Advanced Uterine Cervical Cancer Research Articles

18F]FDG-PET/CT-based risk stratification in women with locally advanced uterine cervical cancer

Background[18F]FDG-PET/CT is used for staging and treatment planning in patients with locally advanced cervical cancer (LACC). We studied if a PET-based prediction model could provide additional risk stratification beyond International Federation of Gynaecology and Obstetrics (FIGO) staging in our population with LACC to aid treatment decision making.MethodsIn total, 183 patients with LACC treated with chemoradiation between 2013 and 2018 were included. Patients were treated according to FIGO 2009 and retrospectively reclassified according to FIGO 2018 staging system. After validation of an existing PET-based prediction model, the predicted recurrent free survival (RFS), disease specific survival (DSS) and overall survival (OS) at 1, 3, and 5 years, based on metabolic tumor volume (MTV), maximum standardized uptake value (SUVmax) and highest level of [18F]FDG-positive node was calculated. Then the observed survival was compared to the predicted survival. An area under the curve (AUC) close to or higher than 0.7 was considered adequate for accurate prediction. The Youden (J) index defined survival chance cutoff values for low and high risk groups.ResultsAll AUC values for the comparison between predicted and observed outcomes were > 0.7 except for 5-year RFS and for 5-year OS which were close to 0.7 (0.684 and 0.650 respectively). Cutoff values for low and high risk survival chance were 0.44 for the 3-year RFS and 0.47 for the 5-year OS. The FIGO 2009 system could not differentiate between the risk profiles. After reclassification according to FIGO 2018, all patients with stage IIIC2 and IVB fell in the high risk and almost all patients with stages IB2-IIIB and IVA in the low risk group. In patients with stage IIIC1 disease the FIGO stage cannot discriminate between the risk profiles.ConclusionsLow and high risk patients with LACC can be identified with the PET-based prediction model. In particular patients with stage IIIC1 need additional risk stratification besides the FIGO 2018 staging. The Kidd model could be a useful tool to aid treatment decision making in these patients. Our results also support the choice of [18F]FDG-PET/CT imaging in patients with LACC.

Early prediction of distant metastasis in patients with uterine cervical cancer treated with definitive chemoradiotherapy by deep learning using pretreatment [ 18 F]fluorodeoxyglucose positron emission tomography/computed tomography.

A deep learning (DL) model using image data from pretreatment [ 18 F]fluorodeoxyglucose ([ 18 F] FDG)-PET or computed tomography (CT) augmented with a novel imaging augmentation approach was developed for the early prediction of distant metastases in patients with locally advanced uterine cervical cancer. This study used baseline [18F]FDG-PET/CT images of newly diagnosed uterine cervical cancer patients. Data from 186 to 25 patients were analyzed for training and validation cohort, respectively. All patients received chemoradiotherapy (CRT) and follow-up. PET and CT images were augmented by using three-dimensional techniques. The proposed model employed DL to predict distant metastases. Receiver operating characteristic (ROC) curve analysis was performed to measure the model's predictive performance. The area under the ROC curves of the training and validation cohorts were 0.818 and 0.830 for predicting distant metastasis, respectively. In the training cohort, the sensitivity, specificity, and accuracy were 80.0%, 78.0%, and 78.5%, whereas, the sensitivity, specificity, and accuracy for distant failure were 73.3%, 75.5%, and 75.2% in the validation cohort, respectively. Through the use of baseline [ 18 F]FDG-PET/CT images, the proposed DL model can predict the development of distant metastases for patients with locally advanced uterine cervical cancer treatment by CRT. External validation must be conducted to determine the model's predictive performance.

Proteogenomic Analysis of Human Uterine Cervical Cancer (UCC) Reveals Treatment-Resistant Subtypes of UCC

