detection of ≥pT1b Disease in Local Staging of Endometrial Cancer.

Magnetic resonance imaging (MRI) can be used for the preoperative local staging of endometrial cancer (EC). The presence of ≥pT1b disease (i.e., tumor invasion in ≥50% of the myometrium, into the cervical stroma or spread outside the uterus) has important prognostic value and implications for the decision to perform lymphadenectomy. The purpose of this study was to assess the performance of MRI for the detection of ≥pT1b disease and to evaluate whether tumor size measured via MRI was predictive for ≥pT1b disease, independent of imaging signs of deep invasion. MRI T-staging and tumor diameter and volume were correlated with histopathology of the hysterectomy specimen in 126 patients. MRI had a sensitivity, specificity, positive predictive value, negative predictive value and accuracy of 70.0%, 83.3%, 79.2%, 75.3% and 77.0%, respectively, for the detection of ≥pT1b disease. A tumor diameter of ≥40 mm and volume of ≥20 mL measured via MRI were predictive for ≥pT1b disease at rates of 78.3% and 87.1%, respectively. An EC size of at least 5 mm upon MRI was predictive for ≥pT1b disease in more than 50% of cases. Our results support the use of MRI in the preoperative staging of EC and suggest including size criteria in EC staging guidelines.

Sexual health in Belgian cervical cancer survivors: an exploratory qualitative study.

PURPOSE: To assess experiences of sexuality and of receiving sexual healthcare in cervical cancer (CC) survivors. METHODS: A qualitative phenomenological study using semistructured one-on-one interviews was conducted with 15 Belgian CC survivors recruited in 5 hospitals from August 2021 to February 2022. The interviews were audiotaped and transcribed verbatim. Data were analyzed using inductive thematic analysis. COREQ and SRQR reporting guidelines were applied. RESULTS: Most participants experienced an altered sexuality after CC treatment with often long-term loss/lack of sex drive, little/no spontaneity, limitation of positions to avoid dyspareunia, less intense orgasms, or no sexual activity at all. In some cases, emotional intimacy became more prominent. Physical (vaginal bleeding, vaginal dryness, dyspareunia, menopausal symptoms) and psychological consequences (guilt, changed self-image) were at the root of the altered sexuality. Treatment-induced menopause reduced sex drive. In premenopausal patients, treatment and/or treatment-induced menopause resulted in the sudden elimination of family planning. Most participants highlighted the need to discuss their altered sexual experience with their partner to grow together toward a new interpretation of sexuality. To facilitate this discussion, most of the participants emphasized the need for greater partner involvement by healthcare providers (HPs). The oncology nurse or sexologist was the preferred HP with whom to discuss sexual health. The preferred timing for information about the sexual consequences of treatment was at treatment completion or during early follow-up. CONCLUSION: Both treatment-induced physical and psychological experiences were prominent and altered sexuality. Overall, there was a need for HPs to adopt proactive patient-tailored approaches to discuss sexual health.

Incidence and radiotherapy treatment patterns of complicated bone metastases.

Background: Despite the encouraging results of the SCORAD trial, single fraction radiotherapy (SFRT) remains underused for patients with complicated bone metastases with rates as low as 18-39%. We aimed to evaluate the incidence and treatment patterns of these metastases in patients being referred to a tertiary centre for palliative radiotherapy. Materials and methods: We performed a retrospective review of all bone metastases treated at our centre from January 2013 until December 2017. Lesions were classified as uncomplicated or complicated. Complicated was defined as associated with (impending) fracture, existing spinal cord or cauda equina compression. Our protocol suggests using SFRT for all patients with complicated bone metastases, except for those with symptomatic neuraxial compression and a life expectancy of ≥28 weeks. Results: Overall, 37 % of all bone metastases were classified as complicated. Most often as a result of an (impending) fracture (56 %) or spinal cord compression (44 %). In 93 % of cases, complicated lesions were located in the spine, most commonly originating from prostate, breast and lung cancer (60 %). Median survival of patients with complicated bone metastases was 4 months. The use of SFRT for complicated bone metastases increased from 51 % to 85 % over the study period, reaching 100 % for patients with the poorest prognosis. Conclusions: Approximately 37 % of bone metastases are classified as complicated with the majority related to (impending) fracture. Patients with complicated bone metastases have a median survival of 4 months and were mostly treated with SFRT.

