Clinical Oncology

Regional Control and Chemoradiotherapy Dose Response for Clinically Involved Lymph Nodes in Patients with Locally Advanced Endometrial Cancers Who are Not Candidates for Upfront Surgical Staging Extrafascial Hysterectomy

There are limited data in endometrial cancer for nodal control and appropriate treatment volume for non-surgically resected nodes treated with chemoradiotherapy (CRT) for patients who are not candidates for upfront extrafascial hysterectomy. Patients (n = 105) with clinical stage ≥ II endometrial cancer who were not candidates for upfront extrafascial hysterectomy treated with preoperative CRT were retrospectively reviewed. CRT included pelvic nodes to the common iliac for node-negative disease and para-aortic nodes to the renal vessel for any node-positive disease. Involved nodes most commonly received a boost of 55 Gy in 25 fractions ± additional 4-6 Gy sequential boost for nodes >2 cm. Of the included 95 patients, 55 patients were node positive, with a total of 300 positive nodes. At a median follow-up of 25 months (interquartile range 9-46), the 3-year regional control was 91%. The 3-year involved nodal control rate was 96%. Involved nodal control was significantly higher in type I histology, nodes 55 Gy, P = 0.03). The 3-year para-aortic failure rate for node negative patients treated with pelvis-only CRT was significantly higher with positron emission tomography/computed tomography (PET/CT) versus computed tomography (CT)-based staging (0% versus 20%). This is the largest study examining regional control rates of involved lymph nodes with CRT for patients who were not candidates for upfront extrafascial hysterectomy. Nodal failure was low following CRT and dose ≥55 Gy in 25 fractions seems to be adequate for involved nodes.

Progression-Free Survival Prediction for Locally Advanced Cervical Cancer After Chemoradiotherapy With MRI-based Radiomics

A significant proportion of locally advanced cervical cancer (LACC) patients experience disease progression post chemoradiotherapy (CRT). Currently existing clinical variables are suboptimal predictors of treatment response. This study reported a radiomics-based model leveraging information extracted from magnetic resonance (MR) T2-weighted image (T2WI) to predict the progression-free survival (PFS) for LACC following CRT. Radiomics features were extracted from pre-treatment MR T2WI in 105 LACC patients. Following pre-feature selection and a step forward feature selection method, an optimal feature set was determined with a Cox proportional hazard (CPH) model. The PFS predictions were generated through a radiomics-clinical combined model utilized five repeated nested 5-fold cross-validation (5-fold CV). Disease progression risk was stratified into high- and low-risk groups based on the predicted PFS and assessed by Kaplan-Meier analysis. The radiomics texture feature extracted from MR T2WI significantly predict PFS in LACC after CRT. In comparison with the model using clinical variables alone, the radiomics-clinical combined model achieves significantly improved performance in testing patient cohort, achieving higher C-index (0.748 vs 0.655) and area under the curve (0.798 vs 0.660 for 2-year PFS). Meanwhile, the proposed method significantly differentiated the high- and low-risk patients groups for disease progression (P < 0.001). An MR T2WI-based radiomics and clinical combined model provided improved prognostic capabilities in predicting the PFS for LACC patients treated with CRT, outperforming a model using clinical variables alone. The incorporation of MR T2WI-based radiomics is promising in assisting in personalized management in LACC, indicating the potential of MR T2WI radiomics as imaging biomarker.

Multi-center Dose Prediction Using Attention-aware Deep learning Algorithm Based on Transformers for Cervical Cancer Radiotherapy

Accurate dose delivery is crucial for cervical cancer volumetric modulated arc therapy (VMAT). We aimed to develop a robust deep-learning (DL) algorithm for fast and accurate dose prediction of cervical cancer VMAT in multicenter datasets and then explore the feasibility of the DL algorithm to endometrial cancer VMAT with different prescriptions. We proposed the AtTranNet algorithm for three-dimensional dose prediction. A total of 367 cervical patients were enrolled in this study. Three hundred twenty-two cervical patients from 3 centers were randomly divided into 70%, 10%, and 20% as training, validation, and testing sets, respectively. Forty-five cervical patients from another center were selected for external testing. Moreover, 70 patients of endometrial cancer with different prescriptions were further selected to test the model. Prediction precision was evaluated by dosimetric difference, dose map, and dose-volume histogram metrics. The prediction results were all clinically acceptable. The mean absolute error within the body in internal testing was 0.66 ± 0.63%. The maximum |δD| for planning target volume was observed in D98, which is 1.24 ± 2.73 Gy. The maximum |δD| for organs at risk was observed in Dmean of bladder, which is 4.79 ± 3.14 Gy. The maximum |δV| were observed in V40 of pelvic bones, which is 4.77 ± 4.48%. AtTranNet showed the feasibility and reasonable accuracy in the dose prediction for cervical cancer in multiple centers. The model can also be generalized for endometrial cancer with different prescriptions without any transfer learning.

Online Adaptive Magnetic Resonance-guided Radiation Therapy for Gynaecological Cancers: Preliminary Results of Feasibility and Outcome

To present the preliminary results on the clinical utilisation of an online daily adaptive magnetic resonance-guided radiation therapy (MRgRT) for various gynaecological cancers. Twelve patients treated between September 2018 and June 2022 were included. Six patients (50%) were treated with pelvic radiation therapy followed by MRgRT boost as brachytherapy boost was ineligible or unavailable, three patients (25%) were treated with pelvic MRgRT followed by high dose rate brachytherapy, two patients (16.7%) were treated with only MRgRT, one patient (8.3%) was treated with linear accelerator-based radiation therapy followed by MRgRT boost for bulky iliac lymph nodes. The median age was 56.5 years (range 31-86 years). Eight patients (66.7%) had a complete response, three patients (25%) had a partial response and one patient (8.3%) died due to acute renal failure. The mean follow-up time was 11.2 months (range 3.1-42.6 months). The estimated 1-year overall survival was 88.9%. The median treatment time was 47 days (range 10-87 days). During external beam radiation therapy, 10 (83.3%) patients had concomitant chemoradiotherapy. Pelvic external beam radiation therapy doses for all cohorts were 45-50.4 Gy with a fraction dose of 1.8 Gy. The median magnetic resonance-guided boost dose was 32 Gy (range 20-50 Gy) and fraction doses ranged between 4 and 10 Gy. Three patients were treated with intracavitary high dose rate brachytherapy (26-28 Gy in four to five fractions). None of the patients had grade >3 late genitourinary toxicities. MRgRT is reliable and clinically feasible for treating patients with gynaecological cancers alone or in combination with brachytherapy with an acceptable toxicity and outcome. MRgRT boost could be an option when brachytherapy is not available or ineligible.

Radiosensitising Effects of Metformin Added to Concomitant Chemoradiotherapy with Cisplatin in Cervical Cancer

The role of metformin on the radiosensitising effect of cisplatin is not clear. Here we investigated the radiosensitising effect of metformin alone and combined with cisplatin in HeLa cells, as well as the implications of the adenosine monophosphate-activated protein kinase (AMPK) pathway on the radiosensitising effect. HeLa cells were treated with ionising radiation, metformin, cisplatin, A769662 (AMPK activator) and dorsomorphin (AMPK inhibitor) or in combination. A cell proliferation assay, Western blot and flow cytometry were carried out. Metformin potentiated cisplatin cytotoxicity when administered 4 h before ionising radiation. Although the radiosensitising effects of metformin and cisplatin alone were observed, which is more apparent at high ionising radiation doses, the metformin-cisplatin combination did not increase the radiosensitivity of cisplatin at any ionising radiation dose. Dorsomorphin alone significantly decreased cell proliferation and potentiated the radiosensitising effects of cisplatin with ionising radiation. Administration of A769662 24 h prior to cisplatin treatment resulted in an increased AMPK level that yielded resistance to cisplatin, but this effect was not observed in HeLa cells concomitantly treated with A769662 and cisplatin. Modulation of AMPK may have a role in cervical cancer treatment. Increased AMPK levels result in higher sensitivity to ionising radiation but causes resistance to cisplatin. Dorsomorphin is proven to be a potent radiosensitising agent. The use of metformin alone may be an option as a radiosensitiser during high-dose ionising radiation (e.g. intracavitary brachytherapy).

Challenges in the Sustainability of Brachytherapy Service in Contemporary Radiotherapy

Brachytherapy has a long history of delivering a highly conformal radiation dose to the target volume with sparing of adjacent normal tissue and has an irreplaceable role in certain cancers, such as cervical and prostate cancers. There have been futile attempts to replace brachytherapy with other radiation techniques. Despite that there are multifaceted challenges in preserving this dying art, from establishment, to a trained workforce, to maintenance of the equipment and source replacement costs. Here we focus on the challenges to access brachytherapy, the availability and distribution of care across the globe and appropriate training leading to proper implementation of the procedure. Brachytherapy holds a significant place in the treatment armamentarium of most common cancers, such as cervical, prostate, head and neck and skin cancers. However, there is an uneven distribution of brachytherapy facilities, not only across the globe, but also at a national level, with a larger proportion of facilities concentrated in certain regions, more so in low and low-middle income countries. The regions with the highest incidence of cervical cancer have the least access to brachytherapy facilities. Attempts to bridge the gap are essential and should be focused on uniform distribution and access to care, improving training of the workforce through specialised training programmes, reducing the cost of care, planning to reduce the recurring cost, generating evidence and research guidelines, renewing interest in brachytherapy through rebranding, use of social media and building an attainable long-term roadmap.

Functional Magnetic Resonance Imaging in Cervical Cancer Diagnosis and Treatment

Cervical Cancer is the fourth most common cancer in women worldwide. Treatment with chemoradiotherapy followed by brachytherapy achieves high local control, but recurrence with metastatic disease impacts survival. This highlights the need for predictive and prognostic biomarkers identifying populations at risk of poorer treatment response and survival. Magnetic resonance imaging (MRI) is routinely used in cervical cancer and is a potential source for biomarkers. Functional MRI (fMRI) can characterise tumour beyond anatomical MRI, which is limited to the assessment of morphology. This review summarises fMRI techniques used in cervical cancer and examines the role of fMRI parameters as predictive or prognostic biomarkers. Different techniques characterise different tumour factors, which helps to explain the variation in patient outcomes. These can impact simultaneously on outcomes, making biomarker identification challenging. Most studies are small, focussing on single MRI techniques, which raises the need to investigate combined fMRI approaches for a more holistic characterisation of tumour.

