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More intense rainfall may cause a range of negative impacts upon society and the environment. In this study we analysed trends in extreme ETCCDI (Expert Team on Climate Change Detection and Indices) rainfall indices in Montenegro for the period between 1951 and 2010. Montenegro has been poorly studied in terms of rainfall extremes, yet it contains the wettest Mediterranean region known as Krivošije. Several indices of precipitation extremes were assessed including the number of dry days and rainfall totals in order to identify trends and possible changes. A spatial pattern relationship between extreme rainfall indices and the North Atlantic Oscillation has also been examined. The results generally suggest that the number of days with precipitation decreased while rainfall intensity increased, particularly in south-western parts of the country. A slight tendency towards intense rainfall events is suggested. The examined rainfall indices and North Atlantic Oscillation over Montenegro seemed to be directly linked to changes in one of the major large-scale circulation modes such as the NAO pattern that is particularly evident during the winter season.

Montenegro so far has been poorly investigated in terms of climate extremes. The aim of this paper was to analyse the extreme ETCCDI (Expert Team on Climate Change Detection and Indices) temperature indices in the Mediterranean region of Montenegro for the period of 1951–2010. Four stations in the coastal area of Montenegro have been analysed: Herceg Novi, Ulcinj, Budva and Bar. Two periods (before 1980 and after 1980) were separately investigated in this study due to a well-known climate shift that occurred in the late 1970s. Seven indices of temperature extremes have been chosen. The trend was analysed using a Mann–Kendall non-parametric test, while the slope was estimated using Sen's slope estimator. A negative trend has been calculated for cold nights and cold days at almost all stations. The most significant positive trends were obtained for warm conditions. The two separately investigated periods have shown contrasting temperature trends.

The aim of this paper is to analyse indices of extreme precipitation in Krivošije, Montenegro, the wettest Mediterranean region, from the period 1951–2007 and their relationships with atmospheric circulation using "SynopVis Grosswetterlagen" (SVG) series. Data from two stations were analysed, namely Crkvice (42°34'N and 18°39'E) and Herceg Novi (42°27'N and 18°31'E). Four indices of precipitation extremes (SDII, R75p, R95p, R95pTOT) were assessed including number of dry days. The results suggest that the number of days with precipitation decreased. To analyse the relationship between extreme precipitation events and circulation types we have used an efficiency coefficient (Ec). Regarding relation to atmospheric circulation, westerly, southwesterly and northwesterly circulation types with anticyclonic features over Central Europe are more frequent for dry days (days with R

Purpose: Magnetic resonance image-guided brachytherapy is essential in the management of locally advanced cervical cancer. This study compares disease and toxicity outcomes in cervical cancer patients treated with 24 Gy/3 fractions (Fr) versus the conventional 28 Gy/4 Fr., Methods and Materials: This retrospective study included 241 consecutive patients with International Federation of Gynecology and Obstetrics 2018 stage IB to IVA cervical cancer treated with definitive chemoradiation between April 2014 and March 2021. Disease-free survival (DFS) was estimated using the Kaplan-Meier method and compared using the log-rank test. Cumulative incidence of local failure (LF), distant failure (DF), and G2+ gastrointestinal (GI), urinary and vaginal toxicity were estimated using the cumulative incidence function with death as a competing risk and compared using Gray's test., Results: Of the 241 patients, 42% received 24 Gy/3 Fr and 58% received 28 Gy/4 Fr. With a median follow-up of 3.2 (range, 0.2-9.2) years, there were 14 local, 41 regional nodal, and 51 distant failures in 63 (26%) patients. No significant differences were found between the 24 Gy/3 Fr and 28 Gy/4 Fr groups in 3-year DFS (77% vs 68%, P = .21), the 3-year cumulative incidence of LF (5% vs 7%, P = .57), DF (22% vs 25%, P = .86), G2+ GI toxicity (11% vs 20%, P = .13), or G2+ vaginal toxicity (14% vs 17%, P = .48), respectively. The 3-year cumulative G2+ urinary toxicity rate was lower in the 24 Gy/3 Fr group (9% vs 23%, P = .03)., Conclusions: Patients with cervical cancer treated with 24 Gy/3 Fr had similar DFS, LF, DF, GI, and vaginal toxicity rates and a trend toward a lower G2+ urinary toxicity rate compared with those treated with 28 Gy/4 Fr. A less resource-intensive brachytherapy fractionation schedule of 24 Gy/3 Fr is a safe alternative to 28 Gy/4 Fr for definitive treatment of cervical cancer., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Sexual health is an important survivorship issue in cervical cancer. We assessed patient-reported sexual health outcomes and correlations with oncologist-assessed vaginal toxicity (VT)., Methods: This was a prospective, cross-sectional study of stage IB-IVA cervical cancer patients treated with definitive chemoradiation, who completed a socio-demographic questionnaire and the following patient-reported-outcomes (PROs): Female Sexual Function Index (FSFI), Female Sexual Distress Scale-Revised (FSDS-R), Menopause Rating Scale (MRS), Hospital Anxiety and Depression Scale (HADS). VT was assessed using the CTCAE v4.0. Sociodemographic, clinical data, PROs and VT were summarized using descriptive statistics; correlations were evaluated using linear regression analyses., Results: Between August 2018 and April 2022, 73 patients were analyzed. Median age was 49 (range 25-81), 57.5% had vaginal involvement at diagnosis and 76.9% were partnered. Sexual dysfunction (FSFI score ≤ 26), sexual distress (FSDS-R ≥ 11), severe menopausal symptoms (MRS ≥ 17), anxiety (HAD-Anxiety >7) and depression (HAS-Depression >7) were reported in 86.3%, 54.5%, 36.2%, 46.6% and 24.7%, respectively. Grade 2+ VT was reported in 27.4%. No significant associations were found between PROs and VT. On multivariable analysis, non-partnered status, use of hormone replacement therapy, and International Commission on Radiation Units and Measurements - rectovaginal dose (ICRU-RV) >65Gy were associated with worse sexual health (p < 0.005)., Conclusion: Cervical cancer patients self-report high rates of sexual distress, dysfunction and menopause symptoms. Discordance between oncologist-assessed VT and PROs highlights the importance of evaluating the patient's experience. Proactive treatment of menopausal symptoms and attention to radiotherapy doses to the vagina should be considered., Competing Interests: Declaration of competing interest Dr. Kathy Han was on the Astra Zeneca Cervical Cancer Radiation Oncology and Merck Gynaecological Cancer Advisory Board. All the other co-authors report no conflict of interest., (Crown Copyright © 2024. Published by Elsevier Inc. All rights reserved.)