Locally advanced uterine cervical cancer (UCC) is treated by radiotherapy with concurrent chemotherapy, but heterogenous treatment responses are frequently observed. To better optimize therapeutic options based on molecular signatures, we performed proteogenomic analysis of UCC. UCC tissue and blood samples were collected from patients who underwent primary radiotherapy ± chemotherapy at the National Cancer Center (NCC) in Korea from July 2004 to March 2020. Most samples were obtained via biopsy. Genomic DNA for WES was isolated from frozen biopsy tumor tissues and peripheral blood buffy-coat of patients. Both global proteome and phosphoproteome were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Whole exome sequencing, RNA sequencing, global proteomics and phosphoproteomics were performed using 253, 337, and 147 cervical cancer samples, respectively. Patient-derived xenograft were established using intratongue implantation using 2 primary cell lines from sub3 and sub5, and flow cytometric analysis was performed. Fourteen significantly mutated genes (SMG) were found in our study cohort which include 5 newly identified SMGs. Mutation-phosphorylation analysis revealed association with apoptosis and actin cytoskeleton pathway. Proteogenomic analysis defined 6 molecular subtypes of UCC. Of those, 3 subtypes (i.e., Sub3, Sub5 and Sub6) were associated with treatment-resistant phenotypes. The cell-type deconvolution analysis suggested activated stroma with activation of cancer-associated fibroblast in Sub 3, while Sub5 showed low levels of activated stroma and high levels of myeloid immune cells. FACS analysis of UCC mouse models established from these 2 radio-resistant primary cell lines showed high component of PDGFRA+CAF infiltration in Sub 3, and high level of PVR+CD45+ immune cells mainly composed of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) in Sub5. For Sub6, genes and/or protein signatures represented mucin-related processes (e.g., mucin glycosylation/sugar metabolism), which are linked to metastasis-associated Tn antigen production. The proteogenomic analysis thus suggests potential targets for radiotherapy-resistant subtypes of UCC; secretory factors from activated stroma and cancer-associated fibroblast (Sub3); RHOA signaling, PVR, and PMN-MDSCs (Sub5), and keratin/chondroitin sulfate proteoglycan and Tn antigen production (Sub6). Our study shows the importance of proteogenomic analysis in unveiling the subtype specific molecular pathways of UCC that are beyond reach by genomic data alone. The validity of our molecular pathway and cellular signatures linking these pathways should be further validated through detailed functional experiments and in larger UCC cohorts.

Access to palliative care in patients with advanced cancer of the uterine cervix in the low- and middle-income countries: a systematic review

BackgroundWomen with advanced uterine cervical cancer suffer from a combination of moderate to severe physical, psychological, social, and spiritual distress due to their disease and are in need of palliative care to improve their quality of life. Approximately 85% of the women live in the low- and middle-income countries. Whether these women and their families access palliative care is not known.ObjectivesTo understand the geographic accessibility, availability, financial accessibility, and acceptability of palliative care by patients with advanced cervical cancer and their families.MethodsWe conducted a Systematic review following PRISMA guidelines in CINAHL, Cochrane Central Register of Controlled Trials, MEDLINE, PsychINFO, PubMed and Scopus for the core concepts: palliative care, access, advanced uterine cervical cancer. Eligible articles were published in English, contained original data on experiences of patients and/or caregivers including symptoms management, and discussed available resources, communication, satisfaction, and healthcare utilization.ResultsOverall there was limited access to palliative care with the few available facilities located in cities, far from the rural areas where most women lived. Pervasive poverty was common with poor affordability of healthcare, travelling, accommodation, and subsistence expenses. Misconceptions and poor knowledge of the disease, cultural beliefs and attitudes, and other health system insufficiencies also presented challenges for access.ConclusionConcerted effort should be made to improve availability of palliative care facilities. Health education to address misconceptions and other cognitive barriers that limit access among cervical cancer patients and their families should be urgently undertaken in the LMICs.

Pain in High-Dose-Rate Brachytherapy for Cervical Cancer: A Retrospective Cohort Study.

High-dose-rate brachytherapy (HDR) is part of the main treatment for locally advanced uterine cervical cancer. Our aim was to evaluate the incidence and intensity of pain and patients' satisfaction during HDR. Risk factors for suffering pain were also analyzed. A retrospective study was carried out by extracting data from patients who had received HDR treatment for five years. Postoperative analgesia had been administered using pre-established analgesic protocols for 48 h. Pain assessment was collected according to a protocol by the acute pain unit. Analgesic assessment was compared according to analgesic protocol administered, number of needles implanted, and type of anesthesia performed during the procedure. From 172 patients treated, data from 247 treatments were analyzed. Pain was considered moderate in 18.2% of the patients, and 43.3% of the patients required at least one analgesic rescue. Patients receiving major opioids reported worse pain control. No differences were found regarding the analgesic management according to the intraprocedural anesthesia used or the patients' characteristics. The number of inserted needles did not influence the postoperative analgesic assessment. Continuous intravenous infusion of tramadol and metamizole made peri-procedural pain during HDR mild in most cases. Many patients still suffered from moderate pain.