Targeting DNA Repair in Ovarian Cancer Treatment Resistance

Most patients with advanced high-grade serous ovarian cancer (HGSOC) develop recurrent disease within 3 years and succumb to the disease within 5 years. Standard treatment for HGSOC is cytoreductive surgery followed by a combination of platinum (carboplatin or cisplatin) and taxol (paclitaxel) chemotherapies. Although initial recurrences are usually platinum-sensitive, patients eventually develop resistance to platinum-based chemotherapy. Accordingly, one of the major problems in the treatment of HGSOC and disease recurrence is the development of chemotherapy resistance. One of the causes of chemoresistance may be redundancies in the repair pathways involved in the response to DNA damage caused by chemotherapy. These pathways may be acting in parallel, where if the repair pathway that is responsible for triggering cell death after platinum chemotherapy therapy is deficient, an alternative repair pathway compensates and drives cancer cells to repair the damage, leading to chemotherapy resistance. In addition, if the repair pathways are epigenetically inactivated by DNA methylation, cell death may not be triggered, resulting in accumulation of mutations and DNA damage. There are novel and existing therapies that can drive DNA repair pathways towards sensitivity to platinum chemotherapy or targeted therapy, thus enabling treatment-resistant ovarian cancer to overcome chemotherapy resistance.

Survival Outcomes of Epithelial Ovarian Cancer Patients Following Dose-dense Versus 3-Weekly Platinum–Paclitaxel Chemotherapy: A Meta-Analysis

Dose-dense chemotherapy has proven its value in several cancer fields. The purpose of the present systematic review is to evaluate the impact of dose-dense chemotherapy on survival outcomes of epithelial ovarian cancer patients. Medline, Scopus, the Cochrane Central Register of Controlled Trials CENTRAL, Google Scholar and Clinicaltrials.gov databases were searched for relevant articles. Effect sizes were calculated in Rstudio using the meta and metafor functions. A sensitivity analysis was carried out to evaluate the possibility of small study effects and P-hacking. The methodological quality of the included studies was assessed using Risk of Bias 2 (RoB2) and Risk of Bias in non-Randomized Trials (RoBINS) tools. Overall, 12 studies were included in the present systematic review, involving 4979 epithelial ovarian cancer patients. The risk of recurrence was substantially improved in patients receiving dose-dense chemotherapy (hazard ratio 0.82, 95% confidence interval 0.70, 0.96); however, the result of the meta-analysis may be attributed to the effect size of smaller studies as following adjustment for small study effects the outcome becomes non-significant (hazard ratio 0.91, 95% confidence interval 0.81, 1.02, P = 0.123). Overall survival rates were not improved by dose-dense chemotherapy (hazard ratio 0.79, 95% confidence interval 0.60, 1.04). Thirty-five types of adverse effect were identified following retrieval of data from the original studies. Dose-dense chemotherapy did not increase significantly the rates of severe adverse effects, although thrombosis, severe diarrhoea and severe nausea were more prevalent in this group of patients. Dose-dense chemotherapy is associated with comparable side-effects to those of standard chemotherapy; however, data related to survival outcomes are not positive; hence, its use outside the setting of clinical trials should be discouraged.

Ultrasound-guided Brachytherapy for Cervix Cancer

Radiotherapy and brachytherapy are the definitive treatments for locally advanced cervix cancer. The use of soft-tissue imaging, particularly magnetic resonance imaging, has enhanced their effectiveness and improved clinical outcomes. However, the use of magnetic resonance imaging is largely restricted to well-resourced centres in both the first and developing world and remains elusive to many less advantaged centres, particularly those in areas with a high burden of cervix cancer. Ultrasound is an accessible, affordable and accurate imaging modality that can be used throughout the brachytherapy procedure. Ultrasound is primarily used to ensure safe insertion of the applicator but can also be used to guide planning. The methods used to utilise ultrasound images for planning are described. Ultrasound is particularly useful as a verification aid to confirm applicator placement after patients are moved and transferred around the radiotherapy department. It can also be used to verify the dimensions of treatment volumes over the course of brachytherapy. There is a crucial unmet need for an accessible economical soft-tissue imaging modality in cervical brachytherapy. Ultrasound has the potential to meet this need.

Adaptive Radiotherapy in the Management of Cervical Cancer: Review of Strategies and Clinical Implementation

The complex and varied motion of the cervix-uterus target during external beam radiotherapy (EBRT) underscores the clinical benefits afforded by adaptive radiotherapy (ART) techniques. These gains have already been realised in the implementation of image-guided adaptive brachytherapy, where adapting to anatomy at each fraction has seen improvements in clinical outcomes and a reduction in treatment toxicity. With regards to EBRT, multiple adaptive strategies have been implemented, including a personalised internal target volume, offline replanning and a plan of the day approach. With technological advances, there is now the ability for real-time online ART using both magnetic resonance imaging and computed tomography-guided imaging. However, multiple challenges remain in the widespread dissemination of ART. This review investigates the ART strategies and their clinical implementation in EBRT delivery for cervical cancer.

Long-Term Outcomes of Cervical Cancer Patients Treated With Definitive Chemoradiation Following a Complete Metabolic Response

A complete metabolic response (CMR) on early post-treatment Patients who received curative-intent chemoradiation from 1998 to 2018 for International Federation of Gynecology and Obstetrics (FIGO) stage IB1-IVA cervical cancer and had a CMR on post-treatment FDG-PET within 5 months of treatment completion were included. Cox proportional hazards models determined factors associated with locoregional and distant failure. Kaplan-Meier estimates of freedom from any recurrence (FFR) of patient subgroups were compared with Log-rank tests. There were 402 patients with a CMR after chemoradiation on FDG-PET. Initial T stage was T1 (38%)/T2 (40%)/T3 (20%)/T4 (2%); initial FDG-avid nodal status was no nodes (50%)/pelvic lymph nodes (40%)/pelvic and para-aortic lymph nodes (10%). After a median follow-up of 6 years, 109 (27%) recurred. The pattern of recurrence was locoregional (27%), distant (61%) or both (12%). No factors were associated with locoregional failure. Distant recurrence was more likely in patients with T3-4 lesions (hazard ratio = 2.4, 95% confidence interval 1.5-3.8) and involvement of pelvic (hazard ratio = 1.6, 95% confidence interval 1.0-2.7) or para-aortic lymph nodes (hazard ratio = 2.7, 95% confidence interval 1.4-5.0) at diagnosis. The 5-year FFR rates for T1-2 patients with no nodes, pelvic nodes alone or para-aortic nodes at diagnosis were 85, 76 and 62%, respectively (P = 0.04, none versus para-aortic nodes). The 5-year FFR for T3-4 patients with no nodes, pelvic nodes alone or para-aortic nodes at diagnosis were 68, 56 and 25%, respectively (P = 0.09, none versus para-aortic nodes). T3-4 tumours and para-aortic nodal involvement at diagnosis are poor prognostic factors, even after a CMR following chemoradiation.

Magnetic Resonance Imaging-Guided Adaptive Brachytherapy for the Treatment of Cervical Cancer and its Impact on Clinical Outcome

We implemented magnetic resonance imaging-based image-guided adaptive brachytherapy (IGABT) for the management of cervical cancer at the Northern Centre for Cancer Care in January 2015. The Royal College of Radiologists recommended IGABT as the new standard of care for the management of cervical cancer in the UK in 2009, following earlier publication of recommendations of Groupe European de Curietherapie of the European Society for Radiotherapy and Oncology for three-dimensional magnetic resonance imaging-based IGABT. The purpose of this study was to investigate if the introduction of IGABT in the management of cervical cancer at our institute indeed improved the treatment outcomes with a better toxicity profile as compared with conventional brachytherapy (CBT). A retrospective analysis of 213 patients with International Federation of Gynecology and Obstetrics stage IB-IVA cervical cancer treated with curative radiotherapy ± chemotherapy at the Northern Centre for Cancer Care was carried out for the period January 2010 to December 2019. Patients were categorised into three groups based on their brachytherapy planning process. Fifty-eight patients were treated with CBT, 35 patients were treated with retrospective brachytherapy (RBT) planning and 120 patients were treated with IGABT. Eighty-six per cent received concomitant chemotherapy with cisplatin. Outcome measures were local control rates, overall and progression-free survival, and impact on treatment-related toxicities. The median follow-up was 36, 32 and 25 months for CBT, RBT and IGABT, respectively. Three-year local control achieved was 70.4, 77.8 and 86.9%, respectively. Three-year overall survival was 53.8, 61.1 and 86.2%, respectively. Grade 2 or 3 bladder and bowel toxicity was 8% and 10% in IGABT group versus 20% and 27% in the CBT group. Our analysis indicated that IGABT proved to be very effective in not only improving locoregional control, but also offered quality survivorship to these women, with a significant drop in radiation-related bladder and bowel toxicities.

Neoadjuvant Chemotherapy in Locally Advanced Cervical Carcinoma – a Role in Patients with Para-aortic Lymph Node Involvement? A 10-year Institutional Experience

Overall survival and progression-free survival with concomitant chemoradiotherapy for locally advanced cervical carcinoma have been described as 66% and 58%, respectively, at 5 years. Para-aortic lymph node involvement significantly increases the risk of relapse and death. The role of additional chemotherapy in these patients is as yet undefined. This aim of the present study was to determine the outcome of a cohort of para-aortic lymph node-positive patients treated with neoadjuvant chemotherapy followed by extended-field chemoradiation compared with patients treated with extended-field chemoradiation without neoadjuvant chemotherapy. We reviewed patients with International Federation of Gynaecology and Obstetrics (FIGO) 2014 stage IB1-IVA cervical carcinoma who received extended-field radiotherapy in addition to standard pelvic chemoradiotherapy with or without neoadjuvant chemotherapy, at University College London Hospital (January 2007 to January 2018). Patients in open clinical trials were excluded. Overall, 47 patients (15.8% of 298 eligible patients) with pelvic and/or para-aortic lymph node-positive cervical carcinoma received extended-field radiotherapy. Nineteen patients (40.4%) had both neoadjuvant chemotherapy (all received six cycles) and extended-field radiotherapy (median 44 days); 28 (59.6%) patients received extended-field radiotherapy alone (median 43 days). All patients completed radical radiotherapy within 49 days. We observed evidence that patients receiving neoadjuvant chemotherapy and extended-field radiotherapy had a lower risk of death (median follow-up 4.8 years, three deaths) compared with extended-field radiotherapy alone (median follow-up 3.0 years, 11 deaths; hazard ratio = 0.27, 95% confidence interval 0.08-1.00; P = 0.05). Three-year overall survival rates were 83.3% (95% confidence interval 66.1-100) and 64.6% (95% confidence interval 44.6-84.6), respectively. A PFS benefit was seen (hazard ratio 0.25, 95% confidence interval 0.08-0.77; P = 0.02), with 3-year PFS rates of 77.8% (95% confidence interval 58.6-97.0) and 35.0% (95% confidence interval 14.0-56.0), respectively. Our institutional experience suggests that the use of additional systemic therapy before chemoradiotherapy benefits patients with locoregionally advanced (FIGO 2018 IIIC2) cervical cancer. Neoadjuvant chemotherapy was associated with longer overall survival and PFS, without compromising definitive extended-field chemoradiation.

