Clinical research in endometrial cancer: consensus recommendations from the Gynecologic Cancer InterGroup.

The Gynecologic Cancer InterGroup (GCIG) Endometrial Cancer Consensus Conference on Clinical Research (ECCC) was held in Incheon, South Korea, Nov 2-3, 2023. The aims were to develop consensus statements for future trials in endometrial cancer to achieve harmonisation on design elements, select important questions, and identify unmet needs. All 33 GCIG member groups participated in the development, refinement, and finalisation of 18 statements within four topic groups, addressing adjuvant treatment in high-risk disease; treatment for metastatic and recurrent disease; trial designs for rare endometrial cancer subgroups and special circumstances; and specific methodology and adaptation for trials in low-resource settings. In addition, eight areas of unmet need were identified. This was the first GCIG Consensus Conference to include patient advocates and an expert on inclusion, diversity, equity, and access to take part in all aspects of the process and output. Four early-career investigators were also selected for participation, ensuring that they represented different GCIG member groups and regions. Unanimous consensus was obtained for 16 of the 18 statements, with 97% concordance for the remaining two. Using the described methodology from previous Ovarian Cancer Consensus Conferences, this conference did not require even one minority statement. The high acceptance rate following active involvement in the preparation, discussion, and refinement of the statements by all representatives confirmed the consensus progress within a global academic setting, and the expectation that the ECCC will lead to greater harmonisation, actualisation, inclusion, and resolution of unmet needs in clinical research for individuals living with and beyond endometrial cancer worldwide.

Bladder function after conservative surgery and high-dose rate brachytherapy for bladder-prostate rhabdomyosarcoma.

BACKGROUND: Conservative surgery (CS) brachytherapy (BT) techniques for local therapy in bladder-prostate rhabdomyosarcoma (BP-RMS) seek to retain organ function. We report bladder function after high-dose rate (HDR) BT combined with targeted CS for any vesical component of BP-RMS. PROCEDURE: Prospective cohort of all BP-RMS patients between 2014 and 2019 receiving HDR-BT (iridium-192, 27.5 Gy in five fractions) with/without percutaneous endoscopic polypectomy (PEP) or partial cystectomy (PC). Functional assessment included frequency-volume chart, voided volumes, post-void residual, flow studies, continence status and ultrasound scanning; abnormalities triggered video urodynamics. RESULTS: Thirteen patients (10 male), aged 9 months to 4 years (median 23 months), presented with localised fusion-negative embryonal BP-RMS measuring 23-140 mm (median 43 mm) in cranio-caudal extent. After induction chemotherapy, local treatment consisted of PC+BT in three, PEP+BT in four and BT alone in six. At a median 3.5 years (range 21 months to 7 years) follow-up, all were alive without relapse. At a median age of 6 years (4-9 years), the median bladder capacity was 86% (47%-144%) of that expected for age, including 75% (74%-114%) after PC. Radiation dose to the bladder was associated with urinary urgency, but not bladder capacity or nocturnal enuresis. Complications occurred in two: one urethral stricture and one vesical decompensation in a patient with pre-existing high-grade vesico-ureteric reflux (VUR). The remaining patients were dry by day; five with anticholinergic medication for urinary urgency. Three patients are enuretic. CONCLUSIONS: Day-time dryness at a median 3.5 years after CS-HDR-BT was achieved in 92%, with 85% voiding urethrally, and 62% attaining day-and-night continence aged 4-9 years. We report reduced open surgery with minimally invasive percutaneous surgery, with HDR-BT or BT alone being suitable for many.

Stratified follow-up for endometrial cancer: a move to more personalized cancer care.