Lymphatic mapping for image-guided radiotherapy in patients with locally advanced uterine cervical cancer: a feasibility study

BackgroundLymph node metastasis is an important prognostic factor in locally advanced cervical cancer (LACC). No imaging method can successfully detect all (micro)metastases. This may result in (lymph node) recurrence after chemoradiation. We hypothesized that lymphatic mapping could identify nodes at risk and if radiation treatment volumes are adapted based on the lymphatic map, (micro)metastases not shown on imaging could be treated. We investigated the feasibility of lymphatic mapping to image lymph nodes at risk for (micro)metastases in LACC and assessed the radiotherapy dose on the nodes at risk.MethodsPatients with LACC were included between July 2020 and July 2022. Inclusion criteria were: ≥ 18 years old, intended curative chemoradiotherapy, investigation under anesthesia. Exclusion criteria were: pregnancy and extreme obesity. All patients underwent abdominal MRI, [18F]FDG-PET/CT and lymphatic mapping after administration of 6–8 depots of 99mTc]Tc-nanocolloid followed by planar and SPECT/CT images 2–4 and 24 h post-injection.ResultsSeventeen patients participated. In total, 40 nodes at risk were visualized on the lymphatic map in 13/17 patients with a median of two [range 0–7, IQR 0.5–3] nodes per patient, with unilateral drainage in 4/13 and bilateral drainage in 9/13 patients. No complications occurred. The lymphatic map showed more nodes compared to suspicious nodes on MRI or [18F]FDG-PET/CT in 8/14 patients. Sixteen patients were treated with radiotherapy with 34 visualized nodes on the lymphatic map. Of these nodes, 20/34 (58.8%) received suboptimal radiotherapy: 7/34 nodes did not receive radiotherapy at all, and 13/34 received external beam radiotherapy (EBRT), but no simultaneous integrated boost (SIB).ConclusionLymphatic mapping is feasible in LACC. Almost 60% of nodes at risk received suboptimal treatment during chemoradiation. As treatment failure could be caused by (micro)metastasis in some of these nodes, including nodes at risk in the radiotherapy treatment volume could improve radiotherapy treatment outcome in LACC.Trail registration The study was first registered at the International Clinical Trial Registry Platform (ICTRP) under number of NL9323 on 4 March 2021. Considering the source platform was not operational anymore, the study was retrospectively registered again on February 27, 2023 at CilicalTrials.gov under number of NCT05746156.

Hands-on seminar for image-guided adaptive brachytherapy and intracavitary/interstitial brachytherapy for uterine cervical cancer.

Compared with the implementation speed of image-guided adaptive brachytherapy for uterine cervical cancer, that of intracavitary and interstitial brachytherapy is slow, possible because it requires more invasive procedure of inserting needles directly into tumours. To accelerate the implementation speed of intracavitary and interstitial brachytherapy, a first hands-on seminar for image-guided adaptive brachytherapy and intracavitary and interstitial brachytherapy for uterine cervical cancer was held on 26 November 2022, supported by Japanese Society for Radiology and Oncology. This article deals with this hands-on seminar and difference of degree of confidence of participants in starting intracavitary and interstitial brachytherapy before and after the seminar. The seminar consisted of lectures regarding intracavitary and interstitial brachytherapy in the morning and hands-on practice of needle insertion and contouring, as well as dose calculation practice using the radiation treatment system in the evening. Prior to and following the seminar, participants completed a questionnaire asking about their level of confidence in performing intracavitary and interstitial brachytherapy, expressed between 0 and 10 (the higher the number, the stronger the confidence). A total of 15 physicians, six medical physicists and eight radiation technologists from 11 institutions attended the meeting. The median level of confidence before and after the seminar was 3 (range, 0-6) and 5.5 (range, 3-7), respectively, and a statistically significant improvement was observed (P<0.001). It was suggested that the hands-on seminar on intracavitary and interstitial brachytherapy for locally advanced uterine cervical cancer improved the level of confidence of the attendees and propelled their motivation, through which it is expected that the implementation of intracavitary and interstitial brachytherapy will be accelerated.

Phase Angle and Nutritional Status: The Impact on Survival and Health-Related Quality of Life in Locally Advanced Uterine Cervical Cancer.