Real World Multi-centre UK Review of Nivolumab Monotherapy in Metastatic Endometrial Cancer With Mismatch Repair Deficiency During COVID-19

Immunotherapy checkpoint inhibition has shown improvement in efficacy and survival in patients with mismatch repair deficient (MMRd) advanced endometrial cancer (mEC) compared to chemotherapy. This is combined with chemotherapy in the first-line setting or as monotherapy in later lines of therapy. To assess the efficacy, survival and toxicity of nivolumab monotherapy in metastatic endometrial cancer (mEC) in both first and later lines of therapy as used in the NICE COVID-19 systemic anti-cancer (SACT) guidelines. A multi-centre retrospective review of mEC patients with associated MMRd who received nivolumab as per NICE COVID NG161 at 10 NHS cancer centres. Patient demographics, molecular classification and previous treatments were recorded in addition to treatment responses, duration of response, overall survival, progression-free survival and toxicities. Kaplan-Meier curves analyse the survival data. 52 patients were identified. Median age was 67 (37-81) years. 87.5% of patients had endometrioid histology and 75% were oestrogen receptor (ER) positive. 10.4% patients were p53 mutated. 33.3% of mEC patients were stage IV at diagnosis. 30 (62.5%) patients received nivolumab as first-line mEC therapy. 33 (68.8%) patients received nivolumab 4-weekly. Treatment response was clinician-observed in 34 (70.8%) patients, with 7 (14.5%) more having stable disease. 52%, 45% and 36% of patients were progression-free at 12, 18 and 24months, respectively. 75%, 55% and 47% of patients were alive at 12, 18 and 24 months. There was no significant difference between survival or response whether nivolumab was given in the first line or subsequent lines. 29 (60.4%) patients have discontinued treatment with 23 (44.2%) being due to progressive disease or death. 18 (37.5%) patients developed G1-2 toxicity, and 3 (6.25%) patients discontinued due to G3 toxicity. This retrospective cohort shows that nivolumab monotherapy has good real-world disease control of mEC patients with MMR deficiency. Toxicity rates were low, and checkpoint monotherapy may be a viable option for selected first-line MMRd mEC patients.

Impact of Nodal Metastatic Volume on Distant Metastasis in Patients with Cervical Cancer and Para-aortic Nodal Metastases Treated With Definitive Radiation Therapy

To report institutional outcomes following definitive radiation therapy (RT) for cervical cancer with para-aortic lymph node (PAN) metastasis and explore the risk factors for subsequent distant metastasis (DM) and the optimal elective radiation field. Ninety-seven patients treated between 2011 and 2023 were evaluated. The median patient age was 60 (range, 29-86) years. The numbers of patients with International Federation of Gynecology and Obstetrics (FIGO) 2008 stages I, II, III, and IVA were 6 (6%), 32 (33%), 43 (44%), and 16 (16%), respectively. Eighty-two patients had squamous cell carcinoma. The median gross tumor volumes of primary (GTVp) and nodal metastasis (GTVn) were 110.4 (range, 20.6-340.7) cm With a median follow-up of 34 (range, 4-143) months, the 3-year in-field recurrence-free survival, DM-free survival, and overall survival rates were 74%, 51%, and 66%, respectively. Patients with a higher GTVn/GTVp ratio had a significantly higher risk of developing DM than their counterparts. Only two (2%) patients developed isolated PAN recurrence outside the irradiated field. DM is the most common mode of recurrence, the risk of which is significantly higher in patients with higher GTVn/GTVp ratios. An ample margin above the involved PAN may not necessarily be required to achieve disease control in the pelvis and PAN.

The Role of Radiotherapy for Metastatic Cervical Cancer: A Real-World Study

Data on the efficacy of radiotherapy (RT) in metastatic cervical cancer (mCC) are limited. Herein, we evaluated the efficiency of RT for mCC. This is a retrospective cohort study. A total of 99 patients with mCC from April 2018 to April 2022 were treated with either radiotherapy group (RT group) or non-radiotherapy group (NRT group). All patients received systemic treatments. The complete response rates (CRRs) were 15.8% and 4.8% (P = 0.322) and the objective response rates (ORRs) were 68.4% and 42.8% (P = 0.011) in the RT group and NRT group, respectively. The median follow-up was 16 months (5-53 months). The RT group showed higher overall survival (OS) (1-year 82.5% vs 57.1%, 2-years 60.7% vs 31.1%, P = 0.035) and progression-free survival (PFS) (1-year 64.7% vs 35.7%, 2-years 41.3% vs 24.4%, P = 0.022). RT extended median OS (mOS) from 16 to 27 months and median PFS (mPFS) from 9 to 18 months. Multivariate analyses revealed radiotherapy, 5-8 chemotherapy cycles, and nonhepatic metastasis as independent prognostic factors for OS and PFS. Subgroup analysis showed improved OS and PFS with RT in patients aged over 60, with squamous cell carcinoma, single organ metastasis, and those receiving 2-4 chemotherapy cycles. Besides, notably, enhanced OS was observed in patients with lymph node-only metastasis who received RT (78.9% vs. 50.0%, P = 0.029). The primary acute adverse event was haematology toxicity. There was no increased toxicity with the addition of RT. Radiotherapy combined with systemic therapy demonstrates an increased objective response rate for mCC. It can also improve OS and PFS and extend mOS and mPFS for mCC without escalating treatment-related toxicity. For patients aged over 60, with squamous cell carcinoma, single organ metastasis, lymph node-only metastasis, and those receiving 2-4 chemotherapy cycles, proactive RT intervention is recommended. Careful patient selection is advised for RT in mCC.

Advanced Epithelial Ovarian Cancer: Have We Really Improved Care for Patients Aged 70 Years and Older? A 20-year Registry-based Study

Advanced epithelial ovarian cancer (aEOC, International Federation of Gynecology and Obstetrics(FIGO) stages IIIC-IV) is the most frequently diagnosed and lethal form of ovarian cancer. The aim of this study was to evaluate net survival (NS) over time and the differences between younger (<70 years) and older (≥70 years) patients (OPs). All patients with aEOC diagnosed in the French department of Côte d'Or between 01 January 1998 and 31 December 2018 were included. Two-year and 5-year NS were calculated for the two age groups over three periods: 1998 to 2004 (T1), 2005 to 2011 (T2), and 2012 to 2018 (T3). A total of 392 patients were included, of whom 154 (39.3%) were aged ≥70 years. Surgery-based treatment was used less frequently in OPs (58.15% vs 83.41%, P < 0.0001) and decreased over time, notably in OPs (74.2% at T1 vs 34.8% at T3, P < 0.001). There was a clear increase in chemotherapy alone at T3 vs T1 in OPs (odds ratio = 8.14, 95% confidence interval [CI]: [2.49-26.58], P < 0.001). The 5-year NS was lower in OPs (23.3%, 95% CI: [17.1-31.8] vs 44.6%, 95% CI: [38.7%-51.6%], P < 0.001) over the 20-year period. The only significant difference in NS between patients aged ≥70 years and <70 years was observed during T3, 17.9% (95% CI: [10.9-29.5]) vs 42.9% (95% CI: [33.8-54.4], P < 0.001) for 5-year NS. NS for aEOC was lower in women aged ≥70 years, especially from 2012 to 2018. Nonoptimal treatment was also more frequent in the older age group.

Three-Dimensional Conformal Radiotherapy Versus Image-Guided Intensity Modulated External Beam Radiotherapy in Locally Advanced Cervical Cancer: A Phase III Randomized Control Study

The standard treatment of locally advanced cervical carcinoma is radical chemoradiation followed by brachytherapy which has improved survival. Hence, a major concern is our attempt to reduce the incidence of acute and late toxicities. IMRT has been shown to reduce toxicities. In this study, we have compared 3DCRT with IG-IMRT using patient-specific margins to evaluate tumor control as well as OAR-related toxicities. This was a single institution prospective phase III randomised control study including patients of squamous cell carcinoma of cervix (stage II-IIIB, FIGO 2009) without pelvic lymph node involvement. All patients were simulated using intermediate bladder filling protocol and those in the IG-IMRT arm, underwent additional scans with full and empty bladder to assess the range of internal motion and generate individualised ITV margin. EBRT dose of 46Gy/23#/4.5 weeks was delivered with weekly concurrent cisplatin followed by brachytherapy. All toxicities during EBRT and till 3 months post brachytherapy were considered acute toxicity. Post-treatment, patients were followed up every 2 months for first 2 years and then once every 6 months. Disease-related outcomes were assessed with clinical examination and symptom-directed imaging. Two hundred patients were screened for inclusion and of them, 89 patients in 3DCRT and 84 patients in IG-IMRT arms were considered for final analysis. The baseline characteristics were comparable in both arms, majority of patients in both arms having stage II disease. For OARs, all dosimetric parameters were significantly better in the IG-IMRT arm. Acute radiation induced toxicities (dermatitis, genito-urinary and gastrointestinal toxicities) were significantly less in the IG-IMRT arm. The local, pelvic, and distant control were comparable in both arms. Based on our experience, the use of IG-IMRT with patient-specific ITV margins results in reduction in acute OAR toxicities in patients without compromising on tumor control.

