Molecular and Clinicopathologic Characterization of Mismatch Repair-Deficient Endometrial Carcinoma Not Related to MLH1 Promoter Hypermethylation.

Universal tumor screening in endometrial carcinoma (EC) is increasingly adopted to identify individuals at risk of Lynch syndrome (LS). These cases involve mismatch repair-deficient (MMRd) EC without MLH1 promoter hypermethylation (PHM). LS is confirmed through the identification of germline MMR pathogenic variants (PV). In cases where these are not detected, emerging evidence highlights the significance of double-somatic MMR gene alterations as a sporadic cause of MMRd, alongside POLE/POLD1 exonuclease domain (EDM) PV leading to secondary MMR PV. Our understanding of the incidence of different MMRd EC origins not related to MLH1-PHM, their associations with clinicopathologic characteristics, and the prognostic implications remains limited. In a combined analysis of the PORTEC-1, -2, and -3 trials (n = 1254), 84 MMRd EC not related to MLH1-PHM were identified that successfully underwent paired tumor-normal tissue next-generation sequencing of the MMR and POLE/POLD1 genes. Among these, 37% were LS associated (LS-MMRd EC), 38% were due to double-somatic hits (DS-MMRd EC), and 25% remained unexplained. LS-MMRd EC exhibited higher rates of MSH6 (52% vs 19%) or PMS2 loss (29% vs 3%) than DS-MMRd EC, and exclusively showed MMR-deficient gland foci. DS-MMRd EC had higher rates of combined MSH2/MSH6 loss (47% vs 16%), loss of >2 MMR proteins (16% vs 3%), and somatic POLE-EDM PV (25% vs 3%) than LS-MMRd EC. Clinicopathologic characteristics, including age at tumor onset and prognosis, did not differ among the various groups. Our study validates the use of paired tumor-normal next-generation sequencing to identify definitive sporadic causes in MMRd EC unrelated to MLH1-PHM. MMR immunohistochemistry and POLE-EDM mutation status can aid in the differentiation between LS-MMRd EC and DS-MMRd EC. These findings emphasize the need for integrating tumor sequencing into LS diagnostics, along with clear interpretation guidelines, to improve clinical management. Although not impacting prognosis, confirmation of DS-MMRd EC may release patients and relatives from burdensome LS surveillance.

Impact of Definitive Chemoradiation on Quality-of-Life Changes for Patients With Anal Cancer: Long-term Results of a Prospective Study.

