Comparison of outcomes and side effects for neoadjuvant chemotherapy with weekly cisplatin and paclitaxel followed by chemoradiation vs. chemoradiation alone in stage IIB–IVA cervical cancer: study protocol for a randomized controlled trial

Background Currently, the standard treatment for locally advanced cervical cancer is concurrent chemoradiation (CCRT). The effect of neoadjuvant chemotherapy in advanced cervical cancer is controversial. Studies have shown that the addition of a weekly regimen of neoadjuvant chemotherapy (NACT) followed by CCRT may be superior to a thrice-weekly regimen of NACT and CCRT. Among patients who had not received prior cisplatin, a cisplatin and paclitaxel (TP) regimen resulted in longer overall survival than other regimens. This study aims to investigate the feasibility, safety, and efficacy of NACT with weekly TP followed by CCRT. Methods This is a prospective, randomized, open-labeled, multicentered phase III study. Based on a 65% of 2-year disease-free survival (DFS) rate in the CCRT group and 80% of that in NACT followed by CCRT group, and on prerequisite conditions including an 8% loss to follow-up, a two-sided 5% of type I error probability, and an 80% of power, a total of 300 cases were required for enrollment. Patients with IIB–IVA cervical cancer will be randomly allocated in a 1:1 ratio to one of two intervention arms. In the study arm, patients will receive dose-dense cisplatin (40 mg/m2) and paclitaxel (60 mg/m2) weekly for 4 cycles followed by CCRT (45 Gy in 5 weeks concurrent with cisplatin 40 mg/m2 weekly) plus image-guided adaptive brachytherapy (IGBRT). In the control arm, patients will undergo CCRT treatment. The primary endpoint of the study is 2-year disease-free survival (DFS); the secondary endpoints are 5-year overall survival (OS) and disease-free survival (DFS), the response rate 3 months after treatment completion, grade III/IV adverse effects, and quality of life, and potential biomarkers for predicting treatment response will also be studied. Discussion The data gathered from the study will be used to determine whether NACT with weekly TP followed by CCRT may become an optimized treatment for locally advanced cervical cancer. Trial registration Chinese Clinical Trial Registry ChiCTR1900025327. Registered on 24 August 2019. medresman.org.cn ChiCTR1900025326

Prognostic value of tumor measurement parameters and SCC-Ag changes in patients with locally-advanced cervical cancer

Objective To investigate the prognostic relevance of specific measurement parameters such as tumor diameter, tumor volume, tumor volume reduction rate (TVRR), and changes in the squamous cell carcinoma antigen (SCC-Ag) level in patients with locally-advanced cervical cancer (LACC) undergoing concurrent radiotherapy and chemotherapy. Methods This was a retrospective study of 203 patients with stage IIA–IVA cervical squamous cell carcinoma who were newly diagnosed at our hospital between January 2011 and March 2015. Clinical data and pre-and post-treatment imaging information were collected and each parameter was calculated using 3DSlicer software. The pre/post-treatment tumor diameter (TDpre/post), tumor volume (TVpre/post), SCC-Ag (SCCpre/post), and TVRR, SCC-Ag reduction rate (SCCRR) were analyzed and their prognostic relevance evaluated. Results The median follow-up was 69 months. The 5-year overall survival (OS) and disease progression-free survival (PFS) rates were 69.5% and 64.5%, respectively. On univariate analysis, TDpre/post, TVpre/post, TVRR, SCCpre/post and SCCRR showed significant association with OS and PFS (P < 0.05). On multivariate analysis, TDpre [Hazard ratio (HR) = 0.373, P = 0.028], TDpost (HR = 0.376, P = 0.003) and SCCpost (HR = 0.374, P = 0.001) were independent predictors of OS. TVRR (HR = 2.998, P < 0.001), SCCpre (HR = 0.563, P = 0.041), and SCCpost (HR = 0.253, P < 0.001) were independent predictors of PFS. Tumor measurement parameters showed a positive correlation with SCC-Ag (P < 0.05). Conclusion TDpre/post, TVpre/post, TVRR, SCCpre/post, and SCCRR were prognostic factors in LACC. TDpre/post and SCCpost showed the most significant prognostic value. TVRR and SCCpre/post were closely related to disease progression. Further studies should investigate the correlation between measurement parameters of tumor and SCC-Ag.