Vaginal morbidity, sexual functioning, and health-related quality of life in cervical cancer survivors: a cross-sectional multicenter study (VAMOS).

PURPOSE: To compare sexual/vaginal functioning between early cervical cancer (ECC) and locally advanced cervical cancer (LACC) survivors. METHODS: VAMOS was a multicenter, cross-sectional, questionnaire, noninferiority study including ECC patients treated with surgery and, if clinically indicated, adjuvant (chemo)radiotherapy and LACC patients treated with neoadjuvant (chemo)radiotherapy followed by surgery. Patient-reported outcomes (PROs) were assessed using the EORTC QLQ-C30, EORTC QLQ-CX24, and Female Sexual Functioning Index (FSFI) questionnaires. Clinical reported outcomes (ClinROs) consisted of vaginal morbidity scored according to the CTCAE v4.0 scoring system. RESULTS: One hundred forty-three patients were included. Compared to ECC patients (n = 97), LACC patients (n = 46) were significantly less sexually active in the 4 weeks prior to completion of the questionnaires (65% vs. 41%; p = .005). The primary endpoint was not met: LACC patients reported a higher mean score (more problems) for sexual/vaginal functioning than ECC patients, with a non-clinically relevant mean difference of 6.38 ([95% CI: - 6.41, 19.17]; p = .570 for noninferiority). Regarding the secondary endpoints, the prevalence of sexual dysfunction between the two groups did not differ significantly (p = 0.124). Compared to ECC patients, LACC patients did not have significantly more vaginal morbidity (adjusted odds ratio [OR] 1.51 [95% CI: 0.22, 10.29]; p = .674). Moreover, there was poor agreement between any vaginal morbidity and sexual dysfunction (Cohen's kappa of 0.17). CONCLUSION: Compared to ECC survivors, LACC survivors were significantly less sexually active and reported equivalent or worse sexual/vaginal functioning, although the proportion of patients with sexual dysfunction was similar. Clinical assessment of vaginal morbidity was poorly correlated with sexual dysfunction.

Dosimetric and Hematologic Implications of Prostate-Only Versus Whole Pelvic Radiotherapy: Results of the Multicentric Phase 3 PROPER Study.

Objectives: The aim is to evaluate the incidental dose to the lymphatic regions in prostate-only radiotherapy (PORT) and to compare hematological outcome between PORT and whole pelvic radiotherapy (WPRT) in node-positive prostate cancer (pN1 PCa), in the era of modern radiotherapy techniques. Methods: We performed a prospective phase 3 trial in which a total of 64 pN1 PCa patients were randomized between PORT (ARM A) and WPRT (ARM B) delivered with volumetric-modulated arc therapy (VMAT). The lymph node (LN) regions were delineated separately and differences between groups were calculated using Welch t-tests. Hematological toxicity was scored according to common terminology criteria for adverse events (CTCAE) version 4.03. To evaluate differences in the evolution of red blood cell (RBC), white blood cell (WBC), and platelet count over time between PORT and WPRT, 3 linear mixed models with a random intercept for the patient was fit with model terms randomization group, study time point, and the interaction between both categorical predictors. Results: Except for dose to the obturator region, the incidental dose to the surrounding LN areas was low in ARM A. None of the patients developed severe hematological toxicity. The change in RBC from time point pre-external beam radiotherapy (EBRT) to month 3 and for WBC from time point pre-EBRT to months 3 and 12 was significantly different with ARM B showing a larger decrease. Conclusion: The incidental dose to the lymphatic areas becomes neglectable when PORT is delivered with VMAT. Hematological toxicity is very low after WPRT with VMAT and when bone marrow constraints are used for planning, although WPRT causes a decrease in RBC and WBC count over time.

Completion surgery after intensity-modulated arc therapy for locally advanced cervical cancer: long-term follow-up and update on surgical outcome and oncologic results of a unique tertiary care single-center retrospective cohort.