The phase angle, an indicator of muscle mass status and membrane cell integrity, has been associated with low survival, poorer clinical outcomes, and worse quality of life among cancer patients, but information on women with uterine cervical cancer (UCCa) is scarce. In this prospective study, we used a bioelectrical impedance analyzer to obtain the PA of 65 women with UCCa. We compared the health-related quality of life and inflammatory and nutritional indicators between low PA and normal PA. The mean age was 52 ± 13. The low PA and normal PA groups differed in terms of the C-reactive protein (15.8 ± 19.6 versus 6.82 ± 5.02, p = 0.022), glucose (125.39 ± 88.19 versus 88.78 ± 23.08, p = 0.021), albumin (3.9 ± 0.39 versus 4.37 ± 0.30, p = 0.000), EORTC QLQ-C30 loss of appetite symptom scale score (33.33 (0.0-100.00) versus 0.0 (0.0-0.0), p = 0.005), and EORTC QLQ-CX24 menopausal symptoms scale score (0.0 (0.0-33.33) versus 0.0 (0.0-100.0), p = 0.03). The main finding of the present study is the interaction between PA and obesity as critical cofactors in the UCCa adeno and adenosquamous histologic variants, to a greater extent than cervical squamous cell carcinoma.

Emphysematous pyelonephritis after urinary diversion by percutaneous nephrostomy in patient with advanced cervical cancer: A case report

Emphysematous pyelonephritis is a severe kidney infection that is common in women and patients with diabetes mellitus, but rare in cancer patients. A 64-year-old patient with advanced uterine cervical cancer developed emphysematous pyelonephritis after urine diversion by percutaneous nephrostomy of the left kidney, which is a possible approach to this infection. Antibiotic therapy was started to achieve clinical improvement and preserve renal function, and radical nephrectomy was not an option due to the functional exclusion of the contralateral kidney. The patient progressed with worsening renal function; thus, she started outpatient hemodialysis, with improvement of the uremic encephalopathy. She died 7.7 months after admission, 1 month after treatment for emphysematous pyelonephritis. Treatment should be adjusted to the patients’ needs, including maintenance of hemodialysis to improve symptoms. Further investigation is needed to identify possible causes and prevent emphysematous pyelonephritis in cancer patients.

Integration of Consolidation Chemotherapy After Concurrent Chemoradiation in the Treatment of Locally Advanced Uterine Cervical Cancer.

Despite the current standard of concurrent chemoradiation (CCRT), around 30-40% are still dying from locally advanced cervical cancer. Increasing the radiation dose further was not a feasible option, but addition of chemotherapy further was tried due to the different toxicity profiles of it. So, the use of consolidation chemotherapy beyond CCRT has been studied. To evaluate the efficacy, toxicity, tumour response and loco-regional control following consolidation chemotherapy after concurrent chemoradiation in locally advanced carcinoma cervix (LACC). The patients were randomized into two arms: the conventional arm (control arm, n = 30) patients received conventional treatment with weekly injection cisplatin (35mg/m2) concurrently with pelvic external beam radiation (50Gy/25 fraction, 2Gy/fraction, 5 fraction weekly) followed by intracavitary radiotherapy of 21Gy in 3 fractions of 7Gy each by HDR brachytherapy. In the interventional arm (study arm, n = 30), patients received the standard treatment followed by 3 cycles of consolidation chemotherapy (paclitaxel + carboplatin) every three weekly. Haematological toxicity (grade 3 anaemia and grade 1 leucopenia, grade 1 and 2 thrombocytopenia) was higher in the study group. Renal, hepatic and gastrointestinal toxicity was more in the study arm. Peripheral neuropathy was mostly seen in the study arm. Median follow-up was 9months. Treatment response was better, and the rate of recurrence was less in the study arm. Addition of few cycles of consolidation chemotherapy after standard treatment is beneficial in patients with LACC with manageable toxicity and good compliance.

Prognostic Impact of Caspase-8, CDK9 and Phospho-CDK9 (Thr 186) Expression in Patients with Uterine Cervical Cancer Treated with Definitive Chemoradiation and Brachytherapy.