OBJECTIVE: Hospital based follow-up has been the standard of care for endometrial cancer. Patient initiated follow-up is a useful adjunct for lower risk cancers. The purpose of this study was to evaluate outcomes of endometrial cancer patients after stratification into risk groupings, with particular attention to salvageable relapses. METHODS: All patients treated surgically for International Federation of Gynecology and Obstetrics (FIGO) stage I-IVA endometrial cancer of all histological subtypes, from January 2009 until March 2019, were analyzed. Patient and tumor characteristics, treatment details, relapse, death, and last follow-up dates were collected. Site of relapse, presence of symptoms, and whether relapses were salvageable were also identified. The European Society of Medical Oncology-European Society of Gynecological Oncology 2020 risk stratification was assigned, and relapse free and overall survival were estimated. RESULTS: 900 patients met the eligibility criteria. Median age was 66 years (range 28-96) and follow-up duration was 35 months (interquartile range 19-57). In total, 16% (n=144) of patients relapsed, 1.3% (n=12) from the low risk group, 3.9% (n=35) from the intermediate risk group, 2.2% (n=20) from the high-intermediate risk group, and 8.7% (n=77) from the high risk group. Salvageable relapses were less frequent at 2% (n=18), of which 33% (n=6) were from the low risk group, 22% (n=4) from the intermediate risk group, 11% (n=2) from the high-intermediate risk group, and 33% (n=6) from the high risk group. There were only three asymptomatic relapses in the low risk patients, accounting for 0.33% of the entire cohort. CONCLUSIONS: Relapses were infrequent and most presented with symptoms; prognosis after relapse remains favorable. Overall salvageable relapses were infrequent and cannot justify intensive hospital based follow-up. Use of patient initiated follow-up is therefore appropriate, as per the British Gynaecological Cancer Society's guidelines, for all risk groupings.

Enumeration and Molecular Characterisation of Circulating Tumour Cells in Endometrial Cancer.

BACKGROUND: This is a feasibility study to determine whether circulating tumour cells (CTCs) are detectable and suitable for molecular profiling in advanced endometrial cancer (aEC). METHOD: Between October 2012 and February 2014, 30 patients with aEC had baseline and up to 3 follow-up samples. CTCs and stathmin expression were evaluated using the CellSearch platform. Epithelial cell adhesion molecule (EpCAM) and stathmin immunohistochemistry were performed on FFPE tumour tissue. RESULTS: Eighteen from 30 (60%) patients had detectable CTCs during study [1 CTC (n = 7), 2 (n = 4), 3 (n = 1), 4 (n = 2), 7 (n = 1), 8 (n = 1), 22 (n = 1), 172 (n = 1) in 7.5 ml blood]. Ten from 18 patients had between 50 and 100% of detectable CTCs that were stathmin positive. More CTC-positive than CTC-negative patients had non-endometrioid versus endometrioid histology, tumour size ≥5 versus <5 cm, higher-stage disease and worse survival [hazard ratio 3.3, p > 0.05, 95% confidence interval 0.7-16.2]. Twenty-one tumour blocks were tested for EpCAM and stathmin immunohistochemistry (IHC). Stathmin tumour immunostaining scores (TIS) on IHC were higher in CTC-positive patients. CONCLUSION: CTC enumeration and molecular profiling with stathmin on the CellSearch platform is feasible in aEC. Stathmin TIS on IHC, a known prognostic marker in EC, was associated with CTC positivity.

Radiotherapy induced ureteric stenosis in locally advanced cervical cancer: A review of current evidence.

BACKGROUND: Concurrent chemo-radiation followed by high dose rate brachytherapy is the standard of care for locally advanced cervical cancer. The proximity of the ureters to the tumor volume risks ureteric stenosis. Here we outline the current understanding of radiotherapy induced ureteric stenosis in patients treated for cervical cancer, focusing on the incidence, risk factors, clinical consequences, and management. METHODS: Searches on EMBASE, PubMed, Science Direct, and Google Scholar were performed for publications reporting on radiotherapy, cervix cancer and ureteric stenosis. Multi and single center, prospective/retrospective, cohort, and cross-sectional studies were included. RESULTS: This narrative review identified key issues relevant to radiation induced ureteric stenosis in cervical cancer in the literature. Thirteen studies were evaluated, identifying crude and actuarial rates of ureteric stenosis of 0.3-13.5% and 1.5-4.4% (at 5 years) respectively. The risk of ureteric stenosis is highest in the first 5 years after radiotherapy but continues to occur at a rate of 0.15% per year. Risk factors including advanced FIGO stage, tumor size >5 cm and baseline hydronephrosis increase the incidence of ureteric stenosis. EQD2 doses of ≥ 77Gy were significantly associated with ≥grade 3 ureteric morbidity. The majority of patients were managed with nephrostomy +/- ureteric stent insertion, with some requiring ureteral reimplantation, urinary diversion or nephrectomy. CONCLUSIONS: This review has identified multiple considerations, highlighting the need to identify patients highest at risk of ureteric stenosis. There is also a need to recognize ureters as organs at risk, record dose exposure, and apply dose constraints, all of which set the landscape for allowing dose optimization.