BACKGROUND: Maintaining and improving quality of life (QOL) are important goals of anal cancer management. This disease is generally curable, with many long-term survivors. OBJECTIVE: Long-term QOL after chemoradiation for patients with anal cancer was evaluated. DESIGN: This was a prospective cohort study. SETTINGS: This study used data from a prospective study of patients with anal cancer who were treated with chemoradiation between 2008 and 2013. PATIENTS: Patients with anal cancer who were treated with image-guided intensity-modulated radiation therapy were included. INTERVENTIONS: English-speaking patients completed European Organization for Research and Treatment of Cancer cancer-specific (C30) and site-specific (CR29) QOL questionnaires at baseline, at end of radiation, at 3 and 6 months, and then annually. MAIN OUTCOMES MEASURES: Long-term QOL was evaluated clinically (a change in score of ≥10 points was considered clinically significant) and statistically (using repeated-measurement analysis) by comparing the subscale scores at 1, 2, and 3 years with baseline scores. Subanalysis compared patients who received a radiation dose of 45 to 54 Gy versus 63 Gy. RESULTS: Ninety-six patients were included (median follow-up of 56.5 months). The symptom and functional scales showed a clinically significant decline at the end of treatment with improvement by 3 months after treatment. There was a long-term statistically significant decline in dyspnea, body image, bowel embarrassment, fecal incontinence, and hair loss, and there was long-term statistically and clinically significant worsening of impotence. Higher radiation dose (63 Gy) was not associated with significantly worse QOL. LIMITATIONS: Limitations included single-institution, single-arm study design, and lack of dose reconstruction (ie, analyses were based on prescribed, rather than delivered, dose). CONCLUSIONS: Patients with anal cancer treated with chemoradiation reported recovery of overall QOL to baseline levels. Specific symptoms remained bothersome, emphasizing the need to address and manage the chemoradiation-induced symptoms, during treatment and in the long term. See Video Abstract at http://links.lww.com/DCR/B905. IMPACTO DE LA QUIMIORRADIACIN DEFINITIVA EN CAMBIOS EN LA CALIDAD DE VIDA DE LOS PACIENTES CON CNCER ANAL RESULTADOS A LARGO PLAZO DE UN ESTUDIO PROSPECTIVE: ANTECEDENTES:Mantener y mejorar la calidad de vida son objetivos importantes del tratamiento del cáncer anal, ya que esta enfermedad generalmente es curable, con muchos sobrevivientes a largo plazo.OBJETIVO:Se evaluó la calidad de vida a largo plazo después de la quimiorradiación en pacientes con cáncer anal.DISEÑO:Este fue un estudio de cohorte prospectivo.ENTORNO CLINICO:Utilizamos datos de un estudio prospectivo en pacientes con cáncer anal tratados con quimiorradiación entre 2008-2013.PACIENTES:Los pacientes con cáncer anal fueron tratados con radioterapia de intensidad modulada guiada por imágenes.INTERVENCIONES:Los pacientes de habla inglesa completaron los cuestionarios de calidad de vida específicos de cáncer (C30) y específicos del sitio (CR29) de la Organización Europea para la Investigación y el Tratamiento del Cáncer al inicio, al final de la radiación, 3 y 6 meses, y luego anualmente.PRINCIPALES MEDIDAS DE RESULTADOS:Se evaluó a largo plazo la calidad de vida clínicamente (un cambio en la puntuación de ≥10 puntos se consideraron clínicamente significativo) y estadísticamente (usando análisis de medición repetida) comparando las subescalas de puntuación al 1, 2, y 3 años. Con puntuaciones de referencia. El subanálisis comparó pacientes que recibieron 45-54 Gy versus 63 Gy.RESULTADOS:Se incluyeron un total de 96 pacientes (mediana de seguimiento: 56,5 meses). La mayoría de las escalas funcionales y de síntomas mostraron una disminución clínicamente significativa al final del tratamiento con una mejoría a los 3 meses posteriores al tratamiento. Hubo una disminución estadísticamente significativa a largo plazo en disnea, imagen corporal, vergüenza intestinal, incontinencia fecal y pérdida de cabello; y hubo un empeoramiento a largo plazo estadística y clínicamente significativo en impotencia. La dosis de radiación más alta (63 Gy) no se asoció con una calidad de vida significativamente peor.LIMITACIONES:Institución única, diseño de estudio de un solo brazo y falta de recomposición de la dosis (es decir, los análisis se basan en la dosis prescrita, en lugar de la administrada).CONCLUSIÓNES:Los pacientes con cáncer anal tratados con quimiorradiación reportaron una recuperación de la QOL en general a los niveles de base. Síntomas específicos siguieron siendo molestos, lo que enfatiza la necesidad de resolver y tartar los síntomas inducidos por la quimiorradiación no solo durante el tratamiento, sino a largo plazo. Consulte Video Resumen en http://links.lww.com/DCR/B905. (Traducción- Dr. Francisco M. Abarca-Rendon).

Postoperative management of vulvar cancer.

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.

Correction: Targeting CXCL12/CXCR4 and myeloid cells to improve the therapeutic ratio in patient-derived cervical cancer models treated with radio-chemotherapy.

Since the publication of this paper, the authors have reported that an incorrect version of Figure 1 was presented. The correct version of Figure 1 is provided.An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Targeting CXCL12/CXCR4 and myeloid cells to improve the therapeutic ratio in patient-derived cervical cancer models treated with radio-chemotherapy.