Current Management Practices for Endometrial Cancer (EC) in the UK: A National Healthcare Professional Survey (KNOW-EC)

The clinical landscape for endometrial cancer in the UK is evolving to include new management guidelines and targeted treatment options. An understanding of current treatment and management practices in the UK will help services plan and adapt to upcoming changes. The purpose of this survey was to understand current and anticipated real-world practices for endometrial cancer care in the UK and potential areas for optimisation. Telephone interviews were conducted in November/December 2021 with UK-based healthcare professionals involved in endometrial cancer management. Questions were aligned with the British Gynaecological Cancer Society/European Society for Medical Oncology recommendations, covering the pathway from diagnosis and treatment to follow-up. A total of 63 healthcare professionals (HCPs) involved in the management of patients with endometrial cancer participated in telephone interviews. The results highlighted variations in management and treatment practices for endometrial cancer and suggest that current UK practice appears to diverge from national and international guidance in some instances. While somatic mismatch repair deficiency testing was used by 89.7% of respondents as mainstream testing, the survey highlighted a lack of access to other key molecular biomarker tests, such as polymerase epsilon (POLE) sequencing (used by only 9.8% of HCPs at the time of the survey). The results highlighted several perceived practical barriers to the swift adoption of new therapeutic options, including funding access, limited staff, treatment-related resources, staff education, and support. Our findings support the need for better access to biomarkers that could enable more effective and targeted treatments.

Endometrial Cancer: Analysing Patterns of Recurrence and Real-Life Outcome Data Using the 2020 ESGO-ESTRO-ESP Risk Stratification System

To evaluate patterns of recurrence and explore the prognostic differences between the 2018 FIGO staging system and the 2020 ESGO-ESTRO-ESP risk stratification system of endometrial cancer with an emphasis on early-stage disease. The incidence of endometrial cancer has risen by around 60% since the 90's. It is projected that by 2035 endometrial cancer will be the sixth most common cause of cancer-related death amongst females. This was a retrospective cohort study which included patients treated between 2010 and 2017. Primary endpoints were overall survival (OS) and recurrence-free survival (RFS). Kaplan-Meyer survival analysis was used to assess OS and RFS across different risk groups. Cox proportional hazards regression was used to evaluate prognostic risk factors implicated in recurrence. Different recurrence patterns across the subgroups were analysed with Pearson's chi-square test. The study included 692 patients with a recurrence rate of 14.9%. The median time to recurrence was 17.1 months (IQR:8.8-28.4). The mean OS varied between 97.2 months in the low-risk group to 63.1 months in the high-risk group (p < 0.001). Mean RFS was 96.1 in the low-risk group and 58.9 in the high-risk group (p < 0.001). RFS was predicted by the following factors; high risk group (OR=3.87; p = 0.041), LVSI (OR=2.54, p = 0.005), carcinosarcoma (OR=2.20, p = 0.021) and serous subtype (OR=1.91, p = 0.01). Logistic regression was used to evaluate risk factors for loco-regional and distant recurrence. Patients in the low-risk group were less likely to have distant recurrence (OR=0.08, p = 0.004). Similarly, negative LVSI and Grade 1 cancers were associated with decreased risk of distant recurrence (OR=0.34, p = 0.006 and OR=0.33, p = 0.007, respectively). There were no significant risk factors for loco-regional recurrence. The 2020 ESGO-ESTRO-ESP risk stratification provides accurate estimates of recurrence risk and survival. Those treated in line with current guidance have significantly better outcomes.

The Royal College of Radiologists National Vulvar Cancer Audit

This audit examined UK vulvar cancer practice from March 2018 to January 2019 and compared it to standards from national and international recommendations. Follow-up data collection in 2020 examined patient outcomes and toxicity. Audit standards were based on Royal College of Radiologists (RCR) guidance and published literature. A web-based questionnaire was sent to the audit leads at all cancer centres in the UK. Prospective data collection included patient demographics, tumour characteristics, radiotherapy indications, dosimetry, timelines, and follow-up data. The audit targets were 95% compliance with the RCR dose/fractionation schemes in definitive and adjuvant patients, 40% use of intensity modulated radiotherapy (IMRT), 100% of radical patients treated as category 1, and 95% use of gap compensation for category 1 patients. 34/54 UK radiotherapy centres (63%) completed data entry for 152 patients. 23 out of 34 (68%) centres submitted follow-up data for 94 patients. One indicator exceeded the audit target: 98% of radical patients received IMRT. The indicators of RCR dose/fractionation compliance for adjuvant/definitive radiotherapy were achieved by 80%/43% for the primary, 80%/86% for elective lymph nodes, and 21%/21% for pathological lymph nodes. The use of concomitant chemotherapy with radical radiotherapy in suitable patients was achieved by 71%. Other indicators demonstrated that 78% were treated as category 1 and 27% used gap compensation. Acute toxicity was mostly related to skin, gastrointestinal, and genitourinary sites. Grade 3 and Grade 4 toxicities were seen at acceptable rates within the radical and adjuvant groups. Late toxicity was mostly grade 0. This audit provides a comprehensive picture of UK practice. IMRT is widely used in the UK, and treatment-related toxicity is moderate. The dose fractionation was very heterogeneous. The designation of vulvar cancer as category 1 was not regularly followed for radical/adjuvant patients, and there was minimal gap compensation during treatment.

Analysis of the Safety and Pregnancy Outcomes of Fertility-sparing Surgery in Ovarian Malignant Sex Cord-stromal Tumours: A Multicentre Retrospective Study

To assess the difference in survival between fertility-sparing surgery (FSS) and radical surgery and explore pregnancy outcomes after FSS in stage I malignant sex cord-stromal tumours (MSCSTs). We carried out a multicentre retrospective cohort study on patients who were diagnosed with MSCSTs and the tumour was confined to one ovary. The patients were divided into FSS and radical surgery groups. Inverse probability of treatment weighting (IPTW) was used to balance variables between the two groups. Kaplan-Meier analysis was used to compare the difference in disease-free survival (DFS). Univariate and multivariate Cox regression analysis was used to find risk factors of DFS. Univariate logistic regression analysis was used to assess risk factors of pregnancy. In total, 107 patients were included, of whom 54 (50.5%) women underwent FSS and 53 (49.5%) received radical surgery. After IPTW, a pseudo-population of 208 was determined and all of the covariates were well balanced. After a median follow-up time of 50 months (range 7-156 months), 10 patients experienced recurrence and two died. There was no significant difference in DFS between the two groups, both in unweighted (P = 0.969) or weighted cohorts (P = 0.792). In the weighted cohort, stage IC (P = 0.014), tumour diameter >8 cm (P = 0.003), incomplete staging surgery (P = 0.003) and no adjuvant chemotherapy (P < 0.001) were the four high-risk factors associated with a shorter DFS. Among 14 patients who had pregnancy desire, 11 (78.6%) women conceived successfully; the live birth rate was 76.9%. In univariate analysis, only adjuvant chemotherapy (P = 0.009) was associated with infertility. On the premise of complete staging surgery, FSS is safe and feasible in early stage MSCSTs with satisfactory reproductive outcomes.

Immunotherapy and Systemic Therapy in Metastatic/Recurrent Endometrial and Cervical Cancers

Despite advances in the treatment of gynaecological malignancies, both recurrent endometrial and cervical cancers when not amenable to localised therapy (surgery or radiotherapy), remain incurable with limited prognosis and effective treatment options. Chemotherapy remains the standard of care for women with metastatic endometrial or cervical cancers. The addition of bevacizumab to first-line chemotherapy for metastatic cervical cancer patients represents a significant step forward in improving survival. More recently, immunotherapeutic strategies targeting the PD-1/-L1 pathway have shown clinical activity in both endometrial and cervical cancers. The increased understanding of the molecular biology of these cancers is shaping target-specific treatments. Here we summarise current treatment options and results from clinical trials of immunotherapy and other targeted therapies that have already changed, or have the potential to change, clinical practice in metastatic/recurrent endometrial and cervical cancer.

Eliminating Cervical Cancer: Progress and Challenges for High-income Countries

In 2020, the World Health Organization launched a major initiative to eliminate cervical cancer globally. The initiative is built around the three key pillars of human papillomavirus (HPV) vaccination, cervical screening and treatment, with associated intervention targets for the year 2030. The '90-70-90' targets specify that 90% of adolescent girls receive prophylactic HPV vaccination, 70% of adult women receive a minimum twice-in-a-lifetime cervical HPV test and 90% receive appropriate treatment for preinvasive or invasive disease. Modelling has shown that if these targets are met, the elimination of cervical cancer, defined as fewer than four cases per 100 000 women per annum, will be achieved within a century. Many high-income countries are well positioned to eliminate cervical cancer within the coming decades, but few have achieved '90-70-90' and many challenges must still be addressed to deliver these critical interventions effectively. This review considers the current status of cervical cancer control in relation to each of the three elimination pillars in high-income countries and discusses some of the developments that will assist countries in reaching these ambitious targets by 2030.

National Survey of Current Follow-up Protocols for Patients Treated for Endometrial Cancer in the UK

The aim of this study was to establish a baseline of national practice for follow-up after treatment for endometrial cancer in the UK. An online cross-sectional survey was developed and distributed through the Royal College of Radiologists via an email link to the audit leads of radiotherapy centres in the UK. The survey was conducted from November 2021 to 5 January 2022. The main themes assessed in the survey were the form, frequency and duration of follow-up practices. There were a total of 43/61 (70%) complete responses. 93% of centres had a standard follow-up protocol and 7% who did not have a follow-up protocol discharged patients after the post-operative review. Five centres (13%) used molecular profiling to inform follow-up practices. Patient-initiated follow-up was mainly used in the cohort of patients who had surgery alone with no adjuvant treatment (68%, (19/28)). In the cohort who had face-to-face follow-up, the majority had pelvic examinations as part of their review and total follow-up for five years. 93% of respondents are interested in a national follow-up protocol. Our data shows that there is national variation in practise with regard to follow-up of women treated for endometrial cancer. Many of the follow-up practises are based on conventional follow-up regimens and these may fail to address the more holistic needs of cancer survivors. Recent publication of updated guidance from the British Gynaecological Cancer Society may help standardise practise and provide a more relevant approach to follow-up for women treated for endometrial cancer.