The management of colorectal cancer liver metastases requires a multidisciplinary approach, which may incorporate systemic therapy, surgery, or local ablative therapies. Stereotactic body radiation therapy (SBRT) is a non-invasive highly conformal radiation technique that enables the delivery of large doses of radiation in a few fractions to well-defined targets using image-guidance and motion management. For selected patients with colorectal cancer liver metastases, stereotactic body radiation therapy can be delivered safely, with excellent long-term local control and overall survival. The purpose of this clinical practice review is to review the background, indications, and treatment details of stereotactic body radiation therapy for the treatment of colorectal liver metastases. SBRT for colorectal cancer liver metastases may be considered for patients with oligometastatic colorectal cancer in combination with surgery or other locally ablative therapies; for patients who are not candidates for surgical resection; or after failure of resection or other ablative therapies. When planning SBRT both a computed tomography and magnetic resonance imaging simulation may be obtained, where feasible, for target delineation. One or 3 fraction SBRT can be considered for lesions away from the central liver and luminal organs at risk, whereas 5 fraction SBRT is preferred otherwise. Image-guidance and motion management strategies are essential components of liver SBRT and will guide the creation of relevant internal and planning target volume margins. For lesions in close proximity to or overlapping with organs-at-risk, the balance between adequate local control and potential for cure with potential acute and late toxicity must be carefully considered., Competing Interests: Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-22-1183/coif). The series “Precision Radiation Oncology in GI Cancers” was commissioned by the editorial office without any funding or sponsorship. L.A.D. serves as an unpaid editorial board member of Journal of Gastrointestinal Oncology from January 2021 to December 2024. Besides, she is the past president of the American Society for Therapeutic Radiation Oncology and the current University of Toronto Department of Radiation Oncology Chair. The authors have no other conflicts of interest to declare., (2024 Journal of Gastrointestinal Oncology. All rights reserved.)

Objective. To develop and validate a dose-of-the-day (DOTD) treatment plan verification procedure for liver and pancreas cancer patients treated with an magnetic resonance (MR)-Linac system. Approach. DOTD was implemented as an automated process that uses 3D datasets collected during treatment delivery. Particularly, the DOTD pipeline's input included the adapt-to-shape (ATS) plan-i.e. 3D-MR dataset acquired at beginning of online session, anatomical contours, dose distribution-and 3D-MR dataset acquired during beam-on (BON). The DOTD automated analysis included (a) ATS-to-BON image intensity-based deformable image registration (DIR), (b) ATS-to-BON contours mapping via DIR, (c) BON-to-ATS contours copying through rigid registration, (d) determining ATS-to-BON dosimetric differences, and (e) PDF report generation. The DIR process was validated by two expert reviewers. ATS-plans were recomputed on BON datasets to assess dose differences. DOTD analysis was performed retrospectively for 75 treatment fractions (12-liver and 5-pancreas patients). Main results. The accuracy of DOTD process relied on DIR and mapped contours quality. Most DIR-generated contours (99.6%) were clinically acceptable. DICE correlated with depreciation of DIR-based region of interest mapping process. The ATS-BON plan difference was found negligible (<1%). The duodenum and large bowel exhibited highest variations, 24% and 39% from fractional values, for 5-fraction liver and pancreas. For liver 1-fraction, a 62% variation was observed for duodenum. Significance. The DOTD methodology provides an automated approach to quantify 3D dosimetric differences between online plans and their delivery. This analysis offers promise as a valuable tool for plan quality assessment and decision-making in the verification stage of the online workflow., (© 2024 Institute of Physics and Engineering in Medicine.)

Background: The risk factors for acute care utilization in gynecologic oncology patients are poorly understood. This study aimed to evaluate risk factors for the utilization of our centre's acute care radiation nursing clinic (RNC) by gynecologic oncology patients receiving radiotherapy (RT)., Methods: This was a retrospective cohort study of gynecological cancer patients treated with RT at an academic cancer centre between 1 August 2021 and 31 January 2022. Data on socio-demographics, clinical and treatment characteristics, and RNC visits were collected and summarized by descriptive statistics. The Wilcoxon rank sum test and chi-squared test/Fisher's exact test were used for comparisons of continuous and categorical variables, respectively., Results: RT was delivered to 180 patients, of whom 42 (23%) received concurrent chemoradiation (CCR). Compared to those receiving RT alone, patients receiving CCR had higher rates of RNC utilization (55% vs. 19%, p < 0.001). Within the CCR cohort, patients who presented to the RNC were more likely to be unpartnered (43% vs. 11%, p = 0.04), receive a referral to Psychosocial Oncology (39% vs. 5.3%, p = 0.01), and experience treatment interruptions (52% vs. 16%, p = 0.02). There were no associations between RNC visits and age, disease site, or distance from the cancer centre., Conclusions: The receipt of CCR and specific psychosocial risk factors were associated with increased RNC utilization. Targeted strategies and early intervention to better meet the supportive care and psychosocial needs of this vulnerable population are needed.