Introduction: After primary platinum-based chemoradiation of locally advanced uterine cervical cancer, a substantial proportion of women present with persistent, recurrent or metastatic disease, indicating an unmet need for biomarker development. Methods: We evaluated the clinical records of 69 cervical cancer patients (Federation of Gynecology and Obstetrics, FIGO Stage &gt; IB3) who were subjected to definitive CRT. Immunohistochemical scoring of caspase-8, cyclin dependent kinase 9 (CDK9) and phosphorylated (phospho-)CDK9 (threonine (Thr) 186) was performed on pretreatment samples and correlated with the histopathological and clinical endpoints, including relapse-free survival (RFS), distant metastasis-free survival (DMFS), cancer-specific survival (CSS) and overall survival (OS). Results: Lower levels of caspase-8 were more prevalent in patients with a higher T-stage (p = 0.002) and a higher FIGO stage (p = 0.003), and were significantly correlated with CDK9 expression (p = 0.018) and inversely with pCDK9 detection (p = 0.014). Increased caspase-8 levels corresponded to improved RFS (p = 0.005), DMFS (p = 0.038) and CSS (p = 0.017) in the univariate analyses. Low CDK9 expression was associated with worse RFS (p = 0.008), CSS (p = 0.015) and OS (p = 0.007), but not DMFS (p = 0.083), and remained a significant prognosticator for RFS (p = 0.003) and CSS (p = 0.009) in the multivariate analyses. Furthermore, low pCDK9 staining was significantly associated with superior RFS (p = 0.004) and DMFS (p = 0.001), and increased CSS (p = 0.022), and remained significant for these endpoints in the multivariate analyses. Conclusion: Increased caspase-8 and CDK9 levels correlate with improved disease-related outcomes in cervical cancer patients treated with CRT, whereas elevated pCDK9 levels predict worse survival in this patient population.

Fyn expression is associated with the response of patients with locally advanced uterine cervical squamous cell carcinoma to neoadjuvant chemotherapy.

Neoadjuvant chemotherapy (NAC) followed by surgery is the current standard of treatment for locally advanced uterine cervical cancer; however, its value and outcomes remain contested. Identifying biomarkers that allow for the prediction of the effect of NAC efficacy before initiation of treatment is essential, in order to assist in choosing the optimum therapeutic regimen to maximize the beneficial outcomes of treatment. In the present retrospective study, 44 patients with locally advanced uterine cervical squamous cell carcinoma who underwent NAC were divided into two groups: A NAC successful group and a NAC failure group, depending on the efficacy of NAC. Subsequently, the association between Fyn expression, a non-receptor tyrosine kinase that is a member of the Src family kinases, and NAC efficacy was determined; Fyn expression was detected by immunohistochemistry and assessed using a weighted scoring method. Additionally, the effect of Fyn knockdown on the sensitivity of a uterine cervical cancer cell line to cisplatin was determined. Notably, there were no significant differences between the two groups of patients regarding their characteristics. Regarding overall survival, the NAC successful group had a significantly longer survival time than the NAC failure group (P=0.01). Furthermore, the expression levels of Fyn in tumor tissues were significantly lower in the NAC successful group compared with those in the NAC failure group (P=0.003). The patients were subsequently divided into two groups (high expression group and low expression group) according to a cutoff value of 3, which was determined by producing a receiver operating characteristic curve from the weighted scores. The low expression group was significantly more sensitive to NAC than the high expression group (P<0.001). In vitro experiments revealed that Fyn knockdown significantly enhanced the sensitivity of uterine cancer cells to cisplatin (P<0.05). In conclusion, Fyn expression may be a potentially useful biomarker for predicting the response to NAC in patients with locally advanced uterine cervical squamous cell carcinoma, and may also be a promising molecular target for the management of uterine cancer.

Absolute band neutrophils count is a predictor of overall survival in advanced uterine cervical cancer.

Neutrophils play a role during the oncogenic process, and their count can be a prognostic marker. The objective was to evaluate the association of band and segmented neutrophils with prognostic factors, overall survival, and disease-free survival in advanced uterine cervical cancer (IIB to IVB staging). This study evaluated 88 patients diagnosed with uterine cervical cancer staging IIB to IVB. The recorded data from medical records were age, parity, staging, histological type, absolute count of total neutrophils, band neutrophils and segmented neutrophils, disease-free survival, and overall survival. Receiver-operating characteristic (ROC) curve was used to obtain the area under the curve (AUC) and determine the best cut-off values for each parameter. Survival was verified by the Kaplan-Meier method, and multivariate analysis was performed by Cox regression. The level of significance was ≤ 0.05. Regarding the total neutrophils, band, and segmented neutrophils count, a cut-off value of 6187/mm3, 273 mm3 and 6062/mm3 were found, respectively. Overall survival was shorter in patients with total neutrophils greater than 6187/mm3 (p = 0.012), band neutrophils greater than 273/mm3 (p = 0.001), and segmented neutrophils greater than 6062/mm3 (p = 0.013). After multivariate analysis considering the two types of neutrophils, only band neutrophils greater than 273/mm3 remained as an independent factor for shorter overall survival. The absolute count of band neutrophils greater than 273/mm3 was a potential predictor of shorter overall survival in women with invasive cervical cancer. This count can be of great clinical use, in addition to being inexpensive, less invasive, and easy to perform.