BACKGROUND: Chemoradiotherapy (CRT) followed by brachytherapy (BT) is the standard treatment for locally advanced cervical cancer (LACC), but replacement of BT by surgery (CRT-S) could be an acceptable alternative. The main concern is the risk of operative morbidity. The aim is to report on therapeutic morbidity, OS, PC, and LC of CRT-S. METHODS: This was a single tertiary center retrospective cohort study in patients treated with CRT-S. A type II Wertheim hysterectomy was performed 6-8 weeks after CRT. Acute and chronic radiotherapy-related and surgical morbidity was classified according to the CTCAE v4.0. OS, and DFS, PC, and LC were calculated using the Kaplan-Meier method. Univariate and multivariate Cox proportional hazard models were performed to determine variables with a prognostic role. RESULTS: A total of 130 consecutive LACC patients were treated with CRT, and 119 underwent completion surgery. The median follow-up was 53 months. Five-year OS rate, local control, pelvic control, and 5-year DFS rate were 73%, 93%, 90%, and 74%, respectively. The 5-year OS rate was 92%/72%/67%/56% for FIGO (2009) stage I/II/III/IV, respectively. The five-year OS rate was 79% and 71% for adenocarcinoma and squamous cell carcinoma (p > 0.05), respectively. There was no intra- and perioperative mortality. Intraoperative and early postoperative complication rates were 7% and 20% (3% ≥ G3), respectively; they resolved within 3 months. The late postoperative complication rate was 9% (7% ≥ G3). Acute/late radiotherapy-related G3 side effects were 5%/3% for gastrointestinal and 3%/7% for genitourinary side effects. CONCLUSIONS: CRT-S is safe with an acceptable rate of complications for both the CRT and completion surgery and shows encouraging outcome data for stage III/IV and adenocarcinoma patients.

Pembrolizumab, radiotherapy, and an immunomodulatory five-drug cocktail in pretreated patients with persistent, recurrent, or metastatic cervical or endometrial carcinoma: Results of the phase II PRIMMO study.

A phase II study (PRIMMO) of patients with pretreated persistent/recurrent/metastatic cervical or endometrial cancer is presented. Patients received an immunomodulatory five-drug cocktail (IDC) consisting of low-dose cyclophosphamide, aspirin, lansoprazole, vitamin D, and curcumin starting 2 weeks before radioimmunotherapy. Pembrolizumab was administered three-weekly from day 15 onwards; one of the tumor lesions was irradiated (8Gyx3) on days 15, 17, and 19. The primary endpoint was the objective response rate per immune-related response criteria (irORR) at week 26 (a lower bound of the 90% confidence interval [CI] of > 10% was considered efficacious). The prespecified 43 patients (cervical, n = 18; endometrial, n = 25) were enrolled. The irORR was 11.1% (90% CI 2.0-31.0) in cervical cancer and 12.0% (90% CI 3.4-28.2) in endometrial cancer. Median duration of response was not reached in both cohorts. Median interval-censored progression-free survival was 4.1 weeks (95% CI 4.1-25.7) in cervical cancer and 3.6 weeks (95% CI 3.6-15.4) in endometrial cancer; median overall survival was 39.6 weeks (95% CI 15.0-67.0) and 37.4 weeks (95% CI 19.0-50.3), respectively. Grade ≥ 3 treatment-related adverse events were reported in 10 (55.6%) cervical cancer patients and 9 (36.0%) endometrial cancer patients. Health-related quality of life was generally stable over time. Responders had a significantly higher proportion of peripheral T cells when compared to nonresponders (p = 0.013). In conclusion, PRIMMO did not meet its primary objective in both cohorts; pembrolizumab, radiotherapy, and an IDC had modest but durable antitumor activity with acceptable but not negligible toxicity.Trial registration ClinicalTrials.gov (identifier NCT03192059) and EudraCT Registry (number 2016-001569-97).

Association of Cell Death Markers With Tumor Immune Cell Infiltrates After Chemo-Radiation in Cervical Cancer.