Purpose: To develop an immune-based gene expression risk score to identify patients with cervical cancer at increased risk of distant metastases (DM)., Experimental Design: Tumor biopsies were obtained from 81 patients prior to chemoradiotherapy. Whole-transcriptome RNA sequencing was performed (Illumina NextSeq500). Beginning with 4,723 immune-related genes, a 55-gene risk score for DM was derived using Cox modeling and principal component analysis. It was validated in independent cohorts of 274 patients treated at the Norwegian Radium Hospital (NRH) and 206 patients from The Cancer Genome Atlas (TCGA)., Results: The risk score was predictive of DM (HR, 2.7; P < 0.0001) and lower cause-specific survival (CSS) by univariate analysis (HR, 2.0; P = 0.0003) and multivariate analysis adjusted for clinical factors (DM HR, 3.0; P < 0.0001; CSS HR, 2.2; P = 0.0004). The risk score predicted DM (HR, 1.4; P = 0.05) and CSS (HR, 1.48; P = 0.013) in the NRH cohort and CSS (HR, 1.4; P = 0.03) in TCGA cohort. Higher risk scores were associated with lower CIBERSORT estimates of tumor-infiltrating immune cells, including CD8 T cells and M1 and M2 macrophages (all P < 0.001). Higher risk scores were associated with lower expression (all P < 0.001) of important chemokines (CXCL12, CXCR4), IFN-regulated genes (IRF1, STAT1, IDO1), and immune checkpoint regulators (PD-1, PD-L1, CTLA-4)., Conclusions: The immune metastatic risk score addresses important challenges in the treatment of cervical cancer-identifying patients at high risk of DM after radiotherapy. The findings of this study indicate that high tumor mutational burden and a "cold," immune-excluded tumor microenvironment influence distant metastatic recurrence. Further validation of the risk score is needed., (©2024 American Association for Cancer Research.)

Introduction: Characterizing the landscape of clinical trials including brachytherapy can provide an overview of the current status and research trends which may guide further areas of investigation., Method: We queried 449,849 clinical trials from the ClinicalTrials.gov registry using brachytherapy-related keywords from 1980 to 2023, yielding 245 multi-arm and 201 single-arm, brachytherapy trials. Multi-arm and single-arm brachytherapy trials were compared using 12 trial protocol elements., Results: The number of trials including brachytherapy has increased over time, with over 60% of trials registered in 2010 onwards. The majority of clinical trials were Phase 2 or 3, evaluated both safety and efficacy, and were funded by academic sponsors. The most common tumor sites evaluated in brachytherapy clinical trials include prostate, cervix, liver, endometrium, and breast., Conclusion: There remains continued interest in clinical trials including brachytherapy focused on evaluation of novel delivery systems, treatment planning, and new indications. More brachytherapy clinical trials are needed to define the optimal clinical utilization and advance prospective research in this field., (© 2024. The Author(s).)

Purpose: Most cervical cancers are caused by human papilloma virus (HPV), and HPV circulating tumor DNA (ctDNA) may identify patients at highest risk of relapse. Our pilot study using digital polymerase chain reaction (dPCR) showed that detectable HPV ctDNA at the end of chemoradiation (CRT) is associated with inferior progression-free survival (PFS) and that a next-generation sequencing approach (HPV-seq) may outperform dPCR. We aimed to prospectively validate HPV ctDNA as a tool for early detection of residual disease., Methods: This prospective, multicenter validation study accrued patients with stage IB-IVA cervical cancer treated with CRT between 2017 and 2022. Participants underwent phlebotomy at baseline, end of CRT, 4-6 weeks post-CRT, and 3 months post-CRT for HPV ctDNA levels. Plasma HPV genotype-specific DNA levels were quantified using both dPCR and HPV-seq. The primary end point was 2-year PFS., Results: With a median follow-up of 2.2 (range, 0.5-5.5) years, there were 24 PFS events among the 70 patients with HPV+ cervical cancer. Patients with detectable HPV ctDNA on dPCR at the end of CRT, 4-6 weeks post-CRT, and 3 months post-CRT had significantly worse 2-year PFS compared with those with undetectable HPV ctDNA (77% v 51%, P = .03; 82% v 15%, P < .001; and 82% v 24%, P < .001, respectively); the median lead time to recurrence was 5.9 months. HPV-seq showed similar results as dPCR. On multivariable analyses, detectable HPV ctDNA on dPCR and HPV-seq remained independently associated with inferior PFS., Conclusion: Persistent HPV ctDNA after CRT is independently associated with inferior PFS. HPV ctDNA testing can identify, as early as at the end of CRT, patients at high risk of recurrence for future treatment intensification trials.