BACKGROUND: The CXCL12/CXCR4 chemokine pathway is involved in cervical cancer pathogenesis and radiation treatment (RT) response. We previously reported that radiochemotherapy (RTCT) and concurrent administration of the CXCR4 inhibitor plerixafor improved primary tumour response. The aims of this study were to determine optimal sequencing of RTCT and plerixafor, the mechanisms responsible for improved response and the effect of plerixafor on late intestinal toxicity. METHODS: Orthotopic cervical cancer xenografts were treated with RTCT (30 Gy in 2 Gy fractions and cisplatin) with or without concurrent, adjuvant or continuous plerixafor. The endpoints were growth delay and molecular and immune cell changes at the end of treatment. Late intestinal toxicity was assessed by histologic examination of the rectum 90 days after a single 20 Gy fraction. RESULTS: RTCT increased CXCL12/CXCR4 signalling and the intratumoral accumulation of myeloid cells; the addition of plerixafor mitigated these effects. All of the RTCT and plerixafor arms showed prolonged tumour growth delay compared to RTCT alone, with the adjuvant arm showing the greatest improvement. Plerixafor also reduced late intestinal toxicity. CONCLUSION: Adding Plerixafor to RTCT blunts treatment-induced increases in CXCL12/CXCR4 signalling, improves primary tumour response and reduces intestinal side effects. This combination warrants testing in future clinical trials.

Molecular characterization of gastric-type endocervical adenocarcinoma using next-generation sequencing.

Gastric-type endocervical adenocarcinoma is an uncommon aggressive type of endocervical adenocarcinoma that is not associated with human papillomavirus (HPV). At present, this tumor is classified under the spectrum of mucinous carcinoma of the uterine cervix. The clinical stage of gastric-type endocervical adenocarcinoma at the time of diagnosis is usually more advanced compared to the HPV-associated endocervical adenocarcinoma. Widespread dissemination to unusual sites, such as omentum, peritoneum, and distant organs, can be present. Owing to its rare incidence, diagnostic dilemmas, and aggressive behavior, clinical management can be challenging. In this study, we aimed to elucidate the molecular characteristics of these tumors by using next-generation sequencing (NGS) to assess 161 unique cancer-driver genes for single-nucleotide and copy-number variations, gene fusions, and insertions/deletions within gastric-type endocervical adenocarcinoma tumors. In total, 92 variants were detected across the 14 samples tested (7 variants on average per tumor). TP53 was the most recurrently mutated gene followed by MSH6, CDKN2A/B, POLE, SLX4, ARID1A, STK11, BRCA2, and MSH2. Abnormal p53 expression was observed in nine cases by immunohistochemistry, of which TP53 variants were present in four cases. MDM2 gene amplification in 12q15 (69202190-69233452) locus was seen in two cases that express normal p53 levels by immunohistochemistry. Four cases had STK11 null (frameshift/nonsense) variants, three of which were previously reported in Peutz-Jeghers syndrome. Overall, genes that are implicated in DNA damage, repair, cell cycle, Fanconi anemia pathway, and the PI3K-AKT signaling pathways were found to be mutated. Of note, genes known to have acquired and/or inherited variants in endometrial tumors were enriched within our cohort. In conclusion, our study shows the genetic heterogeneity of gastric-type endocervical adenocarcinoma with some potentially actionable molecular alterations, which highlights the importance of further molecular characterization for better identification of this rare entity, and hence better clinical management.

FIGO 2018 stage IB2 (2-4 cm) Cervical cancer treated with Neo-adjuvant chemotherapy followed by fertility Sparing Surgery (CONTESSA); Neo-Adjuvant Chemotherapy and Conservative Surgery in Cervical Cancer to Preserve Fertility (NEOCON-F). A PMHC, DGOG, GCIG/CCRN and multicenter study.