Japanese Society for Radiation Oncology Consensus Guidelines of combined intracavitary and interstitial brachytherapy for gynecological cancers.

It has been postulated that the combination of intracavitary and interstitial brachytherapy (IC/IS) is effective and safe for large and irregularly shaped uterine cervical cancer patients. However, due to its invasiveness compared to conventional intracavitary brachytherapy (ICBT), it has to be said that the implementation speed of IC/IS is slow. Until now, there have been no guidelines for required equipment, human resources, and procedural guide focusing solely on IC/IS. The purpose of this guideline is to provide radiation oncologists and medical physicists who wish to start IC/IS with practical and comprehensive guidance for a safe IC/IS introduction and to help accelerate the spread of the utilization of IC/IS nationwide. This is the English translation of the Japanese IC/IS Guidelines, and it was created in an effort to share the Japanese approach to the management of locally advanced uterine cervical cancer worldwide.

THE ROLE OF HYBRID BRACHYTHERAPY IN MANAGEMENT OF LOCALLY ADVANCED CERVICAL CANCER: DOSIMETRIC STUDY AND INITIAL RESULTS

Purpose:The aims of this study were to investigate the clinical feasibility and to report our preliminary treatment outcomes of combined intracavitary/interstitial brachytherapy (IC/IS BT), using a hybrid applicator and magnetic resonance imaging (MRI)based treatment planning in patients with locally advanced cervical cancer. Methods and Materials:Between January 2017 and December 2018, eight patients with locally advanced uterine cervical cancer were treated with primary radiation therapy including hybrid BT. Patients with distant metastasis other than para-aortic lymph node spread were excluded from this study. A hybrid applicator for guidance of parametrial needles was used to perform high-dose-rate-brachytherapy (HDR BT) with MRIbased treatment pre-planning. Parametrial extent of the disease or large residual disease in these patients was judged to exceed the coverage limit of intracavitary brachytherapy alone. The number of needles, chosen guiding holes through the ovoids, and insertion depths were based on the extent of residual disease. We investigated the dosimetric gain by comparing the clinical interstitial optimized plan (IC/IS clinical) with an additionally generated optimized plan without needle use (ICstudy). Results: The clinical use of the hybrid applicator system proved to be feasible in all 32 treatment fractions. The applicator Fletcher interstitial 6mm or Utrecht interstitial consists of the IC tandem and two ovoids that serves as a template for needle insertion. MRI preplanning was performed the week before the implant in 5 cases and the day of application with applicator in place in 3 cases. Four to eight needles were placed per fraction, and overall a total of 152 needles were used. Significant differences in IC/IS plan and IC study plan were derived for dose application to the target volume D90 high-riskclinical target volume (D90 CTV HR) was 90.1Gy (IC/ISclinical) vs 85.36 Gy(IC study)with an average gain of 4.74 Gy. Likewise, sparing of organs at risk differed significantly for bladder D2cc: 82,5 Gy(IC/ISclinical) vs 95.7 Gy (IC study) and rectum D2cc: 65,5 Gy (IC/ISclinical) vs 67.8 Gy (IC study).With an average follow-up of 27,25 months (range 18–34): no patient experienced local relapse, three patients experienced distant metastasis two of them died, no acute complications such as bleeding or organ penetration occurred due to needle placement, one patient developed recto-vaginal fistula. Conclusions: Our preliminary clinical experience indicates that combined intracavitary and interstitial MRI- based brachytherapy in patients with significant residual disease extending up to the distal third of parametriaafter external-beam therapy is feasible and allows excellent local control and a low rate of morbidity.