Purpose: The TOPGEAR phase 3 trial hypothesized that adding preoperative chemoradiation therapy (CRT) to perioperative chemotherapy will improve survival in patients with gastric cancer. Owing to the complexity of gastric irradiation, a comprehensive radiation therapy quality assurance (RTQA) program was implemented. Our objective is to describe the RTQA methods and outcomes., Methods and Materials: RTQA was undertaken in real time before treatment for the first 5 patients randomized to CRT from each center. Once acceptable quality was achieved, RTQA was completed for one-third of subsequent cases. RTQA consisted of evaluating (1) clinical target volume and organ-at-risk contouring and (2) radiation therapy planning parameters. Protocol violations between high- (20+ patients enrolled) and low-volume centers were compared using the Fisher exact test., Results: TOPGEAR enrolled 574 patients, of whom 286 were randomized to receive preoperative CRT and 203 (71%) were included for RTQA. Of these, 67 (33%) and 136 (67%) patients were from high- and low-volume centers, respectively. The initial RTQA pass rate was 72%. In total, 28% of cases required resubmission. In total, 200 of 203 cases (99%) passed RTQA before treatment. Cases from low-volume centers required resubmission more often (44/136 [33%] vs 13/67 [18%]; P = .078). There was no change in the proportion of cases requiring resubmission over time. Most cases requiring resubmission had multiple protocol violations. At least 1 aspect of the clinical target volume had to be adjusted in all cases. Inadequate coverage of the duodenum was most common (53% major violation, 25% minor violation). For the remaining cases, the resubmission process was triggered secondary to poor contour/plan quality., Conclusions: In a large multicenter trial, RTQA is feasible and effective in achieving high-quality treatment plans. Ongoing education should be performed to ensure consistent quality during the entire study period., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Many multicenter randomized clinical trials in oncology are conducted through the National Clinical Trials Network (NCTN), an organization consisting of 5 cooperative groups. These groups are made up of multidisciplinary investigators who work collaboratively to conduct trials that test novel therapies and establish best practice for cancer care. Unfortunately, disparities in clinical trial leadership are evident. To examine the current state of diversity, equity, and inclusion across the NCTN, an independent NCTN Task Force for Diversity in Gastrointestinal Oncology was established in 2021, the efforts of which serve as the platform for this commentary. The task force sought to assess existing data on demographics and policies across NCTN groups. Differences in infrastructure and policies were identified across groups as well as a general lack of data regarding the composition of group membership and leadership. In the context of growing momentum around diversity, equity, and inclusion in cancer research, the National Cancer Institute established the Equity and Inclusion Program, which is working to establish benchmark data regarding diversity of representation within the NCTN groups. Pending these data, additional efforts are recommended to address diversity within the NCTN, including standardizing membership, leadership, and publication processes; ensuring diversity of representation across scientific and steering committees; and providing mentorship and training opportunities for women and individuals from underrepresented groups. Intentional and focused efforts are necessary to ensure diversity in clinical trial leadership and to encourage design of trials that are inclusive and representative of the broad population of patients with cancer in the United States., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Aim: The aim of this study was to describe the baseline clinical features, treatment patterns and outcomes in rectal squamous cell carcinoma (SCC)., Method: This is a retrospective study of patients with rectal SCC treated at the Princess Margaret Cancer Centre (Toronto, Canada) between 1 January 1995 and 31 December 2020. Clinical factors associated with locoregional failure (LRF), distant metastases (DM), disease-free survival (DFS) and overall survival (OS), such as age, sex, HIV status, T-category, nodal status, grade and primary treatment, were investigated with univariate analysis (UVA)., Results: Twenty nine patients with rectal SCC were analysed with a median follow-up of 7.4 years (range 0.3-20.4 years). The median age at diagnosis was 52 years, with the majority presenting with clinical T3 disease or higher (n = 21, 72%) and positive regional lymph nodes (n = 16, 55%), while more than quarter of patients (28%) had metastatic disease. Definitive chemoradiation was the treatment modality of choice in more than half of all cases (n = 17, 59%) with a response rate of 100%. The 10-year cumulative incidence of LRF and DM was, respectively, 12% (95% CI 1.8%-32.9%) and 31% (95% CI: 12.0%-52.6%). The 5- and 10-year OS was 82% (95% CI 66.1%-100%). UVA revealed a trend towards an association of male gender (hazard ratio = 4.65, 95% CI 0.9%-24.1; p = 0.067) and primary surgical treatment (hazard ratio = 0.76, 95% CI 0.09-6.34; p = 0.061) with DFS., Conclusion: Definitive chemoradiation is an effective and preferred treatment for rectal SCC allowing for sphincter preservation with complete clinical response observed in all patients., (© 2022 Association of Coloproctology of Great Britain and Ireland.)

