Pembrolizumab or placebo with chemoradiotherapy followed by pembrolizumab or placebo for newly diagnosed, high-risk, locally advanced cervical cancer (ENGOT-cx11/GOG-3047/KEYNOTE-A18): a randomised, double-blind, phase 3 clinical trial.

BACKGROUND: Pembrolizumab has shown efficacy in persistent, recurrent, or metastatic cervical cancer. The effect of chemoradiotherapy might be enhanced by immunotherapy. In this phase 3 trial, we assessed the efficacy and safety of adding pembrolizumab to chemoradiotherapy in locally advanced cervical cancer. METHODS: In this randomised, double-blind, placebo-controlled, phase 3 ENGOT-cx11/GOG-3047/KEYNOTE-A18 clinical trial, adults (age ≥18 years) at 176 medical centres in 30 countries with newly diagnosed, high-risk, locally advanced cervical cancer were randomly assigned (1:1) using an interactive voice-response system with integrated web response to receive 5 cycles of pembrolizumab (200 mg) or placebo every 3 weeks plus chemoradiotherapy, followed by 15 cycles of pembrolizumab (400 mg) or placebo every 6 weeks. Randomisation was stratified by planned external beam radiotherapy type (intensity-modulated radiotherapy or volumetric-modulated arc therapy vs non-intensity-modulated radiotherapy or non-volumetric-modulated arc therapy), cervical cancer stage at screening (International Federation of Gynecology and Obstetrics 2014 stage IB2-IIB node positive vs stage III-IVA), and planned total radiotherapy (external beam radiotherapy plus brachytherapy) dose (<70 Gy vs ≥70 Gy equivalent dose in 2 Gy fractions). Primary endpoints were progression-free survival per Response Evaluation Criteria in Solid Tumours version 1.1-by investigator or by histopathologic confirmation of suspected disease progression-and overall survival. Primary analysis was conducted in the intention-to-treat population, which included all randomly allocated participants. Safety was assessed in the as-treated population, which included all randomly allocated patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT04221945, and is closed to new participants. FINDINGS: Between June 9, 2020, and Dec 15, 2022, 1060 participants were randomly assigned to treatment, with 529 assigned to the pembrolizumab-chemoradiotherapy group and 531 to the placebo-chemoradiotherapy group. At data cutoff (Jan 9, 2023), median follow-up was 17·9 months (IQR 11·3-22·3) in both treatment groups. Median progression-free survival was not reached in either group; rates at 24 months were 68% in the pembrolizumab-chemoradiotherapy group versus 57% in the placebo-chemoradiotherapy group. The hazard ratio (HR) for disease progression or death was 0·70 (95% CI 0·55-0·89, p=0·0020), meeting the protocol-specified primary objective. Overall survival at 24 months was 87% in the pembrolizumab-chemoradiotherapy group and 81% in the placebo-chemoradiotherapy group (information fraction 42·9%). The HR for death was 0·73 (0·49-1·07); these data have not crossed the boundary of statistical significance. Grade 3 or higher adverse event rates were 75% in the pembrolizumab-chemoradiotherapy group and 69% in the placebo-chemoradiotherapy group. INTERPRETATION: Pembrolizumab plus chemoradiotherapy significantly improved progression-free survival in patients with newly diagnosed, high-risk, locally advanced cervical cancer. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co (MSD).

Top advances of the year: Cervical cancer.

The year 2023 was an extraordinary year for the further development and expansion of novel treatments for all patients with cervical cancer, ranging from early stage to later stage and metastatic or recurrent disease. Individuals with early-stage disease will benefit from less invasive surgery with subsequent improvement in quality of life. The effectiveness of immunotherapy has been demonstrated in upfront, locally advanced cervical cancer and confirmed in advanced metastatic disease. Induction chemotherapy will play a role in some patients with locally advanced disease, particularly those in low resource areas of the world. Novel therapeutics including antibody-drug conjugates have shown efficacy even in pretreated patients. As we continue to explore innovative therapeutics in this space, however, we must also continue to improve the diversity of clinical trial accrual to allow for generalizable results. At the same time, we must focus on eradicating this disease with appropriate screening and vaccination.