Multidisciplinary Tumor Board Smart Virtual Assistant in Locally Advanced Cervical Cancer: A Proof of Concept

AimThe first prototype of the “Multidisciplinary Tumor Board Smart Virtual Assistant” is presented, aimed to (i) Automated classification of clinical stage starting from different free-text diagnostic reports; (ii) Resolution of inconsistencies by identifying controversial cases drawing the clinician’s attention to particular cases worthy for multi-disciplinary discussion; (iii) Support environment for education and knowledge transfer to junior staff; (iv) Integrated data-driven decision making and standardized language and interpretation.Patients and MethodData from patients affected by Locally Advanced Cervical Cancer (LACC), FIGO stage IB2-IVa, treated between 2015 and 2018 were extracted. Magnetic Resonance (MR), Gynecologic examination under general anesthesia (EAU), and Positron Emission Tomography–Computed Tomography (PET-CT) performed at the time of diagnosis were the items from the Electronic Health Records (eHRs) considered for analysis. An automated extraction of eHR that capture the patient’s data before the diagnosis and then, through Natural Language Processing (NLP), analysis and categorization of all data to transform source information into structured data has been performed.ResultsIn the first round, the system has been used to retrieve all the eHR for the 96 patients with LACC. The system has been able to classify all patients belonging to the training set and - through the NLP procedures - the clinical features were analyzed and classified for each patient. A second important result was the setup of a predictive model to evaluate the patient’s staging (accuracy of 94%). Lastly, we created a user-oriented operational tool targeting the MTB who are confronted with the challenge of large volumes of patients to be diagnosed in the most accurate way.ConclusionThis is the first proof of concept concerning the possibility of creating a smart virtual assistant for the MTB. A significant benefit could come from the integration of these automated methods in the collaborative, crucial decision stages.

Development and Feasibility of a Patient-Derived Training Simulator for Image-Guided Adaptive Brachytherapy of Locally Advanced Cervical Cancers

Background Image-guided adaptive brachytherapy (IGABT) plays a pivotal role in definitive radiotherapy of cervical cancer. Although the combination of a tandem and ovoid applicator with interstitial needles (IC/IS brachytherapy) is an efficient IGABT technique for bulky irregular-shaped tumors, training opportunities for IC/IS brachytherapy remain limited. Thus, we developed a training simulator for IC/IS brachytherapy for locally advanced cervical cancer and tested its feasibility. Methods The training simulator combined a patient-derived soft silicone tumor phantom with an acrylic tube mimicking the vagina. The tumor phantom was modeled on a cervical cancer patient treated with IGABT at our institute between 2012–2020, through detailed inspection of their three-dimensional (3D) high-risk clinical target volume (HR-CTV) at the first brachytherapy session. A true-scale tumor phantom was created from the HR-CTV data using 3D-printing. The feasibility of the training simulator was investigated by comparing treatment plans between the following six sessions (sessions #1–#3, with a Fletcher-Suit Asian Pacific applicator; #4–#6, with a Venezia applicator): in sessions #1 and #4, an expert inserted a tandem and ovoids (T&O); in sessions #2 and #5, a resident inserted a T&O plus four needles; and in sessions #3 and #6, an expert inserted a T&O plus four needles. At each session, the highest possible dose was prescribed to the HR-CTV while keeping the D2cc of the rectum and bladder (derived from the model case) below 6 and 7.6 Gy, respectively. Results The training simulator was developed using the HR-CTV data of a FIGO stage IIIB tumor (68 ⋅ 49 ⋅ 45 mm) selected from one of 495 candidates. The feasibility tests with a Fletcher-Suit Asian Pacific applicator resulted in HR-CTV D90 of 4.23, 5.69, and 6.70 Gy for sessions #1, #2, and #3, respectively. With a Venezia applicator, HR-CTV D90 was 4.16, 6.20, and 6.45 Gy for sessions #4, #5, and #6, respectively. Conclusions The tumor phantom was a good representation that resulted in various HR-CTV D90 doses depending on the physician’s experience and applicator type. Further evaluation of the training simulator is warranted to confirm its educational value for IC/IS brachytherapy for locally advanced cervical cancer.