Purpose: To demonstrate the feasibility of treating cervical cancer patients with MRI-guided brachytherapy (MRgBT) using 24 Gy in 3 fractions (F) versus a standard, more resource-intensive regimen of 28 Gy in 4F, and its ability to meet EMBRACE II planning aims., Methods and Materials: A retrospective review of 224 patients with FIGO Stage IB-IVA cervical cancer treated with 28 Gy/4F (n = 91) and 24 Gy/3F (n = 133) MRgBT between 2016-2021 was conducted. Multivariable linear regression models were fitted to compare dosimetric parameters between the two groups, adjusting for CTV HR and T stage., Results: Most patients had squamous cell carcinoma, T2b disease, and were treated with intracavitary applicator plus interstitial needles (96%). The 28 Gy/4F group had higher CTV HR (median 28 vs. 26 cm 3 , p = 0.04), CTV IR D 98% (mean 65.5 vs. 64.5 Gy, p = 0.03), rectum D 2cm3 (mean 61.7 vs. 59.2 Gy, p = 0.04) and bladder D 2cm3 (81.3 vs. 77.9 Gy, p = 0.03). There were no significant differences in the proportion of patients meeting the EMBRACE II OAR dose constraints and planning aims, except fewer patients treated with 28 Gy/4F met rectum D 2cm3 < 65 Gy (73 vs. 85%, p = 0.027) and ICRU rectovaginal point < 65 Gy (65 vs. 84%, p = 0.005)., Conclusions: Cervical cancer patients treated with 24 Gy/3F MRgBT had comparable target doses and lower OAR doses compared to those treated with 28 Gy/4F. A less-resource intense fractionation schedule of 24 Gy/3F is an alternative to 28 Gy/4F in cervix MRgBT., (Copyright © 2022 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Patients with anal squamous cell carcinoma (SCC) are treated with sphincter-preserving radiation therapy and concurrent chemotherapy, achieving excellent oncologic outcomes. Patients, however, may experience treatment-related morbidity including sexual dysfunction. The objective of this systematic review was to review the literature on sexual dysfunction in female patients treated for anal cancer and to identify knowledge gaps., Materials and Methods: This systematic review was registered in PROSPERO prior to initiation. Databases searched included MEDLINE, Embase, PubMed, Cochrane, and Google Scholar. There were no restrictions on the study time period. Studies were limited to English. All study designs were included except review articles, letters to the editor, and case reports with less than ten patients., Results: In total, 1801 studies were retrieved and 19 met the inclusion criteria, including: 13 cross-sectional surveys, 3 prospective studies, 1 longitudinal intervention study, 1 retrospective chart review, 1 case control study. Sexual function was assessed using the female sexual functioning index (FSFI), EORTC-QLQ-CR30 and -CR38; response rates were low (<50 % in most studies). Sexual dysfunction was reported by up to 85 % of women; the most common symptoms being dyspareunia (17-65 %), vaginal dryness (22-88 %), and loss of libido (38-95 %). Gastrointestinal issues, such as bowel problems, and body image concerns additionally affected sexual function and quality of life., Conclusion: Sexual dysfunction is a common issue affecting most female patients treated for anal cancer and there is a paucity of evidence on the management of this important survivorship issue. There is additionally a lack of ethnic, economic, and educational diversity and there are no studies addressing the unique needs of LGBTQ individuals - future studies should make a concerted effort to include a diverse patient population., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: This study investigates the impact of dosimetric parameters on acute and late toxicity for patients with anal squamous cell carcinoma (SCC) treated with image-guided intensity modulated radiation therapy (IG-IMRT) and concurrent chemotherapy., Materials and Methods: Patients were enrolled in an observational cohort study between 2008 and 2013 (median follow-up 3.4 years). They were treated with standardized target and organ-at-risk (OAR) contouring, planning, and IG-IMRT. Radiotherapy dose, based on clinicopathologic features, ranged from 45 Gy to 63 Gy to gross targets and 27 Gy to 36 Gy to elective targets. Chemotherapy was concurrent 5-fluorouracil and mitomycin C (weeks 1&5). Toxicity was prospectively graded using NCI CTCAE v.3 and RTOG scales. Logistic regression was used to assess the association between dose/volume parameters (e.g small bowel V5) and corresponding grade 2 + and 3+ (G2+/3 + ) toxicities (e.g. diarrhea)., Results: In total, 87 and 79 patients were included in the acute and late toxicity analyses, respectively. The most common acute G2 + toxicities were skin (dermatitis in 87 % [inguino-genital skin], 91 % [perianal skin]) and hematologic in 58 %. G2 + late anal toxicity (sphincter dysfunction), gastrointestinal toxicity, and skin toxicity were respectively experienced by 49 %, 38 %, and 44 % of patients. Statistically significant associations were observed between: G2 + acute diarrhea and small bowel V35; G2 + acute genitourinary toxicity and bladder D 0.5cc ; G2 + inguino-genital skin toxicity and anterior skin V35; G2 + perianal skin toxicity and posterior skin V15; G2 + anemia and lower pelvis bone V45. D0.5 cc was significantly predictive of late toxicity (G2 + anal dysfunction, intestinal toxicity, and inguino-genital/perianal dermatitis). Maximum skin toxicity grade was significantly correlated with the requirement for a treatment break., Conclusion: Statistically significant dose-volume parameters were identified and may be used to offer individualized risk prediction and to inform treatment planning. Additional validation of the results is required., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Locally advanced esophageal cancer has a dismal prognosis. Surgery remains the cornerstone treatment with 5-year survival rates of approximately 12-39%. Rates of local failure and distant metastases are high following surgical resection of locally advanced tumors. Neoadjuvant therapy (either radiation therapy, chemotherapy, or a combination) prior to surgery carries the advantage of tackling micrometastases and improving complete resection rates. Neoadjuvant concurrent chemotherapy and radiotherapy are a favored approach with evidence for improved pathologic complete response (pCR) rates and improved survival compared with surgery alone. Randomized trials of the optimal neoadjuvant approach are ongoing., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: The globally dominant treatment with curative intent for locally advanced esophageal squamous cell carcinoma (ESCC) is neoadjuvant chemoradiotherapy (nCRT) with subsequent esophagectomy. This multimodal treatment leads to around 60% overall 5-year survival, yet with impaired post-surgical quality of life. Observational studies indicate that curatively intended chemoradiotherapy, so-called definitive chemoradiotherapy (dCRT) followed by surveillance of the primary tumor site and regional lymph node stations and surgery only when needed to ensure local tumor control, may lead to similar survival as nCRT with surgery, but with considerably less impairment of quality of life. This trial aims to demonstrate that dCRT, with selectively performed salvage esophagectomy only when needed to achieve locoregional tumor control, is non-inferior regarding overall survival, and superior regarding health-related quality of life (HRQOL), compared to nCRT followed by mandatory surgery, in patients with operable, locally advanced ESCC., Methods: This is a pragmatic open-label, randomized controlled phase III, multicenter trial with non-inferiority design with regard to the primary endpoint overall survival and a superiority hypothesis for the experimental intervention dCRT with regard to the main secondary endpoint global HRQOL one year after randomization. The control intervention is nCRT followed by preplanned surgery and the experimental intervention is dCRT followed by surveillance and salvage esophagectomy only when needed to secure local tumor control. A target sample size of 1200 randomized patients is planned in order to reach 462 events (deaths) during follow-up., Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT04460352., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Nilsson, Olafsdottir, Alexandersson von Döbeln, Villegas, Gagliardi, Hellström, Wang, Johansson, Gebski, Hedberg, Klevebro, Markar, Smyth, Lagergren, Al-Haidari, Rekstad, Aahlin, Wallner, Edholm, Johansson, Szabo, Reynolds, Pramesh, Mummudi, Joshi, Ferri, Wong, O’Callaghan, Lukovic, Chan, Leong, Barbour, Smithers, Li, Kang, Kong, Chao, Crosby, Bruns, van Laarhoven, van Berge Henegouwen, van Hillegersberg, Rosati, Piessen, de Manzoni and Lordick.)