Irradiation induces distinct cellular responses such as apoptosis, necroptosis, iron-dependent cell death (a feature of ferroptosis), senescence, and mitotic catastrophe. Several of these outcomes are immunostimulatory and may represent a potential for immunogenic type of cell death (ICD) induced by radiotherapy triggering abscopal effects. The purpose of this study is to determine whether intra-tumoral ICD markers can serve as biomarkers for the prediction of patient's outcomes defined as the metastasis status and survival over a 5-year period. Thirty-eight patients with locally advanced cervical cancer, treated with neoadjuvant chemoradiotherapy using cisplatin were included in this study. Pre-treatment tumor biopsy and post-treatment hysterectomy samples were stained for cell death markers and danger associated molecular patterns (DAMPs): cleaved caspase-3 (apoptosis), phosphorylated mixed lineage kinase domain like pseudokinase (pMLKL; necroptosis), glutathione peroxidase 4 (GPX4; ferroptosis) and 4-hydroxy-2-noneal (4-HNE; ferroptosis), high mobility group box 1 (HMGB1) and calreticulin. Although these markers could not predict the patient's outcome in terms of relapse or survival, many significantly correlated with immune cell infiltration. For instance, inducing ferroptosis post-treatment seems to negatively impact immune cell recruitment. Measuring ICD markers could reflect the impact of treatment on the tumor microenvironment with regard to immune cell recruitment and infiltration. One Sentence Summary: Cell death readouts during neoadjuvant chemoradiation in cervical cancer.

Prone Breast and Lymph Node Irradiation in 5 or 15 Fractions: A Randomized 2 × 2 Design Comparing Dosimetry, Acute Toxicity, and Set-Up Errors.

PURPOSE: Prone whole breast irradiation results in lower dose to organs at risk compared with supine position, especially lung dose. However, the adoption of prone position for whole breast irradiation + lymph node irradiation remains limited and data on lymph node irradiation in 5 fractions are lacking. Although the study was ended prematurely for the primary endpoint (breast retraction at 2 years), we decided to report acute toxicity for prone and supine positions and 5 and 15 fractions. Additionally, dosimetry and set-up accuracy between prone and supine positions were evaluated. METHODS AND MATERIALS: A randomized open-label factorial 2 × 2 design was used for an acute toxicity comparison between prone and supine positions and 5 and 15 fractions. The primary endpoint of the trial was breast retraction 2 years after treatment. In total, 57 patients were evaluated. Dosimetry and set-up errors were compared between prone and supine positions. All patients were positioned on either our in -house developed prone crawl breast couch or a Posirest-2 (Civco). RESULTS: No difference in acute toxicity between prone and supine positions was found, but 5 fractions did result in a lower risk of desquamation (15% vs 41%; P = .04). Prone positioning resulted in lower mean ipsilateral lung dose (2.89 vs 4.89 Gy; P < .001), mean thyroid dose (3.42 vs 6.61 Gy; P = .004), and mean contralateral breast dose (0.41 vs 0.54 Gy; P = .007). No significant difference in mean heart dose (0.90 vs 1.07 Gy; P = .22) was found. Set-up accuracy was similar between both positions. CONCLUSIONS: Unfortunately, the primary endpoint of the trial was not met due to premature closure of the trial. Acceleration in 5 fractions resulted in a lower risk of desquamation. Prone positioning did not influence acute toxicity or set-up accuracy, but did result in lower ipsilateral mean lung dose, thyroid dose, and contralateral breast dose.

Impact of radiotherapy parameters on the risk of lymphopenia in urological tumors: A systematic review of the literature.

BACKGROUND: We investigated how radiotherapy (RT) parameters may contribute to the risk of lymphopenia in urological tumors and we discussed how this may impact clinical outcomes. MATERIAL & METHODS: A systematic review was performed according to the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines. The PubMed, Embase and ISI Web Of Knowledge databases were searched. Study quality was assessed according to the Newcastle-Ottawa Scale. RESULTS: Overall, 8 articles reporting on a total of 549 urological cancer patients met the inclusion criteria. The pooled mean incidence of acute severe lymphopenia (absolute lymphocyte count < 500 cells/µL) was 17.1%. Extended radiation volumes may lead to an increased risk of developing lymphopenia. Medium-high doses (≥ 40 Gy) to the whole pelvic (odds ratio (OR) = 1.01; 95% confidence interval (CI) 1.00-1.01; p = 0.025) and iliac (OR = 1.04; 95% CI 1.01-1.08; p = 0.009) bone marrow (BM) were associated with acute grade 3 and late grade 2 lymphopenia, respectively. CONCLUSION: Multiple studies reported high and severe incidences of lymphopenia. Minimizing radiation volumes and unintentional irradiation of pelvic BM may reduce the incidence of lymphopenia, potentially improving clinical outcomes. More research is needed to further elucidate these findings and effectively implement recently developed new risk assessment tools.