MRI Radiomic Features: A Potential Biomarker for Progression-Free Survival Prediction of Patients With Locally Advanced Cervical Cancer Undergoing Surgery

ObjectivesTo investigate the prognostic role of radiomic features based on pretreatment MRI in predicting progression-free survival (PFS) of locally advanced cervical cancer (LACC).MethodsAll 181 women with histologically confirmed LACC were randomly divided into the training cohort (n = 126) and the validation cohort (n = 55). For each patient, we extracted radiomic features from whole tumors on sagittal T2WI and axial DWI. The least absolute shrinkage and selection operator (LASSO) algorithm combined with the Cox survival analysis was applied to select features and construct a radiomic score (Rad-score) model. The cutoff value of the Rad-score was used to divide the patients into high- and low-risk groups by the X-tile. Kaplan–Meier analysis and log-rank test were used to assess the prognostic value of the Rad-score. In addition, we totally developed three models, the clinical model, the Rad-score, and the combined nomogram.ResultsThe Rad-score demonstrated good performance in stratifying patients into high- and low-risk groups of progression in the training (HR = 3.279, 95% CI: 2.865–3.693, p &lt; 0.0001) and validation cohorts (HR = 2.247, 95% CI: 1.735–2.759, p &lt; 0.0001). Otherwise, the combined nomogram, integrating the Rad-score and patient’s age, hemoglobin, white blood cell, and lymph vascular space invasion, demonstrated prominent discrimination, yielding an AUC of 0.879 (95% CI, 0.811–0.947) in the training cohort and 0.820 (95% CI, 0.668–0.971) in the validation cohort. The Delong test verified that the combined nomogram showed better performance in estimating PFS than the clinical model and Rad-score in the training cohort (p = 0.038, p = 0.043).ConclusionThe radiomics nomogram performed well in individualized PFS estimation for the patients with LACC, which might guide individual treatment decisions.

Identification of Pathways and Genes Associated with Chemoradiotherapy in Locally Advanced Cervical Cancer

The standard treatment approach for locally advanced cervical cancer (LACC) is concurrent chemoradiotherapy (CCRT). However, resistance to radiotherapy and chemotherapy often leads to failure of LACC therapy. Thus, the key pathways and genes associated with CCRT in LACC should be identified urgently. The Weighted Gene Co-Expression Network Analysis (WGCNA) was used for the identification of highly correlated gene modules. A protein-protein interaction (PPI) network was constructed using STRING and hub genes were selected. Furthermore, single-cell transcriptome sequencing was used to elucidate the cell type composition of the cervix sample and analyze the expression levels of key genes in cells. We identified 580 differentially expressed genes (DEGs) in LACCk, which were mainly invovled in Human papillomavirus infection, focal adhesion, and ECM-receptor interaction signaling pathways. Ten hub genes (COL1A1, COL6A1, COL6A2, LAMA4, COL6A3, LAMC1, HSPG2, ITGA9, CTGF, PDGFRB) were screened for further study. We showed that COL1A1, COL6A1, COL6A2 were highly expressed after radiotherapy or chemoradiotherapy. By analyzing the single-cell sequence, we found that the main cell types in cervical tissue include Fibroblasts, Smooth muscle cells, Tissue stem cells, Endothelial cells, Progenitor cells, Epithelial cells, T cells, Basal cells, Macrophages, and Mast cells. COL1A1, COL6A1, COL6A2, COL6A3, CTGF, and PDGFRB were highly expressed in Progenitor cells. Human papillomavirus infection, focal adhesion, and ECM-receptor interaction signaling pathway are related to the failure of CCRT for LACC, which warrants further research to improve CCRT sensitivity in LACC targeting on these candidate genes or pathways.