BACKGROUND: There are limited data regarding the optimal management of pre-menopausal women with cervical lesions measuring 2-4 cm who desire to preserve fertility. PRIMARY OBJECTIVES: To evaluate the feasibility of preserving fertility. STUDY HYPOTHESIS: Neo-adjuvant chemotherapy will be effective in reducing the size of the tumor and will enable fertility-sparing surgery without compromising oncologic outcome. TRIAL DESIGN: Pre-menopausal women diagnosed with stage International Federation of Gynecology and Obstetrics (FIGO) IB2, 2-4 cm cervical cancer who wish to preserve fertility will receive three cycles of platinum/paclitaxel chemotherapy. Patients with complete/partial response will undergo fertility-sparing surgery. Patients will be followed for 3 years to monitor outcome. Patients with suboptimal response (residual lesion ≥2 cm) will receive definitive radical hysterectomy and/or chemoradiation. MAJOR ELIGIBILITY CRITERIA: Patients must have histologically confirmed invasive cervical cancer, 2-4 cm lesion, by clinical examination and magnetic resonance imaging (MRI), negative node, and pre-menopausal (≤40 years old). Following three cycles of neo-adjuvant chemotherapy, patients must achieve a complete/partial response (residual lesion <2 cm). Exclusion criteria include high-risk histology, tumor extension to uterine corpus/isthmus (as per MRI), and suboptimal response/progression following neo-adjuvant chemotherapy. PRIMARY ENDPOINTS: Assess the rate of functional uterus defined as successful fertility-sparing surgery and no adjuvant therapy. SAMPLE SIZE: A total of 90 evaluable patients will be needed to complete the study. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Expected complete accrual in 2022 with presentation of results by 2025. TRIAL REGISTRATION NUMBER: Pending ethics submission.

Targeting the CXCL12/CXCR4 pathway and myeloid cells to improve radiation treatment of locally advanced cervical cancer.

Cervical cancer is the fourth most commonly diagnosed cancer and the fourth leading cause of cancer death in women worldwide. Approximately half of cervical cancer patients present with locally advanced disease, for which surgery is not an option. These cases are nonetheless potentially curable with radiotherapy and cisplatin chemotherapy. Unfortunately, some tumours are resistant to treatment, and lymph node and distant recurrences are major problems in patients with advanced disease at diagnosis. New targeted treatments that can overcome treatment resistance and reduce metastases are urgently needed. The CXCL12/CXCR4 chemokine pathway is ubiquitously expressed in many normal tissues and cancers, including cervical cancer. Emerging evidence indicates that it plays a central role in cervical cancer pathogenesis, malignant progression, the development of metastases and radiation treatment response. Pre-clinical studies of standard-of-care fractionated radiotherapy and concurrent weekly cisplatin plus the CXCR4 inhibitor Plerixafor (AMD3100) in patient-derived orthotopic cervical cancer xenografts have shown improved primary tumour response and reduced lymph node metastases with no increase in early or late side effects. These studies have pointed the way forward to future clinical trials of radiotherapy/cisplatin plus Plerixafor or other newly emerging CXCL12 or CXCR4 inhibitors in women with cervical cancer.

Association of Apparent Diffusion Coefficient with Disease Recurrence in Patients with Locally Advanced Cervical Cancer Treated with Radical Chemotherapy and Radiation Therapy.