Mental Health and Quality of Life among Patients with Cancer during the SARS-CoV-2 Pandemic: Results from the Longitudinal ONCOVID Survey Study.

PURPOSE: This longitudinal survey study aimed to investigate the self-reported outcome measures of COVID-19 peritraumatic distress, depression, anxiety, stress, quality of life (QOL), and their associated factors in a cohort of cancer patients treated at a tertiary care hospital during the SARS-CoV-2 pandemic. METHODS: Surveys were administered at four time points between 1 April 2020 and 18 September 2020. The surveys included the CPDI, DASS-21, and WHOQOL-BREF questionnaires. RESULTS: Survey response rates were high (61.0% to 79.1%). Among the 355 participants, 71.3% were female, and the median age was 62.2 years (IQR, 53.9 to 69.1). The majority (78.6%) were treated with palliative intention. An important proportion of the participants reported symptoms of COVID-19 peritraumatic distress (34.2% to 39.6%), depression (27.6% to 33.5%), anxiety (24.9% to 32.7%), and stress (11.4% to 15.7%) at any time point during the study period. We did not find clinically meaningful mental health and QOL differences during the study period, with remarkably little change in between the pandemic's first and second wave. We found no consistent correlates of mental health or QOL scores, including cancer type, therapy intention, and sociodemographic information. CONCLUSION: This cohort of cancer patients showed considerable resilience against mental health and QOL deterioration during the SARS-CoV-2 pandemic.

Safety of pre- or postoperative accelerated radiotherapy in 5 fractions: A randomized pilot trial.

OBJECTIVE: Neo-adjuvant radiotherapy (NART) for breast cancer has shown promising survival results in retrospective trials. However, there are some obstacles such as a chemotherapy delay, an increased overall treatment time (OTT) and the risk of increasing surgical morbidity. Accelerated radiotherapy (RT) in 5 fractions allows to deliver NART in a very short time span and minimizes the delay of surgery and chemotherapy. This trial investigates this NART schedule for safety, feasibility and OTT. MATERIAL AND METHODS: Twenty patients eligible for neo-adjuvant chemotherapy (NACT) and breast conserving surgery, were randomized between NART before NACT or NACT and postoperative RT. In both arms, RT treatment was given in 5 fractions to the whole breast with a simultaneously integrated boost (SIB) on the tumor(bed). Lymph node irradiation was given concomitantly in case of lymph node involvement. OTT was defined as the time from diagnosis to last surgery in the intervention group, while in the control group the time between diagnosis and last RT-fraction was used. In the intervention group NACT-delay was defined as time between diagnosis and start of chemotherapy. RESULTS: 20 patients were included, and 19 patients completed treatment. OTT was significantly shorter in the intervention group (mean 218 days, range 196-253) compared to the control group (mean 237, range 211-268, p = 0.001). The difference in mean duration from diagnosis to the first treatment was a non-significant 4 days longer (31 vs 27 days, p = 0.28), but the start of NACT after diagnosis was delayed by 21 days (48 vs 27 days, p < 0.001). NART did not result in additional surgery complications. CONCLUSION: This pilot trial is the first to report on accelerated NART in 5 fractions with SIB. NART before NACT resulted in a shorter OTT with good safety results.

A clearer view on ovarian clear cell carcinoma.