The primary treatment for resectable vulvar cancer includes wide local excision of the primary tumor and surgical lymph node assessment. Following surgery, up to 40-50% of patients develop a local recurrence. Historically, the strongest predictor of local recurrence is a positive or close margin (defined as <8 mm), although recent studies question the importance of margin status. Post-operative radiotherapy to the vulva is recommended for all women with a positive margin where re-excision is not possible. Radiotherapy may also be considered in the setting of risk factors for local recurrence: close margin, lymphovascular invasion, large tumor size, and/or depth of invasion >5 mm. Nodal assessment is an important component of vulvar cancer management. A negative sentinel node is associated with a low false-negative predictive value (2% in patients with vulvar tumor <4 cm in GOG 173), 2-year groin recurrence rate of 2.3%, and 3-year disease-specific survival rate of 97% in patients with unifocal vulvar tumor <4 cm in the GROningen INternational Study on Sentinel nodes in Vulvar Cancer (GROINSS-V I) study. Thus, patients with tumor size <4 cm (without additional local risk factors) and negative sentinel node can be observed. Patients with sentinel node metastasis ≤2 mm can be treated with post-operative radiotherapy (2-year isolated groin recurrence rate of 1.6% in GROINSS-V II), as a safe alternative to lymphadenectomy. Patients with sentinel node metastasis >2 mm following sentinel node biopsy should undergo inguinofemoral lymphadenectomy followed by post-operative radiotherapy-based on the GROINSS-V II study, the 2-year isolated groin recurrence rate remains unacceptably high (22%) with radiotherapy alone. Retrospective studies suggest that the addition of concurrent chemotherapy to radiotherapy may improve survival. The ongoing GROINSS-V III study is investigating concurrent chemotherapy and radiotherapy dose escalation. The main goal of these post-operative treatments is to reduce the risk of local, and especially groin, recurrences, which are almost universally fatal., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Anal adenocarcinoma is a rare clinical entity for which the optimal management is not defined., Objective: This study aimed to describe the multidisciplinary management and outcomes of patients with anal adenocarcinoma., Design: This is a retrospective cohort study., Setting: This study was conducted at a quaternary cancer center., Patients: Men and women with anal adenocarcinoma treated between 1995 and 2016 were selected., Interventions: Fifty-two patients were treated with either chemoradiotherapy or trimodality therapy including radiation therapy, chemotherapy, and surgical resection., Main Outcome Measures: Local failure, regional failure, and distant metastasis rates were estimated using the cumulative incidence method. The Kaplan-Meier method was used to estimate progression-free survival and overall survival. The multivariable Cox proportional hazards model was used to evaluate the clinical predictors of outcome., Results: There was a higher 5-year rate of local failure in patients treated with chemoradiotherapy compared with trimodality therapy (53% vs 10%; p < 0.01). The 5-year incidence of distant metastases was 29% (trimodality therapy) versus 30% (chemoradiotherapy; p = 0.9); adjuvant chemotherapy did not reduce the incidence of distant metastases (p = 0.8). Five-year overall survival was 73% (trimodality therapy) versus 49.4% (chemoradiotherapy; p = 0.1). On multivariable analysis, factors associated with worse overall survival were treatment with chemoradiotherapy, cT3-4 category disease, and node-positive disease., Limitations: This study is limited by its small sample size and retrospective nature., Conclusions: Although treatment may continue to be tailored to individual patients, better outcomes with a trimodality therapy approach were observed. See Video Abstract at http://links.lww.com/DCR/B708.ADENOCARCINOMA ANAL: UNA ENTIDAD POCO FRECUENTE EN NECESIDAD DE UN MANEJO MULTIDISCIPLINARIO., Antecedentes: El adenocarcinoma anal es una entidad clínica poco frecuente por lo que aún no se define el manejo óptimo., Objetivo: Describir el manejo multidisciplinario y los resultados de los pacientes con adenocarcinoma anal., Diseo: Estudio de cohorte retrospectivo., Entorno Clinico: Centro de cáncer cuaternario., Pacientes: Hombres y mujeres con adenocarcinoma anal tratados entre 1995 y 2016., Intervenciones: Cincuenta y dos pacientes fueron tratados con quimiorradioterapia o terapia trimodal que incluyó: radioterapia, quimioterapia y resección quirúrgica., Principales Medidas De Valoracion: Se estimaron las tasas de falla local, falla regional y metástasis a distancia mediante el método de incidencia acumulada. Se utilizó el método de Kaplan-Meier para estimar la supervivencia libre de progresión y la supervivencia global. Los riesgos proporcionales de multivariable Cox se utilizaron para evaluar los predictores clínicos de los resultados., Resultados: Hubo una mayor tasa de falla local a cinco años en pacientes tratados con quimiorradioterapia en comparación con terapia trimodal (53% vs 10%; p < 0,01). La incidencia a cinco años de metástasis a distancia fue del 29% (terapia trimodal) versus 30% (quimiorradioterapia) (p = 0,9); la quimioterapia adyuvante no redujo la incidencia de metástasis a distancia (p = 0,8). La supervivencia global a cinco años fue del 73% (terapia trimodal) versus 49,4% (quimiorradioterapia); p = 0,1. En el análisis multivariable, los factores asociados con una peor supervivencia general fueron el tratamiento con quimiorradioterapia, enfermedad de categoría cT3-4 y enfermedad con ganglios positivos., Limitaciones: Este estudio está limitado por su pequeño tamaño de muestra y su naturaleza retrospectiva., Conclusiones: Aunque el tratamiento puede seguir adaptándose a pacientes individuales, se observaron mejores resultados con un enfoque TTM. Conslute Video Resumen en http://links.lww.com/DCR/B708. (Traducción- Dr. Francisco M. Abarca-Rendon)., (Copyright © The ASCRS 2021.)