PURPOSE: To investigate whether volumetrically derived apparent diffusion coefficient (ADC) from pretreatment diffusion-weighted (DW) magnetic resonance (MR) imaging is associated with disease recurrence in women with locally advanced cervical cancer treated with chemotherapy and radiation therapy. MATERIALS AND METHODS: An ethics board-approved, retrospective study was conducted in 85 women with stage IB-IVA cervical cancer treated with chemo- and radiation therapy in 2009-2013. All patients underwent MR imaging for staging, including T2-weighted and DW MR imaging series, by using a 1.5- or 3.0-T imager. The mean, median, 75th, 90th, and 95th percentile ADCs (ADCmean, ADC50, ADC75, ADC90, and ADC95, respectively) of all voxels that comprised each tumor were extracted and normalized to the mean urine ADC (nADCmean, nADC50, nADC75, nADC90, and nADC95, respectively) to reduce variability. The primary outcome was disease-free survival (DFS). Uni- and multivariable Cox regression analyses were used to evaluate the association of ADC parameters and relevant clinical variables with DFS. RESULTS: Of the 85 women included, 62 were free of disease at last follow-up. Median follow-up was 37 months (range, 5-68 months). Significant variables at univariable analysis included T2-weighted derived tumor diameter, para-aortic nodal involvement, advanced stage, ADC90 and ADC95, nADC75, nADC90, and nADC95. Normalized parameters were more highly associated (hazard ratio per 0.01 increase in normalized ADC, 0.91-0.94; P < .04). Because nADC75, nADC90, and nADC95 were highly correlated, only nADC95 (which had the lowest P value) was included in multivariable analysis. At multivariable analysis, absolute and normalized ADC95 remained associated with DFS (hazard ratio, 0.90-0.98; P < .05). CONCLUSION: The volumetric ADC95 may be a useful imaging metric to predict treatment failure in patients with locally advanced cervical cancer treated with chemo- and radiation therapy.

Brachytherapy in Gynecologic Cancers: Why Is It Underused?

Despite its established efficacy, brachytherapy is underused in the management of cervical and vaginal cancers in some parts of the world. Possible reasons for the underutilization of brachytherapy include the adoption of less invasive techniques, such as intensity-modulated radiotherapy; reimbursement policies favoring these techniques over brachytherapy; poor physician or patient access to brachytherapy; inadequate maintenance of brachytherapy skills among practicing radiation oncologists; transitioning to high-dose-rate (HDR) brachytherapy with increased time requirements; and insufficient training of radiation oncology residents.

Generalizability of deep learning in organ-at-risk segmentation: A transfer learning study in cervical brachytherapy.

PURPOSE: Deep learning can automate delineation in radiation therapy, reducing time and variability. Yet, its efficacy varies across different institutions, scanners, or settings, emphasizing the need for adaptable and robust models in clinical environments. Our study demonstrates the effectiveness of the transfer learning (TL) approach in enhancing the generalizability of deep learning models for auto-segmentation of organs-at-risk (OARs) in cervical brachytherapy. METHODS: A pre-trained model was developed using 120 scans with ring and tandem applicator on a 3T magnetic resonance (MR) scanner (RT3). Four OARs were segmented and evaluated. Segmentation performance was evaluated by Volumetric Dice Similarity Coefficient (vDSC), 95 % Hausdorff Distance (HD95), surface DSC, and Added Path Length (APL). The model was fine-tuned on three out-of-distribution target groups. Pre- and post-TL outcomes, and influence of number of fine-tuning scans, were compared. A model trained with one group (Single) and a model trained with all four groups (Mixed) were evaluated on both seen and unseen data distributions. RESULTS: TL enhanced segmentation accuracy across target groups, matching the pre-trained model's performance. The first five fine-tuning scans led to the most noticeable improvements, with performance plateauing with more data. TL outperformed training-from-scratch given the same training data. The Mixed model performed similarly to the Single model on RT3 scans but demonstrated superior performance on unseen data. CONCLUSIONS: TL can improve a model's generalizability for OAR segmentation in MR-guided cervical brachytherapy, requiring less fine-tuning data and reduced training time. These results provide a foundation for developing adaptable models to accommodate clinical settings.

Updated Trends in Cervical Cancer Brachytherapy Utilization and Disparities in the United States From 2004 to 2020.