Ureter dose optimization during image guided brachytherapy for cervical cancer.

PURPOSE: In the era of image guided radiotherapy and interstitial needle use, radiation dose to ureters can cause toxicity. METHODS: A retrospective analysis of 106 patients with cervical cancer was performed to investigate ureter dose in brachytherapy patients. Re-optimization of brachytherapy treatment plans in 20 MRI planned patients was performed to reduce ureter dose whilst maintaining HRCTV D90 and OAR dose constraints. RESULTS: A total of 212 ureters were contoured and dose recorded. The crude incidence of ureteric stenosis was 6.6%. Ureter dose for all patients was 75.8 Gy and 74.4 Gy on the right and left respectively. A cohort of 20 MRI planned patients were reoptimized to reduce dose to ureters. Ureter dose was reduced from 91.1 Gy to 84.4 Gy and 73.9 Gy to 67.8 Gy on the right and left side respectively. A subgroup of patients with HRCTV D90 ≥84.3 Gy prior to reoptimisation saw a greater reduction in ureter dose of 13.3%. These were smaller tumours with better HRCTV coverage at the outset. Larger tumours with poorer HRCTV coverage (<84.3 Gy) saw a smaller reduction in ureter dose of 6.4%. Organ at risk dose to rectum, sigmoid and bladder were also significantly reduced. CONCLUSIONS: Patients treated with MRI guided brachytherapy and interstitial needles are at risk of ureteric stenosis. Contouring ureters and setting dose constraints should be considered to reduce ureteric dose while tracking HRCTV coverage.

Feasibility of ureter delineation and dose recording in the assessment of ureteric stenosis during brachytherapy for cervical cancer.

INTRODUCTION: Ureteric stenosis is the commonest complication to affect the ureter after radiotherapy for cervical cancer; despite this ureters are not contoured as organs at risk and limited dosimetric data exist for them. METHODS/MATERIALS: Bilateral ureters were retrospectively delineated on brachytherapy planning imaging for patients treated for cervical cancer between 2014 and 2019. Ureteric stenosis toxicity data and D2cc, D1cc, D0.1cc of the right and left ureter were collated. Ureter V80, V100, V120, and V150 were also analyzed. Univariate analysis was performed to identify predictors of high ureter dose and ureteric stenosis. RESULTS: 95 patients were identified and 190 ureters contoured on brachytherapy planning imaging, with a median follow-up duration of 24 months (IQR23.7). 4.2% (4) of patients had grade 3/4 ureteric stenosis. Mean ureter D0.1cc, D1.0cc and D2.0cc on the right were 80.4Gy (±28.9), 56.2Gy (±7.2) and 52.8Gy (±7.6), and on the left were 75.6Gy (±14.6), 54.3Gy (±5.5) and 52.7Gy (±5.5) respectively. Significantly higher ureter doses were present in patients with baseline hydronephrosis (p < 0.002) and interstitial needle use (p = 0.047). Ureters affected by ureteric stenosis received D0.1cc doses between 60-98Gy. 10-14% received point doses in excess of 150% of the prescribed dose (7Gy) with no resulting ureteric stenosis. No significant difference in D0.1cc was found in patients with or without ureteric stenosis. CONCLUSIONS: It is feasible to accurately contour ureters on brachytherapy planning imaging. Baseline hydronephrosis and interstitial needle use contribute to higher ureter doses. No association between dose and ureteric stenosis was found.