Purpose: To describe a comprehensive workflow for MRI-guided online adaptive stereotactic body radiation therapy (SBRT) specific to upper gastrointestinal cancer patients with abdominal compression on a 1.5T MR-Linac system. Additionally, we discuss the workflow's clinical feasibility and early experience in the case of 16 liver and pancreas patients., Methods: Eleven patients with liver cancer and five patients with pancreas cancer were treated with online adaptive MRI-guidance under abdominal compression. Two liver patients received single-fraction treatments; the remainder plus all pancreas cancer patients received five fractions. A total of 65 treatment sessions were investigated to provide analytics relevant to the online adaptive processes. The quantification of target and organ motion as well as definition and validation of internal target volume (ITV) margins were performed via multi-contrast imaging provided by three different 2D cine sequences. The plan generation was driven by full re-optimization strategies and using T2-weighted 3D image series acquired by means of a respiratory-triggered exhale phase or a time-averaged imaging protocol. As a pre-requisite for the clinical development of the procedure, the image quality was thoroughly investigated via phantom measurements and numerical simulations specific to upper abdominal sites. The delivery of the online adaptive treatments was facilitated by real-time monitoring with 2D cine imaging., Results: Liver 1-fraction and 5-fraction online adaptive session time were on average 80 and 67.5 min, respectively. The total session length varied between 70-90 min for a single fraction and 55-90 min for five fractions. The pancreas sessions were 54-85 min long with an average session time of 68.2 min. Target visualization on the 2D cine image data varied per patient, with at least one of the 2D cine sequences providing sufficient contrast to confidently identify its location and confirm reproducibility of ITV margins. The mean/range of absolute and relative dose values for all treatment sessions evaluated with ArcCheck were 90.6/80.9-96.1% and 99/95.4-100%, respectively., Conclusion: MR-guidance is feasible for liver and pancreas tumors when abdominal compression is used to reduce organ motion, improve imaging quality, and achieve a robust intra- and inter-fraction patient setup. However, the treatment length is significantly longer than for the conventional linac, and patient compliance is paramount for the successful completion of the treatment. Opportunities for reducing the online adaptive session time should be explored. As the next steps, dose-of-the-day and dose accumulation analysis and tools are needed to enhance the workflow and to help further refine the online re-planning processes.