PURPOSE: Lower brachytherapy utilization for cervical cancer patients is associated with decreased survival. This study examines more recent trends in brachytherapy utilization from 2004 to 2020 to assess any trend reversal after awareness increased regarding the importance of brachytherapy. METHODS AND MATERIALS: This study analyzed data from the National Cancer Database of patients with Federation of Gynecology and Obstetrics (FIGO) IB to IVA cervical cancer treated with radiation therapy between 2004 and 2020. To compare brachytherapy utilization over time, 2- to 3-year categories were created to account for potential variation seen in individual years. A multivariate log binomial regression with robust variance was used to estimate the incidence rate ratio (IRR) of brachytherapy utilization in each year category in reference to the 2004-2006 category. Additionally, risk factors for brachytherapy utilization were identified. RESULTS: Overall brachytherapy utilization for cervical cancer increased from 54.9% in 2004 to 75.7% in 2020. Compared with 2004 to 2006 when rates of utilization totaled 55.2%, brachytherapy utilization significantly increased to 63.4% in 2011 to 2014 (IRR, 1.15; 95% CI, 1.11-1.19), 66.0% in 2015 to 2017 (1.20 [1.16-1.23]), and 76.0% in 2018 to 2020 (1.38 [1.34-1.42]). Sociodemographic factors associated with lower brachytherapy utilization included Black race (0.94 [0.92-0.97]), Hispanic ethnicity (0.92 [0.90-0.95]), and age >59 years (age ≥60-69: 0.96 [0.94-0.98]; age ≥70-79: 0.89 [0.87-0.92]; age ≥80: 0.73 [0.69-0.77]). Positive predictors of brachytherapy utilization included having insurance (IRR, 1.11; 95% CI, 1.07-1.14). CONCLUSIONS: In patients with FIGO IB-IVA cervical cancer treated with radiation therapy from 2004 to 2020, brachytherapy utilization has increased during the past decade. These results are encouraging given the known benefit to cause-specific survival and overall survival provided by brachytherapy treatment and indicate a reversal in the trend of declining brachytherapy noted previously. Concerns related to disparities by race, ethnicity, and insurance status require further interventions.

Updated Trends in the Utilization of Brachytherapy in Cervical Cancer in the United States: A Surveillance, Epidemiology, and End-Results Study.

PURPOSE: Our previous Surveillance, Epidemiology, and End Results (SEER) study revealed a concerning decline in brachytherapy utilization in the United States between 1988 and 2009. This study evaluates recent trends in brachytherapy utilization in cervical cancer and identifies factors and survival benefit associated with the use of brachytherapy treatment. METHODS AND MATERIALS: Using SEER data, 8500 patients with International Federation of Gynecologists and Obstetricians 2009 stage IB2-IVA cervical cancer treated with external beam radiation therapy (EBRT) between 2000 and 2020 were identified. Logistic regression analysis was performed on potential factors associated with brachytherapy use: age, marital status, race, ethnicity, income, metropolitan status, year of diagnosis, SEER region, histology, grade, and stage. To adjust for differences between patients who received brachytherapy and those who did not, propensity-score matching was used. Multivariable Cox regression analysis assessed the association of brachytherapy use with cervical cancer-specific mortality (CSM) and all-cause mortality (ACM) in the matched cohort. RESULTS: Sixty-four percent of the 8500 women received brachytherapy in combination with EBRT; 36% received EBRT alone. The brachytherapy utilization rate declined sharply in 2003/2004 (lowest rate 44% in 2003) and then gradually improved especially in 2018 to 2020 (76%). Factors associated with higher odds of brachytherapy use included younger age, married (vs single), later years of diagnosis, certain SEER regions, and earlier stage. In the propensity-score matched cohort, brachytherapy treatment was associated with lower 4-year cumulative incidence of cancer death (32.1% vs 43.4%; P < .001) and better overall survival (64.0% vs 51.4%; P < .001). Brachytherapy treatment was independently associated with lower CSM (hazard ratio, 0.70; 95% CI, 0.64-0.76; P < .001) and ACM (hazard ratio, 0.72; 95% CI, 0.67-0.78; P < .001). CONCLUSIONS: Brachytherapy utilization among SEER regions has improved since 2004 in patients with stage IB2-IVA cervical cancer. Brachytherapy use remains independently associated with significantly lower CSM and ACM and is an essential component of treatment for patients with locally advanced cervical cancer.