British Gynaecological Cancer Society (BGCS) cervical cancer guidelines: Recommendations for practice.

Cervix cancer in many countries is declining and screening programmes and immunisation will reduce the incidence in the next few decades. This guideline attempts to cover management of invasive disease reflecting diagnosis and imaging including new imaging and sentinel lymph node biopsies. Smaller volume disease is usually managed surgically whereas advanced disease is treated with (chemo)- radiation. It also includes discussion of fertility sparing procedures. Practices are changing frequently for all aspects of care usually in attempts to reduce complications and improve quality of life. The management of advanced disease is treated by chemotherapy and the use of newer agents is also discussed. Other sections discuss specialist situations such as cancer in pregnancy, rare cervical tumours, late effects and supportive measures and fertility preserving approaches.

Understanding the impact of pelvic organ motion on dose delivered to target volumes during IMRT for cervical cancer.

BACKGROUND: Advanced radiotherapy techniques reduce normal tissue dose by conforming closely to target volumes. In cervical cancer radiotherapy, organ filling affects clinical target volume (CTV; cervix, uterus) position. This study estimates the dosimetric effect of this primary CTV position variation during chemoradiation. METHODS/MATERIALS: Twice weekly cone-beam computed tomography (CBCT) images of ten patients undergoing cervical chemoradiation were retrospectively analysed. Primary CTV, bladder and rectum were delineated. RapidArc plans were created using 10-15mm CTV-PTV margins and dose delivered to CTV based on each CBCT position was calculated using a novel vector approach. Dose delivered along the central uterine, mid-uterus and cervix vectors were analysed as well as dose delivered to points at uterine tip, anterior mid-uterus and anterior cervix. Additional RapidArc plans were created for large planning bladder volume cases using the CTV acquired with bladder volume at 150-300cc. RESULTS: 105 scans for 10 patients were analysed. Vector analysis revealed CTV underdosing in certain cases. Below 95% average vector coverage was found for all three vectors in 2 cases and one vector in 1 case. Volumetric analysis revealed D99<95% in 48% of fractions. Patients with large planning bladder volumes (>300cc) demonstrated the largest variation. Replanning improved this coverage. The anterior mid-uterus point was least well-covered; median 98.7% dose, reducing to 91.4% in cases with large planning bladder volumes. Again, replanning significantly improved this. D99>95% was maintained in 93% of fractions when bladder volume was 50cc below to 150cc above planning volume compared to 24% of fractions if bladder volume was outside this range. Similarly, D95>95% was 100% versus 84%. CONCLUSION: Organ position variation detrimentally affected dose delivered to CTV including cervix. Large planning bladder volumes (>300cc) led to more variation. We recommend bladder volumes of 150-300cc at planning and a range of 50cc below to 150cc above planning for treatment.

The dosimetric impact of target volume delineation variation for cervical cancer radiotherapy.

BACKGROUND: Cervical cancer inter-observer delineation variation has been demonstrated. This article addresses its dosimetric impact. METHODS: 21 centres outlined two INTERLACE trial quality assurance test cases. A gold standard clinical target volume (GSCTV) was created from a consensus and STAPLE outline. RapidArc plans were created for all centres' planning target volumes (PTVs; PTV1+2). Gold standard PTVs (GSPTVs) were created for each plan by applying each centre's CTV-PTV margins to GSCTV. DVH parameters including D95% and Dmean for each PTV1+2 and GSPTV were compared, representing planned versus GSPTV delivered dose. PTV1+2 and GSPTV V95% was also calculated. RESULTS: Reviewing all parameters, no plans achieved acceptable GSPTV coverage. GSPTV V95%⩾95% was not achieved for any plan. GSPTV V95%<90% in 15/21 (case 1) and 14/22 (case 2) and <80% in 2 plans from both cases. GSPTV V95% is on average 10-15% lower than planned and GSPTV D95% is 10-20% lower than planned. Most common GSCTV anatomical areas not receiving 95% dose were vagina, obturator and external iliac nodes and, in case 1, the superior nodal aspect. CONCLUSION: Cervical cancer CTV delineation variation leads to significant reductions in dose delivered to GSPTV. This highlights the ongoing importance of standardising delineation in the IMRT era.