INTRODUCTION: Ovarian clear cell carcinoma (OCCC) is a less common subtype accounting for approximately 5% of all epithelial ovarian cancers (EOCs). Clinical experience and research findings confirm the remarkable differences in clinical behavior, molecular alterations and pathogenesis of OCCC. The diagnosis of OCCC is typically set at a younger age, and earlier stage and in a background of endometriosis. RESULTS: Molecularly, OCCCs rarely harbor BRCA1/BRCA2 mutations and have fewer copy number variants (CNVs). The most common molecular changes occur in the SWI/SNF chromatin remodeling complex genes, the PI3K/AKT signaling pathway and the receptor tyrosine kinase (RTK)/Ras signaling pathway.Five-year disease-specific survival of patients with OCCC is worse compared to high grade serous carcinomas (HGSOC). The current treatment options for OCCC are based on studies that included patients with predominantly HGSOC and only a minor proportion of cancers with clear cell histology. In order to improve outcomes for patients with OCCC, research should be specific for this subtype. DISCUSSION: As the available information about the specific characteristics of OCCC is increasing, especially at a molecular level, it should be possible to continuously improve the specific diagnostics and treatment. Since OCCC is so rare, it is essential to collect new evidence at an international level. To avoid extrapolation from EOC trials with possible erroneous conclusions, patients should always be encouraged to participate in specific histological trials and basket trials, while paying extra attention to OCCC-like subtypes.

Adoption of single fraction radiotherapy for uncomplicated bone metastases in a tertiary centre.

BACKGROUND: Single-fraction radiotherapy (SFRT) offers equal pain relief for uncomplicated painful bone metastases as compared to multiple-fraction radiotherapy (MFRT). Despite this evidence, the adoption of SFRT has been poor with published rates of SFRT for uncomplicated bone metastases ranging from <10% to 70%. We aimed to evaluate the adoption of SFRT and its evolution over time following the more formal endorsement of the international guidelines in our centre starting from 2013. MATERIALS AND METHODS: We performed a retrospective review of fractionation schedules at our centre for painful uncomplicated bone metastases from January 2013 until December 2017. Only patients treated with 1 × 8 Gy (SFRT-group) or 10 × 3 Gy (MFRT-group) were included. We excluded other fractionation schedules, primary cancer of the bone and post-operative radiotherapy. Uncomplicated was defined as painful but not associated with impending fracture, existing fracture or existing neurological compression. Temporal trends in SFRT/MFRT usage and overall survival were investigated. We performed a lesion-based patterns of care analysis and a patient-based survival analysis. Mann-Whitney U and Chi-square test were used to assess differences between fractionation schedules and temporal trends in prescription, with Kaplan-Meier estimates used for survival analysis (p-value <0.05 considered significant). RESULTS: Overall, 352 patients and 594 uncomplicated bone metastases met inclusion criteria. Patient characteristics were comparable between SFRT and MFRT, except for age. Overall, SFRT was used in 92% of all metastases compared to 8% for MFRT. SFRT rates increased throughout the study period from 85% in 2013 to 95% in 2017 (p = 0.06). Re-irradiation rates were higher in patients treated with SFRT (14%) as compared to MFRT (4%) (p = 0.046). Four-week mortality and median overall survival did not differ significantly between SFRT and MFRT (17% vs 18%, p = 0.8 and 25 weeks vs 38 weeks, p = 0.97, respectively). CONCLUSIONS: Adherence to the international guidelines for SFRT for uncomplicated bone metastasis was high and increased over time to 95%, which is the highest reported rate in literature.

Acute toxicity and health-related quality of life after accelerated whole breast irradiation in 5 fractions with simultaneous integrated boost.

INTRODUCTION: Acceleration of radiotherapy in 5 fractions for breast cancer can reduce the burden of treatment. We report on acute toxicity after whole-breast irradiation with a simultaneous integrated boost in 5 fractions over 10-12 days. MATERIAL AND METHODS: Acute toxicity and health-related quality of life (HRQoL) of 200 patients, randomized between a 15- or 5-fractions schedule, were collected, using the CTCAE toxicity scoring system, the Multidimensional Fatigue Inventory, EORTC QLQ-C30 and BR23 and the BREAST-Q questionnaire. The prescribed dose to the breast was either 15∗2.67 Gy (40.05 Gy) or 5∗5.7 Gy (28.5 Gy). 90% of patients received a SIB to a cumulative dose of 46.8 Gy (15∗3.12 Gy) or 31 Gy (5∗6.2 Gy). RESULTS: Physician-assessed toxicity was lower for the 5-fractions group. A significant difference was observed for breast pain (p = 0.002), fatigue (p < 0.0001), breast edema (p = 0.001) and dermatitis (p = 0.003). Patients treated in 5 fractions reported better mean HRQoL scores for breast symptoms (p = 0.001) and physical well-being (p = 0.001). A clinically important deterioration in HRQoL of 10 points or more was also less frequently observed in the latter group for physical functioning (p = 0.0005), social functioning (p = 0.0007), fatigue (p = 0.003), breast symptoms (p = 0.0002) and physical well-being (p = 0.002). CONCLUSION: In this single institute study, acute toxicity of accelerated breast radiotherapy in 5 fractions over 10-12 days seems to compare favourably to hypofractionated breast radiotherapy in 15 fractions. Less breast edema, dermatitis, desquamation, breast pain and fatigue are seen. Social and physical functioning are also less disturbed and patients have a better future perspective.