Long-term Clinical Outcomes of a Resource-conserving Accelerated Magnetic Resonance Imaging-guided Brachytherapy Schedule for Cervix Cancer

The EMBRACE-I study has shown that magnetic resonance imaging (MRI)-based image-guided brachytherapy (IGBT) results in local control (LC) rates of >90% across all stages without increasing late morbidity. However, resource implications and logistical challenges are major barriers to implementation. This paper describes the long-term results of a resource-conserving accelerated IGBT schedule of 3-4 fractions delivered in a single insertion over 3 days compared with EMBRACE-I. Between January 2010 and March 2020, 166 patients were treated with chemo-radiotherapy to the pelvis ± paraaortic nodes followed by a single insertion of high-dose rate MRI-based IGBT. Ninety-nine (60%) patients received intracavitary IGBT alone while 67 (40%) received combined intracavitary-interstitial IGBT. Seventy-six (46%) patients received 3 fractions of IGBT while 90 (54%) received 4 fractions. The median follow-up was 60 months. The actuarial 5-year LC, pelvic control (PC) and disease-free survival (DFS) were similar to that in EMBRACE-I (LC: 92% vs 92%; PC: 89% vs 87%; DFS: 68% vs 68%) even though more of our patients had advanced disease (stage 3/4: 39% vs 25%). The 5-year overall survival was lower (69% vs 74%), possibly because our patients were older (median age: 53 years vs 49 years). The 5-year actuarial rate of ≥G3 toxicity was similar to EMBRACE-I (gastrointestinal: 6.8% vs 8.5%; genito-urinary: 7.0% vs 6.8%; fistula: 3.2% vs 3.2%), even though our organs-at-risk (OAR) doses tended to be higher. Although our dose-fractionation schedule could nominally be described as 7 Gy x 3 or 4 fractions, only 14 patients received this dose-fractionation schedule to point 'A' and none to the D90% of the high-risk clinical target volume (CTV-HR). Our accelerated brachytherapy schedule of 3-4 fractions in a single insertion over 3 days gives commensurate tumour control and ≥G3 toxicity to EMBRACE-I. Any centre wishing to adopt this schedule should monitor their prescribed doses and patient outcomes carefully.

Real World Outcomes in Patients With Recurrent, Advanced, or Metastatic Endometrial Cancer Treated With Lenvatinib Plus Pembrolizumab

Patients with endometrial cancer who progress following first line therapy have improved survival outcomes with pembrolizumab and lenvatinib (pem/len) compared with standard of care chemotherapy, as demonstrated in KEYNOTE-775. This was in a group of trial patients with good performance status and excluded those with carcinosarcoma histology. In KEYNOTE-775 pem/len was associated with significant toxicity, leading to dose reductions, treatment cessation, and patient morbidity. We set out to assess the tolerability, toxicity and outcomes following pem/len for patients with recurrent, advanced or metastatic endometrial cancer in a real-world setting. UK centres treating patients with pem/len for advanced endometrial cancer within the compassionate access programme were approached. Retrospective data were analysed for those treated between May 2022 and June 2023. Data on patient demographics, treatment, toxicity and outcomes were extracted from medical records. Toxicity and tolerability were compared in those over and under the age of 70. Seven centres returned data for 70 patients. Median age of patients was 68.5 years (range 45-85) with a performance status of 0-1 in 77.1% and of 2 in 22.9%. Histological subtypes included serous (34.3%), endometrioid (32.9%), carcinosarcoma (14.3%), clear cell (7.1%), mixed (2.9%) and other (8.6%). Grade ≥3 toxicity was reported in 55.7% with any-grade toxicity observed in 85.7%. In those aged ≥70 years (n = 30) the rate of grade ≥3 toxicity was 60.0%. Rates of dose reduction of lenvatinib were 64.3%, and toxicity-related treatment interruption was 45.7%. The 6-month progression-free and overall survival rates were 54.0% (95%CI: 39.0-66.8) and 70.1% (95%CI:56.5-80.1) respectively. This real-world, observational study of pem/len showed comparable tolerability, toxicity, and outcomes to previously reported clinical trial data. Our cohort included patients with a poorer PS and a broader range of histological subtypes including carcinosarcoma.

A Risk-scoring Model for Predicting Post-recurrence Survival in Patients With Endometrial Carcinoma

The survival time of patients with recurrent endometrial carcinoma is generally short. However, considerable interindividual variation exists. We developed a risk-scoring model for predicting post-recurrence survival in patients with endometrial carcinoma. Patients with endometrial carcinoma treated at a single institution between 2007 and 2013 were identified. Pearson chi-squared analyses were used to compute odds ratios for the associations between risk factors and short survival after cancer recurrence. The results for biochemical analyses represented values at diagnosis of disease recurrence or values at initial diagnosis for those patients who had a primary refractory disease. Logistic regression models were constructed for the identification of variables that independently predict short post-recurrence survival. The models were used to assign points based on odds ratios for risk factors and risk scores were derived. In total, 236 patients with recurrent endometrial carcinoma were included in the study. Based on overall survival analysis, 12 months was selected as the cut-off for short post-recurrence survival. Factors associated with short post-recurrence survival were platelet count, serum CA125 concentration and progression-free survival. A risk-scoring model with an area under the receiver operating characteristic curve (AUC) of 0.782 (95% confidence interval 0.713-0.851) was developed in patients without missing data (n = 182). When patients with a primary refractory disease were excluded, age and blood haemoglobin concentration were identified as additional predictors of short post-recurrence survival. For this subpopulation (n = 152), a risk-scoring model with an AUC of 0.821 (95% confidence interval 0.750-0.892) was developed. We report a risk-scoring model that shows acceptable to excellent accuracy in predicting post-recurrence survival in patients with endometrial carcinoma, with primary refractory diseases included or excluded. This model has potential applications in precision medicine in patients with endometrial carcinoma.

Innovative Follow-up Strategies for Endometrial Cancer

Increasing recognition of the heterogeneous nature of endometrial cancer, the excellent prognosis of low-risk cases and improvements in risk stratification offer opportunities for innovative, personalised follow-up strategies. This review article outlines the evidence base for alternative follow-up strategies in the different risk categories of endometrial cancer, cancer survivorship programmes and considers future directions in endometrial cancer follow-up, including emerging new techniques, such as the liquid biopsy, and opportunities for combining molecular and clinicopathological features to personalise endometrial cancer follow-up.

Instant Oncology: PORTEC-3

Feasibility Study of an Efficient Plan Pool Adaptive Radiotherapy Technology Based on Low-dose Computed Tomography for Cervical Cancer

Online adaptive radiotherapy (oART) involves a complex workflow across multiple departments, requiring significant resources and increasing the workload of radiation oncologists (ROs) and physicists. For cervical cancer, there is a need for a low-dose, image-guided adaptive radiotherapy solution that is both efficient and clinically effective AIMS: The aim is to explore the feasibility and performance of a plan-pool adaptive radiotherapy (plan-pool ART) workflow, with a focus on efficiency and dosimetric benefits for both the tumour and organs at risk (OARs). A plan-pool ART framework was developed for cervical cancer radiotherapy based on the daily low-dose computed tomography (LDCT). The LDCT images were synthesised into high-quality restorative CT (RCT) images by an image-synthesis model. A total of 257 fractionated fan-beam computed tomography (FBCT) datasets from 17 cervical cancer patients treated with the oART regimen were collected (171 fractions treated with oART and 86 fractions treated with the original plan). A support vector machine (SVM) was used to train (180 cases) and evaluate (77 cases) the oART classification model, which predicts whether the fraction needs to execute oART. The oART classification model selects the daily treatment plan that best aligns with the patient's anatomical positions from the plan pool. Finally, the performance of image-guided radiotherapy (IGRT), plan-pool ART, and triggered oART (trigger-oART) techniques was compared by simulating treatments for 5 cervical cancer cases. The oART classification model achieved high predictive performance, with an under the curve (AUC) of 0.98, accuracy of 0.86, recall of 0.89, and specificity of 0.92. Plan-pool ART reduced the number of oART execution (1.4 vs 3.0 for trigger-oART) while optimising dosimetry. Compared to IGRT, plan-pool ART decreased mean bladder dose (3122cGy vs 3258cGy) and rectum dose (3265cGy vs 3325cGy), along with lower V The simulation results demonstrate that the plan-pool ART technology is feasible, ensuring reliable target dose coverage, reducing the dose to OARs, and lowering the number of oART implementation. This approach offers a promising new technical solution for clinical treatment.

Early Results of Hypofractionated Chemoradiation in Cervical Cancer with 44 Gy/ 20 F vs 45 Gy/ 25 F: A Phase II, Open-Label, Randomised Controlled Trial (HYPOCx-iRex Trial)

To compare the safety and efficacy of hypofractionated chemoradiation (HYPO) regimen with a conventional fractionation (CVRT) for locally advanced cervical cancer (LACC). A single-centre, open-label, randomised controlled trial enrolled patients with LACC to receive either HYPO (44 Gy/20 fractions) or CVRT (45 Gy/25 fractions) with intensity-modulated radiotherapy, image-guided adaptive brachytherapy, and concurrent weekly cisplatin. The primary outcome was the incidence of acute and late gastrointestinal (GI) and genitourinary (GU) toxicity assessed using the Common Terminology Criteria for Adverse Events version 5.0. Secondary outcomes included health-related quality of life (HRQoL), disease control, and survival. Forty patients with a median follow-up of 19 months were enrolled (HYPO: n=21; CVRT: n=19). The HYPO achieved a significantly shorter overall treatment time (OTT) compared with CVRT (39 vs 47 days, P < .001). GI and GU toxicities were manageable, with a trend towards higher rates in the HYPO compared with CVRT for both acute (grading [Gr]≥3 CTCAE/patient-reported outcome 43%/29% vs 32%/11%, P=.53/0.24) and actuarial 18-month late GI toxicity (Gr≥2/Gr≥3 26.2%/21.2% vs 20.6%/14.4%, P=.537/0.438), although not statistically significant. No Gr≥3 GU toxicity was observed. HRQoL scores during treatment were lower in the HYPO compared with CVRT; however, recovering within the 3-month post-radiotherapy period. A trend toward superior locoregional control was observed in the HYPO. Notably, para-aortic control at 24 months was significantly higher in the HYPO (100% vs 71.2%, P=.003). No significant differences were observed in local control or overall survival at the time of analysis. HYPO with modern techniques is feasible for LACC, significantly reducing OTT. A trend towards higher yet tolerable acute and late GI toxicity warrants further investigation. Encouragingly, HYPO showed promising locoregional control. thaiclinicaltrials.org (TCTR20210812003).