THE ROLE OF HYBRID BRACHYTHERAPY IN MANAGEMENT OF LOCALLY ADVANCED CERVICAL CANCER: DOSIMETRIC STUDY AND INITIAL RESULTS

Purpose: The aims of this study were to investigate the clinical feasibility and to report our preliminary treatment outcomes of combined intracavitary/interstitial brachytherapy (IC/IS BT), using a hybrid applicator and magnetic resonance imaging (MRI)based treatment planning in patients with locally advanced cervical cancer. Materials and Methods: Between January 2017 and December 2018, eight patients with locally advanced uterine cervical cancer were treated with primary radiation therapy including hybrid BT. Patients with distant metastasis other than para-aortic lymph node spread were excluded from this study. A hybrid applicator for guidance of parametrial needles was used to perform highdoseratebrachytherapy (HDR BT) with MRIbased treatment pre-planning. Parametrial extent of the disease or large residual disease in these patients was judged to exceed the coverage limit of intracavitary brachytherapy alone. The number of needles, chosen guiding holes through the ovoids, and insertion depths were based on the extent of residual disease. We investigated the dosimetric gain by comparing the clinical IC/IS optimized plan (IC/IS clinical) with an additionally generated optimized plan without needle use (ICstudy). Results: The clinical use of the hybrid applicator system proved to be feasible in all 32 treatment fractions. The applicator Fletcher interstitial 6mm or Utrecht interstitial consists of the IC tandem and two ovoids thatserves as a template for needle insertion. MRI preplanning was performed the week before the implant in 5 cases and the day ofapplication with applicator in place in 3 cases. Four to eight needles were placed per fraction, and overall a total of 152 needles were used. Significant differences in (IC/IS) plan and (IC study) plan were derived for dose application to the target volume D90 high-riskclinical target volume (D90 CTV HR) was 90.1Gy in (IC/ISclinical) plan vs 85.36 Gy in (IC study) plan with an average gain of 4.74 Gy. Likewise, sparing of organs at risk (OAR) differed significantly for bladder D2cc:82,5 Gy(IC/ISclinical) vs95.7 Gy (IC study) and rectum D2cc: 65,5 Gy (IC/ISclinical) vs 67.8 Gy (IC study).With an average follow-up of 27,25 months (range 18–34 months): no patient experienced local relapse, three patients experienced distantmetastasis two of them died, no acute complications such as bleeding or organ penetration occurred due to needle placement, one patient developed recto-vaginal fistula. Conclusions: Our preliminary clinical experience indicates that combined intracavitary and interstitial MRI based brachytherapy in patients with significant residual disease extending up to the distal third of parametriaafter externalbeam therapy is feasible and allows excellent local control and a low rate of morbidity.

Specific Immunotherapy in Advanced Cervical-Uterine Cancer Using Humanized Monoclonal Antibody Nimotuzumab and CIMAvax-EGF&lt;sup&gt;&amp;reg;&lt;/sup&gt; Therapeutic Vaccine

Cervical uterine cancer represents the fourth most common malignant neoplasm worldwide in the female sex in terms of incidence, principally from epithelial origen. The high expression of EGFR in this tumor leads to the search for therapeutic alternatives. An Expanded Access Clinical Program was carried out in parallel groups, randomized, multicenter and prospective study, to evaluate the survival of patients with advanced cervical carcinoma, without therapeutic alternative, who would be treated with the therapeutic vaccine CIMAvax-EGF®, the humanized mAb nimotuzumab or the combination of both products, which targeted EGF and EGFR respectively. The patients were included between 2008 and 2010 with a more than five years follow-up. The results show that the serious adverse events related to the experimental treatments were 0.9%; 1.1% and 2.6% and a median ITT survival of 9.1, 23.5, and 16.3 months for CIMAvax-EGF®, nimotuzumab and the combination of both, respectively. Thus fulfilling the hypothesis of safety and efficacy proposed in the investigation was achieved. The three therapeutic regimens achieved overall survival rates greater than 35% at 60 months, encouraging results for advanced uterine cervical cancer. A phase III clinical trial is proposed to consolidate these results in a greater number of patients with nimotuzumab as study drug.

PRMT1 expression predicts response to neoadjuvant chemotherapy for locally advanced uterine cervical cancer.