Ionizing radiation results in a mixture of cellular outcomes including mitotic catastrophe, senescence, methuosis, and iron-dependent cell death.

Radiotherapy is commonly used as a cytotoxic treatment of a wide variety of tumors. Interestingly, few case reports underlined its potential to induce immune-mediated abscopal effects, resulting in regression of metastases, distant from the irradiated site. These observations are rare, and apparently depend on the dose used, suggesting that dose-related cellular responses may be involved in the distant immunogenic responses. Ionizing radiation (IR) has been reported to elicit immunogenic apoptosis, necroptosis, mitotic catastrophe, and senescence. In order to link a cellular outcome with a particular dose of irradiation, we performed a systematic study in a panel of cell lines on the cellular responses at different doses of X-rays. Remarkably, we observed that all cell lines tested responded in a similar fashion to IR with characteristics of mitotic catastrophe, senescence, lipid peroxidation, and caspase activity. Iron chelators (but not Ferrostatin-1 or vitamin E) could prevent the formation of lipid peroxides and cell death induced by IR, suggesting a crucial role of iron-dependent cell death during high-dose irradiation. We also show that in K-Ras-mutated cells, IR can induce morphological features reminiscent of methuosis, a cell death modality that has been recently described following H-Ras or K-Ras mutation overexpression.

Feasibility study on pre or postoperative accelerated radiotherapy (POP-ART) in breast cancer patients.

BACKGROUND: In early-stage breast cancer, the cornerstone of treatment is surgery. After breast-conserving surgery, adjuvant radiotherapy has shown to improve locoregional control and overall survival rates. The use of breast radiotherapy in the preoperative (preop) setting is far less common. Nevertheless, it might improve disease-free survival as compared to postoperative radiotherapy. There is also a possibility of downsizing the tumour which might lead to a lower need for mastectomy. There are some obstacles that complicate its introduction into daily practice. It may complicate surgery or lead to an increase in wound complications or delayed wound healing. Another fear of preop radiotherapy is delaying surgery for too long. At Ghent University Hospital, we have experience with a 5-fraction radiotherapy schedule allowing radiotherapy delivery in a very short time span. METHODS: Twenty female breast cancer patients with non-metastatic disease receiving preop chemotherapy will be randomized between preop or postoperative radiotherapy. The feasibility of preop radiotherapy will be evaluated based on overall treatment time. All patients will be treated in 5 fractions of 5.7 Gy to the whole breast with a simultaneous integrated boost to the tumour/tumour bed of 5 × 6.2 Gy. In case of lymph node irradiation, the lymph node regions will receive a dose of 27 Gy in 5 fractions of 5.4 Gy. The total duration of therapy will be 10 to 12 days. In the preop group, overall treatment time is defined as the time between diagnosis and the day of last surgery, in the postop group between diagnosis and last irradiation fraction. Toxicity related to surgery, radio-, and chemotherapy will be evaluated on dedicated case-report forms at predefined time points. Tumour response will be evaluated on the pathology report and on MRI at baseline and in the interval between chemotherapy and surgery. DISCUSSION: The primary objective of the trial is to investigate the feasibility of preop radiotherapy. Secondary objectives are to search for biomarkers of response and toxicity and identify the involved cell death mechanisms and the effect of preop breast radiotherapy on the in-situ immune micro-environment.

PORTEC-4a: international randomized trial of molecular profile-based adjuvant treatment for women with high-intermediate risk endometrial cancer.