Improving target volume delineation in intact cervical carcinoma: Literature review and step-by-step pictorial atlas to aid contouring.

PURPOSE: Accurate delineation of target volume and normal tissue is critical for intensity modulated radiation therapy (IMRT) use in cervical cancer. Phase III Multicentre Trial of Weekly Induction Chemotherapy Followed by Standard Chemoradiation versus Standard Chemoradiation Alone in Patients With Locally Advanced Cervical Cancer (INTERLACE) radiation therapy quality assurance (RTQA) has highlighted significant interobserver delineation variation. Prescriptive guidelines reduce interobserver variation in other cancers. METHODS AND MATERIALS: A literature search using PubMed/Medline database of guidelines for target anatomy delineation in cervical cancer was undertaken. Differences in practice in these publications and INTERLACE trial RTQA were identified. Consensus best practice delineation was derived and a pictorial atlas produced. The proportion of outlines complying with protocol in test and real-time cases was compared before and after atlas implementation within the INTERLACE RTQA pack. RESULTS: Seven key papers were reviewed. Eleven areas of variation were identified. These included the definition and editing of bowel, definition of the femur, vagina, parametria, inferior and superior nodal borders, nodal clinical target volume (CTV) editing, para-aortic nodal CTV definition, and the margin to be used around enlarged nodes. The average proportion of outlines (of 4; primary CTV, nodal CTV, bladder, rectum) complying with protocol in test and real-time cases improved from 1.8 to 2.7 (difference, 0.9; 95% confidence interval, 0.3-1.5; P = .003) with atlas use. CONCLUSION: Differences exist in the published literature and clinical practice. This pictorial atlas reflects consensus recommendations and is now available to INTERLACE participating centers. Atlas use has reduced interobserver delineation variation in this trial setting.

Variability of clinical target volume delineation for definitive radiotherapy in cervix cancer.

BACKGROUND/PURPOSE: Accurate target volume delineation is essential for radiotherapy delivery, yet significant intra and inter-observer variability is documented. We analysed the variation in cervical cancer clinical target volume (CTV) delineation. MATERIALS/METHODS: All INTERLACE participating centres completed two RTQA outlining exercises. The Trial Management Group created a consensus outline. A separate STAPLE algorithm outline was created. Using these two outlines an optimised gold standard was generated. Volume, maximum distance from DICOM centre in all directions, and Jaccard Conformity Index (JCI) were calculated and compared for each centres' outlines. Anatomical areas included within CTV were recorded to detect systematic differences. RESULTS: 21 outlines were compared for case 1 and 22 for case 2. Volume ranged from 340 cc to 676 cc (case 1) and from 458 cc to 806 cc (case 2). A maximum 4 cm difference between outlines was observed in one direction. JCI ranged from 0.51 to 0.81 (case 1) and 0.57 to 0.81 (case 2). Variation in anatomical areas included in CTV exists between the two cases and between centres. CONCLUSIONS: Significant inter-observer variation in cervical cancer delineation has been demonstrated. Ongoing efforts are needed to ensure inter-observer consistency through education, guidelines and multi-centre collaboration.

Validation of clinical acceptability of an atlas-based segmentation algorithm for the delineation of organs at risk in head and neck cancer.