The standard care for patients with locally advanced cervical cancer is concurrent chemoradiotherapy. Successful neoadjuvant chemotherapy (NAC) can reduce tumor size and enable patients to be eligible for a hysterectomy, which can improve their prognosis. Selecting the right candidate for NAC is important since NAC failure results in switching to radiation therapy and can lead to a worse prognosis due to a delay in the initiation of the core therapy. Therefore, the identification of biomarkers that can predict the effect of NAC is essential. Previous reports have suggested a relationship between protein arginine methyltransferase (PRMT1) and chemoresistance in several types of cancer. PRMT1 has been demonstrated to methylate apoptosis signal-regulated kinase 1 and to inhibit its activity, thereby contributing to chemoresistance. The present study investigated the association between PRMT1 expression and the efficacy of NAC in locally advanced cervical cancer. Data from 53 patients with locally advanced uterine cervical cancer who were classified into two groups based on effective (n=28) and ineffective (n=25) responses to NAC treatment were evaluated. PRMT1 expression was investigated by immunohistochemistry and scored using a weighted scoring system. Additionally, the present study investigated the effect of RNA interference-mediated downregulation of PRMT1 on the sensitivity of cervical cancer cells to cisplatin in vitro. The results demonstrated that the NAC effective group had significantly lower weighted PRMT1 scores than the NAC ineffective group (P=0.030). In addition, lower tumor expression levels of PRMT1 were significantly associated with increased sensitivity to NAC (P=0.033). Furthermore, downregulation of PRMT1 expression in cervical cancer cells markedly improved their sensitivity to cisplatin in vitro. The present study suggested that PRMT1 expression has potential as a predictive marker of the efficacy of NAC in patients with locally advanced cervical cancer. This finding can contribute to improvements in the prognosis of these patients.

EANM/SNMMI practice guideline for [18F]FDG PET/CT external beam radiotherapy treatment planning in uterine cervical cancer v1.0

PurposeThe aim of this EANM / SNMMI Practice Guideline with ESTRO endorsement is to provide general information and specific considerations about [18F]FDG PET/CT in advanced uterine cervical cancer for external beam radiotherapy planning with emphasis on staging and target definition, mostly in FIGO stages IB3-IVA and IVB, treated with curative intention.MethodsGuidelines from related fields, relevant literature and leading experts have been consulted during the development of this guideline. As this field is rapidly evolving, this guideline cannot be seen as definitive, nor is it a summary of all existing protocols. Local variations should be taken into consideration when applying this guideline.ConclusionThe background, common clinical indications, qualifications and responsibilities of personnel, procedure / specifications of the examination, documentation / reporting and equipment specifications, quality control and radiation safety in imaging is discussed with an emphasis on the multidisciplinary approach.

Real-World Experience of Pembrolizumab Monotherapy in Patients with Recurrent or Persistent Cervical Cancer: A Korean Multi-Center Retrospective Study (KGOG1041).

Simple SummaryImmune checkpoint inhibitors have received considerable interest because of their ability to generate durable response in many intractable malignant solid tumors. The therapeutic results of immune checkpoint inhibitors in recurrent or advanced uterine cervical cancer, which associated with persistent infection with human papillomavirus, from several well-designed clinical trials are reported. However real-world experiences are not yet provided. In this study, we retrospectively assessed the efficacy and safety of pembrolizumab, one of the immune checkpoint inhibitors, in real-world practice among patients in Korea with recurrent or persistent cervical cancers. The results of this study show modest antitumor activity comparable to that found in previously reported clinical trials. Although in patients with favorable performance status, pembrolizumab showed effective antitumor activity. Some safety profiles should be carefully monitored during treatment.This study investigated the antitumor activity and safety of pembrolizumab in patients with recurrent cervical cancer in real-world practice. We conducted a multi-center retrospective study of patients with recurrent or persistent cervical cancer treated with pembrolizumab at sixteen institutions in Korea between January 2016 and March 2020. The primary endpoints were the objective response rate (ORR) and safety. Data were available for 117 patients. The median age was 53 years (range, 28–79). Sixty-four (54.7%) patients had an Eastern Cooperative Oncology Group (ECOG) performance status of ≥2. Forty-nine (41.9%) patients were stage ≥III at diagnosis. Eighty-eight (75.2%) patients had squamous cell carcinoma. The median number of prior chemotherapy lines was two (range, 1–6). During the median follow-up of 4.9 months (range, 0.2–35.3), the ORR was 9.4%, with three complete responses and eight partial responses. The median time to response was 2.8 months (range 1.3–13.1), and the median duration of response (DOR) was not reached. In the population of patients with favorable performance status (ECOG ≤1) (n = 53), the ORR was 18.9%, and the median DOR was 8.9 months (range, 7.3–10.4). Adverse events occurred in 55 (47.0%) patients, including eight (6.8%) patients who experienced grade ≥3 events, and two of them were suspicious treatment-related deaths. Pembrolizumab had modest antitumor activity in patients with recurrent cervical cancer comparable to that found in previously reported clinical trials. However, in patients with favorable performance status, pembrolizumab showed effective antitumor activity. Some safety profiles should be carefully monitored during treatment.