Background: Despite persistently poor oncological outcomes, approaches to the management of T4 colonic cancer remain variable, with the role of neoadjuvant therapy unclear. The aim of this review was to compare oncological outcomes between direct-to-surgery and neoadjuvant therapy approaches to T4 colon cancer., Methods: A librarian-led systematic search of MEDLINE, Embase, the Cochrane Library, Web of Science, and CINAHL up to 11 February 2020 was performed. Inclusion criteria were primary research articles comparing oncological outcomes between neoadjuvant therapies or direct to surgery for primary T4 colonic cancer. Based on PRISMA guidelines, screening and data abstraction were undertaken in duplicate. Quality assessment was carried out using Cochrane risk-of-bias tools. Random-effects models were used to pool effect estimates. This study compared pathological resection margins, postoperative morbidity, and oncological outcomes of cancer recurrence and overall survival., Results: Four studies with a total of 43 063 patients met the inclusion criteria. Compared with direct to surgery, neoadjuvant therapy was associated with increased rates of margin-negative resection (odds ratio (OR) 2.60, 95 per cent c.i. 1.12 to 6.02; n = 15 487) and 5-year overall survival (pooled hazard ratio 1.42, 1.10 to 1.82, I2 = 0 per cent; n = 15 338). No difference was observed in rates of cancer recurrence (OR 0.42, 0.15 to 1.22; n = 131), 30-day minor (OR 1.12, 0.68 to 1.84; n = 15 488) or major (OR 0.62, 0.27 to 1.44; n = 15 488) morbidity, or rates of treatment-related adverse effects., Conclusion: Compared with direct to surgery, neoadjuvant therapy improves margin-negative resection rates and overall survival., (© The Author(s) 2021. Published by Oxford University Press on behalf of BJS Society Ltd. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: The main objective of this study was to review the clinicopathologic characteristics and outcome of patients with oncocytic papillary thyroid carcinoma (PTC) and oncocytic poorly differentiated thyroid carcinoma (PDTC). The secondary objective was to evaluate the prevalence and outcomes of RAI use in this population., Methods: Patients with oncocytic PTC and PDTC who were treated at a quaternary cancer centre between 2002 and 2017 were retrospectively identified from an institutional database. All patients had an expert pathology review to ensure consistent reporting and definition. The cumulative incidence function was used to analyse locoregional failure (LRF) and distant metastasis (DM) rates. Univariable analysis (UVA) was used to assess clinical predictors of outcome., Results: In total, 263 patients were included (PTC [n=218], PDTC [n=45]) with a median follow up of 4.4 years (range: 0 = 26.7 years). Patients with oncocytic PTC had a 5/10-year incidence of LRF and DM, respectively, of 2.7%/5.6% and 3.4%/4.5%. On UVA, there was an increased risk of DM in PTC tumors with widely invasive growth (HR 17.1; p<0.001), extra-thyroidal extension (HR 24.95; p<0.001), angioinvasion (HR 32.58; p=0.002), focal dedifferentiation (HR 19.57, p<0.001), and focal hobnail cell change (HR 8.67, p=0.042). There was additionally an increased risk of DM seen in male PTC patients (HR 5.5, p=0.03).The use of RAI was more common in patients with larger tumors, angioinvasion, and widely invasive disease. RAI was also used in the management of DM and 43% of patients with oncocytic PTC had RAI-avid metastatic disease. Patients with oncocytic PDTC had a higher rate of 5/10-year incidence of LRF and DM (21.4%/45.4%; 11.4%/40.4%, respectively). Patients with extra-thyroidal extension had an increased risk of DM (HR 5.52, p=0.023) as did those with angioinvasion. Of the patients with oncocytic PDTC who received RAI for the treatment of DM, 40% had RAI-avid disease., Conclusion: We present a large homogenous cohort of patients with oncocytic PTC and PDTC, with consistent pathologic reporting and definition. Patients with oncocytic PTC have excellent clinical outcomes and similar risk factors for recurrence as their non-oncocytic counterparts (angioinvasion, large tumor size, extra-thyroidal extension, and focal dedifferentiation). Compared with oncocytic PTCs, the adverse biology of oncocytic PDTCs is supported with increased frequency of DM and lower uptake of RAI., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lukovic, Petrovic, Liu, Armstrong, Brierley, Tsang, Pasternak, Gomez-Hernandez, Liu, Asa and Mete.)

Dose painting of hypoxic tumour sub-volumes using positron-emission tomography (PET) has been shown to improve tumour control in silico in several sites, predominantly head and neck and lung cancers. Pancreatic cancer presents a more stringent challenge, given its proximity to critical gastro-intestinal organs-at-risk (OARs), anatomic motion, and impediments to reliable PET hypoxia quantification. A radiobiological model was developed to estimate clonogen survival fraction (SF), using 18 F-fluoroazomycin arabinoside PET (FAZA PET) images from ten patients with unresectable pancreatic ductal adenocarcinoma to quantify oxygen enhancement effects. For each patient, four simulated five-fraction stereotactic body radiotherapy (SBRT) plans were generated: (1) a standard SBRT plan aiming to cover the planning target volume with 40 Gy, (2) dose painting plans delivering escalated doses to a maximum of three FAZA-avid hypoxic sub-volumes, (3) dose painting plans with simulated spacer separating the duodenum and pancreatic head, and (4), plans with integrated boosts to geometric contractions of the gross tumour volume (GTV). All plans saturated at least one OAR dose limit. SF was calculated for each plan and sensitivity of SF to simulated hypoxia quantification errors was evaluated. Dose painting resulted in a 55% reduction in SF as compared to standard SBRT; 78% with spacer. Integrated boosts to hypoxia-blind geometric contractions resulted in a 41% reduction in SF. The reduction in SF for dose-painting plans persisted for all hypoxia quantification parameters studied, including registration and rigid motion errors that resulted in shifts and rotations of the GTV and hypoxic sub-volumes by as much as 1 cm and 10 degrees. Although proximity to OARs ultimately limited dose escalation, with estimated SFs (∼10 -5 ) well above levels required to completely ablate a ∼10 cm 3 tumour, dose painting robustly reduced clonogen survival when accounting for expected treatment and imaging uncertainties and thus, may improve local response and associated morbidity., (© 2021 Institute of Physics and Engineering in Medicine.)

While adjuvant treatment of colon cancers that penetrate the serosa (T4) have been well-established, neoadjuvant strategies have yet to be formally evaluated. Our objective was to perform a scoping review of eligibility criteria, treatment regimens, and primary outcomes for neoadjuvant approaches to T4 colon cancer. A librarian-led, systematic search of MEDLINE, Embase, Cochrane Library, Web of Science, and CINAHL up to 11 February 2020 was performed. Primary research evaluating neoadjuvant treatment in T4 colon cancer were included. Screening and data abstraction were performed in duplicate; analyses were descriptive or thematic. A total of twenty studies were included, most of which were single-arm, single-center, and retrospective. The primary objectives of the literature to date has been to evaluate treatment feasibility, tumor response, disease-free survival, and overall survival in healthy patients. Conventional XELOX and FOLFOX chemotherapy were the most commonly administered interventions. Rationale for selecting a specific regimen and for treatment eligibility criteria were poorly documented across studies. The current literature on neoadjuvant strategies for T4 colon cancer is overrepresented by single-center, retrospective studies that evaluate treatment feasibility and efficacy in healthy patients. Future studies should prioritize evaluating clear selection criteria and rationale for specific neoadjuvant strategies. Validation of outcomes in multi-center, randomized trials for XELOX and FOLFOX have the most to contribute to the growing evidence for this poorly managed disease.