PURPOSE: The aim of this study was to assess whether clinically acceptable segmentations of organs at risk (OARs) in head and neck cancer can be obtained automatically and efficiently using the novel "similarity and truth estimation for propagated segmentations" (STEPS) compared to the traditional "simultaneous truth and performance level estimation" (STAPLE) algorithm. METHODS: First, 6 OARs were contoured by 2 radiation oncologists in a dataset of 100 patients with head and neck cancer on planning computed tomography images. Each image in the dataset was then automatically segmented with STAPLE and STEPS using those manual contours. Dice similarity coefficient (DSC) was then used to compare the accuracy of these automatic methods. Second, in a blind experiment, three separate and distinct trained physicians graded manual and automatic segmentations into one of the following three grades: clinically acceptable as determined by universal delineation guidelines (grade A), reasonably acceptable for clinical practice upon manual editing (grade B), and not acceptable (grade C). Finally, STEPS segmentations graded B were selected and one of the physicians manually edited them to grade A. Editing time was recorded. RESULTS: Significant improvements in DSC can be seen when using the STEPS algorithm on large structures such as the brainstem, spinal canal, and left/right parotid compared to the STAPLE algorithm (all p < 0.001). In addition, across all three trained physicians, manual and STEPS segmentation grades were not significantly different for the brainstem, spinal canal, parotid (right/left), and optic chiasm (all p > 0.100). In contrast, STEPS segmentation grades were lower for the eyes (p < 0.001). Across all OARs and all physicians, STEPS produced segmentations graded as well as manual contouring at a rate of 83%, giving a lower bound on this rate of 80% with 95% confidence. Reduction in manual interaction time was on average 61% and 93% when automatic segmentations did and did not, respectively, require manual editing. CONCLUSIONS: The STEPS algorithm showed better performance than the STAPLE algorithm in segmenting OARs for radiotherapy of the head and neck. It can automatically produce clinically acceptable segmentation of OARs, with results as relevant as manual contouring for the brainstem, spinal canal, the parotids (left/right), and optic chiasm. A substantial reduction in manual labor was achieved when using STEPS even when manual editing was necessary.

Solitary atrial metastases: a rare clinical challenge.

This case describes a 55-year-old lady presenting with lethargy, migraines and a cardiac mass on a background history of breast cancer. She had been treated initially with a mastectomy, axillary node clearance, reconstruction and hormone manipulation followed by chemotherapy and high dose radiotherapy for an isolated supraclavicular metastases. She was disease free for 5 years when she complained of lethargy and migraines. A CT confirmed an isolated cardiac lesion, confirmed on echocardiogram A percutaneous atrial biopsy revealed an atrial metastases from breast carcinoma. She was treated with chemotherapy achieving a good response but was still deemed inoperable after treatment. She currently is receiving letrozole.

Are statins being underdosed in clinical practice? Data from TACTICS-TIMI 18.

BACKGROUND: Although clinical trials in the 1990s have found significant reductions in cardiovascular events with fixed doses of statins, specifically 40 mg of simvastatin or pravastatin, in clinical practice, treatment is usually initiated at lower doses. It is not clear, however, if the doses are then titrated upward after the initial dosing. METHODS: We examined the dosing for patients receiving statins at the time of entry and at 6 months follow-up in the Treat angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis In Myocardial Infarction (TACTICS-TIMI) 18 trial, and their relationship to the measured low-density lipoprotein cholesterol (LDL-C) on admission. RESULTS: In the TACTICS-TIMI 18 trial, 727 of 2220 (33%) patients with unstable angina and non-ST elevation MI were on statins at study entry, of whom 371 had both LDL-C measurements and statin dose recorded on admission: 132 (36%) received atorvastatin, 126 (34%) simvastatin, 58 (16%) pravastatin, and the remainder lovastatin, fluvastatin, or cerivastatin. Only 18% and 38% of patients were treated with the 40-mg dose of simvastatin or pravastatin, respectively. Only 3 patients on atorvastatin were treated with 80 mg. At entry, 46% of these patients had LDL-C < or =100 mg/dL (and even among all patients with either prior MI, CABG, PTCA, or diabetes, only 33% had LDL-C < or =100 mg/dL, increasing modestly to 48% for those also on a statin). At 6 months after the UA/NSTEMI event, although more patients (1113, 50%) were on statins, the doses used were not higher then those used at baseline. CONCLUSION: We observed that the doses of statins in clinical practice were usually lower than those used in the clinical efficacy trials. Furthermore, LDL-C of < or =100 mg/dL was achieved in fewer then 50% of acute coronary syndrome patients receiving statins at time of presentation. These data suggest that, in addition to previously documented underutilization of statins in clinical practice, there is also underdosing of this important class of drugs.