Factors Affecting D90 High-risk Clinical Target Volumes (HR-CTV dose) of Intracavitary and Interstitial Brachytherapy in Locally Advanced Cervical Cancer

Intracavitary brachytherapy alone covers a limited target volume; however, intracavitary and interstitial brachytherapy (IC/IS) can increase the dose coverage. We aim to assess the factors that impact D90 high-risk clinical target volume (HR-CTV) dose. We also assess clinical outcomes and toxicities for 3D image-based brachytherapy. We included a total of 424 cervical cancer patients with FIGO stage IB1 to IVA who received chemoradiation and high-dose-rate brachytherapy between 2014 and 2023. Target delineation was per GEC-ESTRO guidelines with the aim to achieve total dose of ≥85 Gy (D90 HR-CTV) in equivalent dose (EQD2). Implantation, tumour size, lateral extension, and HR-CTV volume were analysed. The median follow-up time was 24 months (range 1-107). The overall 2-year local control, progression-free survival, and overall survival rate were 90.3%, 75%, and 95.5%, respectively. Of 424 patients, 86.8% received a total dose of at least 85 Gy of D90 HR-CTV in EQD2. In multivariate analysis, IC/IS brachytherapy and HR-CTV volume were significant factors associated with HR-CTV D90 ≥ 85Gy in EQD2 (P = 0.012 and P = 0.000, respectively). Subgroup analysis of patients with HR-CTV volume >35 ml found that IC/IS was a significant factor in achieving HR-CTV D90 ≥ 85Gy in EQD2 (P = 0.017). At the median follow-up, patients with D90 HR-CTV ≥85 Gy achieved local control rates of 72.08% in small volume (<20 cm IC/IS brachytherapy may be used in patients with HR-CTV volumes greater than 35 ml to achieve total doses of D90 HR-CTV ≥85 Gy in EQD2. IC/IS brachytherapy also provide good local control with favorable toxicity profile.

Clinical Outcome Comparison between CT-Guided Versus all MRI-Guided Scenarios in Brachytherapy for Cervical Cancer: A Single-Institute Experience

Image-guided adaptive brachytherapy (IGABT) is the standard of care for patients with cervical cancer. The objective of this study was to compare the treatment outcomes and adverse effects of computed tomography (CT)-guided and magnetic resonance imaging (MRI)-guided scenarios. Data of patients with cervical cancer treated using external beam radiotherapy followed by IGABT from 2012 to 2016 were retrospectively reviewed. CT-guided IGABT was compared with the three modes of MRI-guided IGABT: pre-brachytherapy (MRI Pre-BT) without applicator insertion for fusion, planning MRI with applicator in-place in at least 1 fraction (MRI ≥1Fx), and MRI in every fraction (MRI EveryFx). Patient characteristics, oncologic outcomes, and late radiation toxicity were analyzed using descriptive, survival, and correlation statistics. Overall, 354 patients were evaluated with a median follow-up of 60 months. The 5-year overall survival (OS) rates were 61.5%, 65.2%, 54.4%, and 63.7% with CT-guided, MRI PreBT, MRI ≥1Fx, and MRI EveryFx IGABT, respectively with no significant differences (p = 0.522). The 5-year local control (LC) rates were 92.1%, 87.8%, 80.7%, and 76.5% (p = 0.133), respectively, with a significant difference observed between the CT-guided and MRI ≥1Fx (p = 0.018). The grade 3-4 late gastrointestinal toxicity rates were 6% in the CT-guided, MRI ≥1Fx, and MRI EveryFx, and 8% in MRI PreBT. The grade 3-4 late genitourinary toxicity rates were 4% in the CT-guided, 2% in MRI PreBT, 1% in MRI ≥1Fx, and none in MRI EveryFx. No significant differences were observed in the oncologic and toxicity outcomes among MRI PreBT, MRI ≥1Fx, and MRI EveryFx. CT-guided IGABT yielded an acceptable 5-year OS, LC, and toxicity profile compared with all MRI scenarios and is a potentially feasible option in resource-limited settings.

Platinum-Based Chemotherapy ‘Rechallenge’ in Advanced Non-ovarian Solid Malignancies

Platinum-based chemotherapy forms the backbone of treatment for many solid cancers. However, resistance inevitably develops in those with advanced disease. Platinum rechallenge is a well-established concept in the management of ovarian cancer, small cell lung cancer and germ cell tumours. In other solid malignancies there is a lack of quality evidence to support platinum rechallenge, yet it is a widely adopted strategy. Often, patients are within the last year of life, making questions of efficacy, treatment-related toxicity and quality of life critical factors for treatment recommendations. In this overview we appraise the available evidence for platinum rechallenge and strategies being developed to attempt resensitisation of tumours to platinum-based chemotherapy.

Modern Tools for Modern Brachytherapy

This review aims to showcase the brachytherapy tools and technologies that have emerged during the last 10 years. Soft-tissue contrast using magnetic resonance and ultrasound imaging has seen enormous growth in use to plan all forms of brachytherapy. The era of image-guided brachytherapy has encouraged the development of advanced applicators and given rise to the growth of individualised 3D printing to achieve reproducible and predictable implants. These advances increase the quality of implants to better direct radiation to target volumes while sparing normal tissue. Applicator reconstruction has moved beyond manual digitising, to drag and drop of three-dimensional applicator models with embedded pre-defined source pathways, ready for auto-recognition and automation. The simplified TG-43 dose calculation formalism directly linked to reference air kerma rate of high-energy sources in the medium water remains clinically robust. Model-based dose calculation algorithms accounting for tissue heterogeneity and applicator material will advance the field of brachytherapy dosimetry to become more clinically accurate. Improved dose-optimising toolkits contribute to the real-time and adaptive planning portfolio that harmonises and expedites the entire image-guided brachytherapy process. Traditional planning strategies remain relevant to validate emerging technologies and should continue to be incorporated in practice, particularly for cervical cancer. Overall, technological developments need commissioning and validation to make the best use of the advanced features by understanding their strengths and limitations. Brachytherapy has become high-tech and modern by respecting tradition and remaining accessible to all.

A Narrative Synthesis of Literature on the Barriers to Timely Diagnosis and Treatment of Cancer in Sub-Saharan Africa

Poor cancer survival outcomes in sub-Saharan Africa (SSA) have been linked to delays in diagnosis and treatment. Here we present a detailed overview of the qualitative literature evaluating the barriers to receiving timely diagnosis and treatment of cancer in SSA. The PubMed, EMBASE, CINAHL, PsycINFO databases were searched to identify qualitative studies reporting on barriers to timely diagnosis of cancer in SSA published between 1995 and 2020. A systematic review methodology was applied, including quality assessment and narrative data synthesis. We identified 39 studies, of which 24 focused on breast or cervical cancer. Only one study focused on prostate cancer and one on lung cancer. When exploring factors contributing to delays, six key themes emerged from the data. The first theme was health service barriers, which included: (i) inadequate numbers of trained specialists; (ii) limited knowledge of cancer among healthcare providers; (iii) poor co-ordination of care; (iv) inadequately resourced health facilities; (v) negative attitudes of healthcare providers towards patients; (vi) high cost of diagnostic and treatment services. The second key theme was patient preference for complementary and alternative medicine; the third was the limited understanding of cancer among the population. The fourth barrier was a patient's personal and family obligations; the fifth was the perceived impact of cancer and its treatment on sexuality, body image and relationships. Finally, the sixth was the stigma and discrimination faced by patients following a diagnosis of cancer. In conclusion, health system, patient level and societal factors all influence the likelihood of timely diagnosis and treatment for cancer in SSA. The results provide a focus for targeting health system interventions, particular with regards to awareness and understanding of cancer in the region.

Lichen Sclerosis is Associated With a High Rate of Local Failure After Radio(chemo)therapy for Vulvar Cancer

Radio(chemo)therapy plays an important role in the treatment of vulvar cancer, either as postoperative treatment or as definitive treatment in patients who present with inoperable disease. Only limited data are available regarding outcome after modern state of the art radio(chemo)therapy and more information regarding prognostic factors are warranted. The aim of this study was to evaluate disease outcomes after radio(chemo)therapy in patients with vulvar cancer with special emphasis on the impact of lichen sclerosis on local control. All consecutive patients (n = 109) from the western half of Denmark who were treated with definitive (n = 52) or postoperative (n = 57) radio(chemo)therapy between January 2013 and January 2020 were included. Local control, cause-specific survival and overall survival, as well as morbidity, were analysed using Kaplan-Meier statistics. Prognostic factors for local control were analysed in univariate and multivariate analysis. At a median follow-up of 35 (4-95) months, 46 (42.0%) patients were diagnosed with recurrence. Eighty per cent of the recurrences were located to the vulva region, leading to a 5-year local control of 58.9% (confidence interval 47.9-69.9). Cause-specific survival was 62.9% (confidence interval 53.1-72.7), whereas overall survival was 58.0% (confidence interval 47.6-68.5). Grade 3-4 morbidity was diagnosed in 10 (9%) patients. Lichen sclerosis (hazard ratio 3.89; confidence interval 1.93-7.79) was an independent risk factors for local recurrence. Patients without lichen sclerosis had a 5-year local control rate of 83.6% (confidence interval 67.2-99.0) and 62.6% (confidence interval 43.2-82.0) after postoperative and definitive radio(chemo)therapy, respectively. In patients with lichen sclerosis, the local control rate was 44.0% (confidence interval 19.3-69.0) and 17.6% (confidence interval 0-30.0) after postoperative and definitive radio(chemo)therapy, respectively. Radio(chemo)therapy plays an important role in the treatment of vulvar cancer. However, despite dose escalation, a substantial proportion of patients experienced local relapse. Pre-existing lichen sclerosis seems to have a significant impact on the risk of recurrence. This should influence surveillance programmes for these patients.

The Current use of Adaptive Strategies for External Beam Radiotherapy in Cervical Cancer: A Systematic Review

Variability in the target and organs at risk (OARs) in cervical cancer treatment presents challenges for precise radiotherapy. Adaptive radiotherapy (ART) offers the potential to enhance treatment precision and outcomes. However, the increased workload and a lack of consensus on the most suitable ART approach hinder its clinical adoption. This systematic review aims to assess the current use of adaptive strategies for cervical cancer and define the optimal approach. A systematic review of current literature published between January 2012 and May 2023 was conducted. Searches used PubMed/Medline, Cochrane Library, and Web of Science databases, supplemented with the University of Manchester, Google Scholar, and papers retrieved from reference lists. The review assessed workflows, compared dosimetric benefits, and examined resources for each identified strategy. Excluded were abstracts, conference abstracts, reviews, articles unrelated to ART management, proton therapy, brachytherapy, or qualitative studies. A narrative synthesis involved data tabulation, summarizing selected studies detailing workflow for cervical cancer and dosimetric outcomes for targets and OARs. Sixteen articles met the inclusion criteria; these were mostly retrospective simulation planning studies, except four studies that had been clinically implemented. We identified five approaches for ART radiotherapy for cervical cancer: reactive and scheduled adaptation, internal target volume (ITV)-based approach using library of plans (LOP), fixed-margin approach using LOP, and real-time adaptation, with each approach reducing irradiated volumes without compromising target coverage compared to the non-ART approach. The LOP-based ITV approach is the most used and clinically assessed. Identifying the optimal strategy is challenging due to dosimetric assessment limitations. Implementing cervical cancer ART necessitates strategic optimization of clinical benefits and resources through research, including studies to identify the optimal frequency, and prospective evaluations of toxicity.