Review of brachytherapy clinical trials: a cross-sectional analysis of ClinicalTrials.gov.

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.

An Immune Gene Expression Risk Score for Distant Metastases after Radiotherapy for Cervical Cancer.

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.

Utilization and Impact of a Radiation Nursing Clinic to Address Acute Care Needs for Patients with Gynecologic Cancers.

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.

Clinical outcomes of three vs four fractions of MRI-guided brachytherapy in cervical cancer.

PURPOSE: MRI-guided brachytherapy (MRgBT) 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 FIGO 2018 stage IB-IVA cervical cancer treated with definitive chemoradiation between April 2014 - 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 (GU) and vaginal toxicity were estimated using the cumulative incidence function with death as a competing risk and compared using the 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 vs 28 Gy/4 Fr group in 3-year DFS (77% vs 68%, P = 0.21), 3-year cumulative incidence of LF (5% vs 7%, P = 0.57), DF (22% vs 25%, P = 0.86), G2+ GI toxicity (11% vs 20%, P = 0.13), or G2+ vaginal toxicity (14% vs 17%, P = 0.48), respectively. The 3-year cumulative G2+ urinary toxicity rate was lower in the 24 Gy/3 Fr group (9% vs 23%, P = 0.03). CONCLUSION: Cervical cancer patients treated with 24 Gy/3 Fr had similar DFS, LF, DF, GI and vaginal toxicity rates, and a trend towards lower G2+ urinary toxicity rate compared to 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.

Clinical Validation of Human Papilloma Virus Circulating Tumor DNA for Early Detection of Residual Disease After Chemoradiation in Cervical Cancer.

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.

A two-center experience: The impact of COVID-19 on two brachytherapy programs in Ontario - virtual care, service suspension and radiation therapy workflow.

INTRODUCTION: Most brachytherapy (BT) procedures require general anesthesia and are therefore considered aerosol generating medical procedures (AGMPs). The COVID-19 pandemic impacted BT as services were prioritized by balancing the harm associated with COVID-19 infection versus the effect of delay of potentially curative treatment. This article summarizes the impact of the pandemic on BT programs in two cancer centers in a Canadian province. METHODS: As part of a quality assurance project, a retrospective study was conducted for the first five months of the pandemic (March 1 to July 31, 2020). Chart review and COVID-19 related mitigation strategies were identified by BT Clinical Specialist Radiation Therapists (bCSRT) in each center using electronic medical records, departmental reports, policies and procedures. RESULTS: Impact included start of virtual care (VC), shortened fractionation, suspension of services and workflow changes.  Both centers implemented VC strategies to reduce clinic visits: "same-day size and treat" strategy for post-operative endometrial cancer patients and virtual patient education for all patients. BT services that were suspended were low-dose-rate and high-dose-rate (HDR) prostate treatments (Center 1), lung and esophagus HDR treatments (Center 2).  Workflow changes that affected staff and patients in both centers included COVID-19 screening and the use of personal protective equipment. The centers were marginally different in workflow adjustments for AGMP procedures.  Those considered high-risk AGMP and low-risk cancer were suspended temporarily with alternate treatment strategies sought for some patients. Others had temporizing treatment such as androgen deprivation therapy to facilitate oncological safe deferral of procedures. CONCLUSION: Both BT programs delivered treatment to most patients with minimal delays and cancellations, where feasible. Some of the pandemic workflow changes continued to the current state of the pandemic. Long-term follow-up is needed to assess the impact of COVID-19 and treatment interruptions on oncologic outcomes.