BACKGROUND: Vaginal brachytherapy is currently recommended as adjuvant treatment in patients with high-intermediate risk endometrial cancer to maximize local control and has only mild side effects and no or limited impact on quality of life. However, there is still considerable overtreatment and also some undertreatment, which may be reduced by tailoring adjuvant treatment to the patients' risk of recurrence based on molecular tumor characteristics. PRIMARY OBJECTIVES: To compare the rates of vaginal recurrence in women with high-intermediate risk endometrial cancer, treated after surgery with molecular-integrated risk profile-based recommendations for either observation, vaginal brachytherapy or external pelvic beam radiotherapy or with standard adjuvant vaginal brachytherapy STUDY HYPOTHESIS: Adjuvant treatment based on a molecular-integrated risk profile provides similar local control and recurrence-free survival as current standard adjuvant brachytherapy in patients with high-intermediate risk endometrial cancer, while sparing many patients the morbidity of adjuvant treatment and reducing healthcare costs. TRIAL DESIGN: A multicenter, international phase III randomized trial (2:1) of molecular-integrated risk profile-based adjuvant treatment (experimental arm) or adjuvant vaginal brachytherapy (standard arm). MAJOR INCLUSION/EXCLUSION CRITERIA: Women aged 18 years and over with a histological diagnosis of high-intermediate risk endometrioid endometrial cancer after total abdominal or laparoscopic hysterectomy and bilateral salpingo-oophorectomy. High-intermediate risk factors are defined as: (i) International Federation of Gynecology and Obstetrics stage IA (with invasion) and grade 3; (ii) stage IB grade 1 or 2 with age ≥60 and/or lymph-vascular space invasion; (iii) stage IB, grade 3 without lymph-vascular space invasion; or (iv) stage II (microscopic and grade 1). ENDPOINTS: The primary endpoint is vaginal recurrence. Secondary endpoints are recurrence-free and overall survival; pelvic and distant recurrence; 5-year vaginal control (including treatment for relapse); adverse events and patient-reported symptoms and quality of life; and endometrial cancer-related healthcare costs. SAMPLE SIZE: 500 eligible and evaluable patients. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Estimated date for completing accrual will be late 2021. Estimated date for presentation of (first) results is expected in 2023. TRIAL REGISTRATION: The trial is registered at clinicaltrials.gov (NCT03469674) and ISRCTN (11659025).

Splenic 18F-FDG uptake on baseline PET/CT is associated with oncological outcomes and tumor immune state in uterine cervical cancer.

OBJECTIVE: The spleen represents an important contributor to tumor immune escape, but the relevance of increased splenic metabolic activity remains to be fully elucidated. METHODS: We retrospectively measured the spleen-to-liver standard uptake value (SLR) on 18F-FDG PET/CT examinations of 92 consecutive patients with FIGO stage IB1 to IVA cervical cancer and integrated the results with survival, response to treatment, tumor immune infiltrate, and baseline characteristics. RESULTS: SLRmax > 0.92 (p = .026) and SLRmean > 0.94 (p = .005) were significantly associated with decreased DFS in univariable analysis. Multivariable models were built using best subset selection; ΔSLRmax and either SLRmax or SLRmean were consistently selected, strongly reinforcing the association between SLR variables and DFS in relation to potential confounders (all models p ≤ .002). Independent associations were found for SLRmax using multivariable Cox regression models for DFS (all p ≤ .003). Further, uni- and multivariable analyses demonstrated the negative impact of higher SLR values on pathological complete response. A statistically significant higher proportion of patients with high SLRmax had a dense infiltrate of CD20+ (p = .036) and CD68+ (p = .015) immune cells, as well as PD-L1+ tumor cells (p = .019) as compared to those with low SLRmax. Finally, high SLRmax status was neither associated with systemic inflammatory markers (except for an increased white blood cell count; p = .038), nor with clinically overt infection. CONCLUSION: This hypothesis-generating study provides the first evidence that increased splenic metabolic activity is a negative prognostic and predictive biomarker in locally advanced cervical cancer. In addition, it might help to discriminate immunologically 'hot' from 'cold' cervical tumors.