Improved Dosimetry with Daily Online Adaptive Radiotherapy for Cervical Cancer: Waltzing the Pear

Standard of care radiotherapy for locally advanced cervical cancer includes large margins to ensure the uterocervix remains within the treatment fields over the course of treatment. Daily online cone-beam adaptive radiotherapy corrects for interfractional changes by adjusting the plan to match the target position during each treatment session, thus allowing for significantly reduced clinical target volume (CTV) to planning target volume (PTV) margins. We hypothesise that reduced margins from daily online adaptive radiotherapy will reduce organ at risk dose without compromising target coverage. Ten patients with cervical cancer (stage IIB-IIIC2) were treated with definitive chemoradiation using daily online cone-beam adaptive radiotherapy in 25-27 fractions. Initial and all adapted treatment plans were generated with CTV to PTV margins versus standard of care image-guided radiotherapy (IGRT) plans as follows: cervix/uterus/gross tumour volume (0.5 versus 1.5 cm), parametria/vagina (0.5 versus 1.0 cm) and nodal chains and gross nodes (0.5 versus 0.5 cm). IGRT plans were created and copied to synthetic computed tomography scans and contours generated from each daily adapted fraction. The dosimetry of each clinically treated online adapted fraction was compared with emulated IGRT plans. Statistical significance was defined as P < 0.05. Daily online cone-beam adaptive radiotherapy significantly improves bowel bag dosimetry compared with IGRT, with a reduction in V40 by an average of 91.3 cm Reduced CTV to PTV margins achievable with daily online adaptive radiotherapy improves organ at risk dosimetry and target coverage when compared with standard of care IGRT for locally advanced cervical cancer. The clinical impact of improved dosimetry is currently undergoing investigation.

Particle Beam Re-irradiation in Oligo Recurrent Gynecological Malignancies

This study aimed to evaluate the efficacy and safety of proton beam radiotherapy (PBRT) and carbon ion radiotherapy (CIRT) as salvage treatments for oligorecurrent gynecological cancers. A retrospective analysis was performed on consecutive patients treated with PBRT or CIRT for recurrent gynecological tumors. The primary endpoints included the objective response rate (ORR) as well as 1- and 2-year local control (LC) survival rates. Toxicity was assessed as a secondary endpoint and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) 5.0 scale. Actuarial outcomes were evaluated using the Kaplan-Meier method, and predictors were identified with the Log-rank test. A total of 27 patients (median age: 64.5 years; IQR = 56.0, 69.0) with 28 recurrent lesions were treated with either PBRT (N = 12) or CIRT (N = 16), without concurrent systemic therapies. The majority of patients were treated for recurrences of cervical cancer (N = 8, 29%), endometrial cancer (N = 7, 25%), and ovarian cancer (N = 6, 21%). The most frequent site of recurrence was lymph nodes (N = 14, 50%). Lesions treated with CIRT had a larger volume (median volume 118 [IQR = 66, 233.5] vs. 99 [IQR = 54, 152.3]) and lower alpha/beta ratios (median = 3.8 [IQR = 3.5, 4.5] vs. 7.3 [IQR = 3.5, 10.0]). The overall ORR was 68% within 6 months and did not significantly vary between the groups (p = 0.687). The 1- and 2-year LC rates were 100% and 100% for PBRT, compared to 83% and 62% for CIRT (p = 0.075). Larger lesion volumes (p = 0.035) and failure to achieve an ORR (p = 0.009) were associated with worse LC outcomes, while lymph node recurrences (p = 0.052) and lower alpha/beta ratios (p = 0.078) were potentially linked to better LC. Both treatments were well tolerated, with no grade ≥3 toxicities observed. PBRT and/or CIRT appeared as an effective and safe option for recurrent gynecological cancers in a real-world setting. Larger cohorts and longer follow-up are needed for further validation and refining patient selection.

Long-term Outcomes of Cervical Cancer Patients Treated With Definitive Chemoradiation Following a Complete Metabolic Response

In Reply to Onal et al. Long-term Outcomes of Cervical Cancer Patients Treated with Definitive Chemoradiation Following a Complete Metabolic Response

Clinical Outcomes of Radiotherapy in Vaginal and Vulvar Melanoma: A High-volume Centre's Experience With a Rare Disease

Incidence, Treatment and Outcomes of Cervical Cancer in Low- and Middle-income Countries

Cervical cancer is one of the most common cancers in developing nations. It has had a tremendous impact on the lifetime of millions of women over the last century and continues to do so. In this collaborative clinicians' review, we highlight the incidence, treatment and clinical outcomes of cervical cancer in low-income (LICs) and low- and middle-income countries (LMICs) across Asia, South America, South Africa and Eastern Europe. With the cervical cancer burden and locally advanced cancers being high, the majority of LICs/LMICs have been striving to adhere to optimal evaluation and treatment guidelines. However, the huge gap in resource availability, rural versus urban disparity and access to resources have led to poor compliance to evaluation, treatment and post-treatment rehabilitation. To mitigate the overwhelming numbers, various treatment strategies like neoadjuvant chemotherapy, hypofractionation radiation schedules (both external and brachytherapy) have been attempted with no major success. Also, the compliance to concurrent chemoradiation in various regions is a major challenge. With the burden of advanced cancers, the lack of palliative care services and their integration in cancer care is still a reality.

Component Patterns and Survival Outcomes in Patients with Mixed Malignant Ovarian Germ Cell Tumors: A Retrospective Cohort Study

To evaluate the component patterns and risk stratification in patients with mixed malignant ovarian germ cell tumors (mMOGCT). A retrospective study of 70 mMOGCT patients treated in our hospital between 2000 and 2022 was conducted. The recurrence-free survival (RFS), disease-specific survival (DSS), and risk stratification systems based on scoring the identified prognostic factors were assessed. Yolk sac tumor component was the most common type (80%), followed by dysgerminoma (50%), immature teratoma (40%), embryonic carcinoma (27.1%), and chorionic carcinoma (15.7%). The 5-year RFS and DSS rates were 77.9% and 87.9%, respectively. International federation of gynecology and obstetrics (FIGO) stage III-IV (RR 3.253, P = 0.029) and normalization of tumor marker (TM) ≤ 3 cycles of chemotherapy (RR 6.249, P = 0.017) were risk factors for RFS and DSS, respectively. Significant DSS (RR 8.268, P = 0.006) was also noted between patients who had normalized TM ≤ 4 and ≥5 cycles of chemotherapy. FIGO stages I-II and stages III-IV were scored as 0 and 2, respectively. AFP normalization ≤3, 4, and ≥5 cycles of chemotherapy were scored as 0, 1, and 4, respectively. A total score of 0, 1-2, and ≥3 stratified patients into low-risk (43 patients), intermediate-risk (13 patients), and high-risk groups (14 patients), respectively. Patients in three risk stratifications manifested significant differences in DSS (P = 0.010) but not in RFS (P > 0.05). Distinct different component patterns existed among mMOGCT patients, and predicting survival outcomes in a universal model was challenging.

Perspectives of Healthcare Professionals on the Management and Treatment of Advanced Ovarian Cancer in the UK: Results From the KNOW-OC Survey

New treatment options for advanced ovarian cancer have the potential to significantly change the treatment pathway in the UK. Understanding the structures and responsibilities of multidisciplinary teams/tumour boards (MDT) and regional variations will enable services to adapt more effectively to these changes. The KNOW-OC survey was conducted in 2020 to understand the views of a selected group of 66 healthcare professionals (HCPs) involved in advanced ovarian cancer care in UK hospitals. The results showed that MDT involvement in the management of advanced ovarian cancer varied depending on pathway stage and line of relapse, with 98.5% of HCPs responding that the MDT was involved in decisions at initial presentation, but only 40.9% for patients with multiple relapses. The MDT was mostly responsible for determining whether the patients would undergo primary or interval cytoreductive surgery according to 75.8% of respondents, and most HCPs (80.3%) stated that tumour dissemination patterns were the most important factor influencing this decision. The most commonly assessed biomarkers at the time of the survey were CA125, gBRCA and tBRCA. Homologous recombination deficiency was viewed as the second most important factor for determining prognosis, but few centres had access to testing at the time of survey completion. The use of active surveillance was expected to decrease in favour of first-line targeted therapies. Nearly all (98.5%) HCPs agreed there is a role for secondary cytoreductive surgery for the treatment of recurrence (for carefully selected patients). The results highlighted UK-specific geographical variation in the views of HCPs on MDT involvement and specific practices, such as molecular biomarker testing, and the overall treatment approach. Together, these findings improve the understanding of reported clinical practice across the UK for ovarian cancer and provide insight into decision-making associated with updates to recommendations for best practice (e.g. European Society for Medical Oncology/European Society of Gynaecological Oncology consensus statements) and the introduction of new treatment options.

Set-Up Errors, Organ Motion, Tumour Regression and its Implications on Internal Target Volume–Planning Target Volume During Cervical Cancer Radiotherapy: Results From a Prospective Study

Uterocervical motions and organ filling during cervical cancer conformal radiotherapy is complex. This prospective, observational study investigated set-up margins (clinical target vo, ume [CTV] to planning target volume [PTV]) for pelvic nodal CTV and internal margin (CTV to internal target volume [ITV]) expansions for uterocervical movements during cervical cancer radiotherapy. During cervical cancer radiotherapy, a daily kilovoltage, cone-beam computed tomography (CBCT) scan was acquired. Bony anatomy-based rigid co-registration and matching to vessels/pelvic nodal region was carried out to document shifts, errors (systematic and random) and to calculate CTV to PTV margins. Subsequently, soft-tissue matching was carried out at the mid-cervical region and uterine fundus to record shifts, errors and to calculate CTV to ITV margins. In 67 patients, 1380 CBCT scans were analysed. The mean (±standard deviation) couch shifts for CTV pelvic nodal region in all directions were within 4.5-5.3 mm, systematic and random errors 3.0-3.6 mm and set-up margins of within 10 mm (except anterior margin 10.3 mm). For the mid-cervical region, mean shifts were 4.5-5.5 mm, systematic and random errors 2-4 mm amounting to <10 mm internal margins (CTV-ITV for cervix) and for uterine fundus mean (±standard deviation) shifts were larger in the superior direction (12.1 mm) but 4.0-7.5 mm in other directions, systematic and random errors 2-7 mm amounting to anisotropic margins in various directions (10 mm in anterior-posterior and lateral directions, 12-20 mm in superior-inferior directions) (CTV-ITV for uterine fundus). Our study suggests anisotropic CTV to ITV and CTV to PTV margins for cervical cancer radiotherapy.

Adjuvant Radiotherapy in Stage II Endometrial Cancer: Selective De-intensification of Adjuvant Treatment

Risk stratification, including nodal assessment, allows for selective de-intensification of adjuvant radiotherapy in stage II endometrial cancer. Patterns of treatment and clinical outcomes, including the use of reduced volume 'mini-pelvis' radiotherapy fields, were evaluated in a population-based study. All patients diagnosed with pathological stage II endometrial cancer between 2000 and 2014, and received adjuvant radiotherapy in a regional healthcare jurisdiction were reviewed. Registry data were supplemented by a comprehensive review of patient demographics, disease characteristics and treatment details. The Charlson Comorbidity Score was calculated. Survival and recurrence data were analysed. In total, 264 patients met the inclusion criteria. Most patients had endometrioid histology (83%); 41% of patients had International Federation of Gynecologists and Obstetricians grade 1 disease. Half (49%) had surgical nodal evaluation; 11% received chemotherapy. Most patients (59%) were treated with full pelvic radiotherapy fields ± brachytherapy. Seventeen per cent of patients received mini-pelvis radiotherapy ± brachytherapy, whereas 24% received brachytherapy alone. Five-year recurrence-free survival was 87% for the entire cohort, with no significant difference by adjuvant radiotherapy approach. Only one patient receiving mini-pelvis radiotherapy ± brachytherapy recurred in the pelvis but outside of the mini-pelvis field. Recorded late toxicity rates were highest for full pelvis radiotherapy + brachytherapy. Risk stratification in a real-world setting allowed for selective de-intensification of adjuvant radiation with equivalent outcomes for stage II endometrial cancer. Mini-pelvis radiotherapy combined with brachytherapy is effective in highly selected patients, with the potential to decrease toxicity without compromising local control. Brachytherapy should be considered in low-risk stage II patients.

Defining the Optimal Treatment Strategy in Patients With Uterine Serous Carcinoma

Uterine serous carcinoma (USC) is an aggressive subtype of endometrial cancer with high rates of relapse and death. As adjuvant therapy might be beneficial in early-stage disease, the impact of standard complete surgical staging is questioned. Therefore, we wanted to explore the optimal treatment strategy for women diagnosed with USC. A retrospective multicentre study of women diagnosed with primary USC in the UK and the Netherlands. Treatment strategy in relation to overall survival and progression-free survival was recorded and evaluated with Kaplan-Meier and Cox regression analysis. Furthermore, primary surgical staging and/or adjuvant treatment in relation to patterns of recurrence were evaluated. In total, 272 women with a median age of 70 years were included. Most patients presented with International Federation of Gynecology and Obstetrics (FIGO) stage I disease (44%). Overall, 48% of patients developed recurrent disease, most (58%) with a distant component. Women treated with chemotherapy showed significantly better overall survival (hazard ratio 0.50, 95% confidence interval 0.31-0.81; P = 0.005) and progression-free survival (hazard ratio 0.48, 95% confidence interval 0.28-0.80; P = 0.04) in multivariable analysis. Furthermore, even in surgically staged women with FIGO stage IA disease, a high recurrence rate of 42% was seen. Women with USC who received adjuvant chemotherapy showed better survival rates compared with those who received other or no adjuvant treatment. The benefit of adjuvant chemotherapy was observed across all tumour stages, including surgically staged FIGO stage IA. These data question the role of surgical staging in the absence of macroscopic disease in USC.

Impact of Treatment Modality on Quality of Life Among Uterine Cancer Survivors

Our understanding of the impact of adjuvant therapy on longitudinal quality of life (QoL) following surgery for patients with uterine cancer is limited. The purpose of this study was to compare QoL in patients who have undergone surgery with or without radiation therapy for uterine cancer. This was a cross-sectional cohort study that examined women treated for uterine cancer at MD Anderson Cancer Center from 2006 to 2017. Participants included those who underwent hysterectomy/bilateral salphingo-oophorectomy alone, with brachytherapy or external beam radiation therapy (EBRT). A non-cancer cohort of women who underwent a hysterectomy/bilateral salphingo-oophorectomy for benign indications was also identified (non-CA). To compare QoL we used the Functional Assessment of Cancer Therapy - Endometrial survey (FACT-En), a validated survey used to assess QoL. The survey has five subscales: physical, social, emotional, functional and an endometrial cancer-specific subscale. Cohorts were compared using ANOVA tests. In total, 309 women responded to the questionnaire (hysterectomy/bilateral salphingo-oophorectomy 64, brachytherapy 77, EBRT 96, non-CA 72). The median time from surgery to survey completion was 6.7 years. The mean total FACT-En score for the entire cohort was 144 [standard deviation 22]. Overall QoL was different between cohorts, with the EBRT cohort reporting the lowest QoL (mean 139.4 [21.6]) and the brachytherapy cohort the highest (150.6 [18.2], P = 0.006). Among patients who had undergone cancer treatment, the EBRT cohort reported the worst endometrial-specific QoL (53.5 [8.6]), while again the brachytherapy group reported the highest score (57.5 [6.1], P = 0.007). QoL differences in women who have undergone different treatments for uterine cancer may persist years after treatment. In women with endometrial cancer who require adjuvant therapy, brachytherapy does not appear to have any long-term detriments on QoL.

Computed Tomography-Based Interstitial Brachytherapy for Recurrent Cervical Carcinoma in the Vaginal Apex

To determine the factors influencing the outcomes of patients with recurrences post-hysterectomy for cervical cancers treated with external beam radiotherapy (EBRT) and interstitial brachytherapy. This prospective study accrued 90 patients between October 2008 and May 2014. All patients had had a prior hysterectomy and were diagnosed with recurrent vaginal apex cancers with squamous cell carcinomas. All underwent EBRT of 50 Gy (2 Gy/fraction) using tomotherapy-based image-guided intensity-modulated radiotherapy with concurrent chemotherapy of weekly cisplatin (40 mg/m At a median follow-up of 74 months (4-123 months), 10/90 (11%) patients had local failure as the first site of relapse and 12/90 (13.3%) had first distant relapse. Only one patient had synchronous local and distant relapse. The 7-year local relapse-free, disease-free and overall survival were 87.6, 68.3 and 68.3%, respectively. Grade 2 and 3 rectal toxicity were seen in 5.6 and 3.1% of patients, respectively. Among these, two (2.2%) patients underwent temporary diversion colostomy due to vaginal sigmoid and rectovaginal fistula. Grade 2 and 3 bladder toxicity were seen in 5.6 and 1.1% of patients, respectively. In summary, the lateral disease extent (P = 0.048) and the presence of nodal disease at diagnosis (P = 0.08) had a statistically significant or borderline impact on local relapse without any impact on disease-free survival. Tumour size in itself did not affect overall survival. With the integration of EBRT and interstitial brachytherapy, most vaginal apex recurrences can be salvaged. An excellent local control and survival is achievable using intensity-modulated radiotherapy with image guidance and concurrent chemotherapy followed by high dose rate interstitial brachytherapy.

Cervical and Endometrial Cancer – A Tale of Two Halves?

Adjuvant Therapy for High-risk Endometrial Carcinoma

About one-fifth of endometrial cancers are 'high risk', which carries a poorer prognosis. Management strategies to optimise their survival have been under investigation for many years. Despite recent advances, their overall survival remains relatively poor. The definition of high risk in endometrial cancers has been based on clinicopathological factors until recently, when molecular profiling has shown greater discrimination. There is, however, poor correlation between traditional clinicopathological factors and their molecular profile. This is the subject of ongoing trials to better individualise adjuvant post-hysterectomy treatment. The management of high-risk tumours is traditionally based on surgery followed by radiotherapy, despite no proven overall survival benefit in early stages. The place of chemotherapy remains under investigation, with recent trials showing benefit in more advanced stages. The Post Operative Radiation Therapy in Endometrial Carcinoma (PORTEC) and Gynecologic Oncology Group trials support the use of chemoradiation and chemotherapy for stage III and adverse histological subgroups. In addition, there is now early evidence of correlation between benefit from adjuvant chemotherapy based on molecular alterations in the tumour cells. In this review, we look at the current evidence on management strategies in the evolving era of molecular diagnosis and stratification.

Laparoscopic and Robotic Surgery for Endometrial and Cervical Cancer

Minimally invasive surgery (MIS) has many benefits, in the form of reduced postoperative morbidity, improved recovery and reduced inpatient stay. It is imperative, however, when new techniques are adopted, in the context of treating oncology patients, that the oncological efficacy and safety are established rigorously rather than assumed based on first principles. Here we have attempted to provide a comprehensive review of all the contentious and topical themes surrounding the use of MIS in the treatment of endometrial and cervix cancer following a thorough review of the literature. On the topic of endometrial cancer, we cover the role of laparoscopy in both early and advanced disease, together with the role and unique benefits of robotic surgery. The surgical challenge of patients with a raised body mass index and the frail and elderly are discussed and finally the role of sentinel lymph node assessment. For cervical cancer, the role of MIS for staging and primary treatment is covered, together with the interesting and highly specialist topics of fertility-sparing treatment, ovarian transposition and the live birth rate associated with this. We end with a discussion on the evidence surrounding the role of adjuvant hysterectomy following radical chemoradiation and pelvic exenteration for recurrent cervical cancer. MIS is the standard of care for endometrial cancer. The future of MIS for cervix cancer, however, remains uncertain. Current recommendations, based on the available evidence, are that the open approach should be considered the gold standard for the surgical management of early cervical cancer and that MIS should only be adopted in the context of research. Careful counselling of patients on the current evidence, discussing in detail the risks and benefits to enable them to make an informed choice, remains paramount.