Significance of HIV status in cervical cancer patients receiving curative chemoradiation therapy, definitive radiation alone, or palliative radiation in Botswana.

BACKGROUND: Cervical cancer associated with human papillomavirus has the highest cancer incidence and mortality for women in Botswana because of a high HIV prevalence and limited screening. This study investigates the significance of HIV on the overall survival (OS) of patients with locally advanced cervical cancer by various treatment categories (curative chemoradiation, definitive radiation [RT] alone, or palliative RT alone). METHODS: This study included patients diagnosed with cervical cancer between 2013 and 2020, prospectively enrolled in the Botswana Prospective Cancer Cohort. OS based on HIV status and completion of planned treatment regimen was estimated by the Kaplan-Meier method. Comparisons of 2-year OS by HIV status was performed by the log-rank test, univariate and multivariable Cox analyses adjusting for cancer stage, RT dose, number of chemotherapy cycles, and baseline hemoglobin levels. RESULTS: Of 1131 patients diagnosed with stage IB-IVB cervical cancer, 69.8% were women living with HIV (n = 789). For patients receiving curative chemoradiation, HIV status was not significantly associated with OS in unadjusted (p = .987) and adjusted (p = .578) analyses. For RT only treatment and definitive (high-dose) RT alone, HIV status was significantly associated with OS in unadjusted analysis (HR = 1.77, p = .002; HR = 1.95, p = .014), but not in adjusted analysis (p = .227, p = .73). For patients receiving palliative (low-dose) RT, HIV status was not associated with OS in unadjusted (p = .835) or adjusted analysis (p = .359). CONCLUSIONS: In Botswana, a resource-limited setting, HIV status had no significant effect on 2-year OS in patients with cervical cancer with well-managed HIV receiving chemoradiation, RT alone, or palliative RT. This demonstrates that patients living with HIV receiving antiretroviral treatment can receive clinically appropriate treatment with no evidence that HIV may lead to poorer outcomes.

Adherence to Treatment and Follow-Up of Precancerous Cervical Lesions in Ethiopia.

BACKGROUND: In Ethiopia, both incidence and mortality of cervical cancer are relatively high. Screening services, which were implemented during the past few years, are currently being expanded. The World Health Organization recommends patients with a positive VIA (visual inspection with acetic acid) result should immediately receive treatment followed by rescreening after 1 year as precancerous lesions can reoccur or become residential despite treatment. MATERIALS AND METHODS: Screening logbooks dating between 2017 and 2020 were retrospectively reviewed in 14 health facilities of Addis Ababa and Oromia region. Data for 741 women with a VIA-positive result were extracted and those women were asked to participate in a questionnaire-based phone interview to gain insights about adherence to treatment and follow-up. Data were analyzed using descriptive methods and then fitted into 2 generalized linear models to test variables for an influence on adherence to follow up. RESULTS: Around 13 800 women had received a VIA screening, of which approximately 820 (5.9%) were VIA positive. While over 90% of women with a positive screen received treatment, only about half of the treated patients returned for a follow-up examination. After treatment, 31 women had a VIA-positive re-screen. We found that educational status, age over 40, no/incorrect follow-up appointment, health facility-related barriers, and use of reminders are important drivers of adherence to follow up. CONCLUSION: Our results revealed that adherence to treatment after VIA positive screening is relatively high whereas adherence to follow up recommendations still needs improvement. Reminders like appointment cards and phone calls can effectively reduce the loss of follow-up.

Vaginal microbial profile of cervical cancer patients receiving chemoradiotherapy: the potential involvement of Lactobacillus iners in recurrence.

The vaginal microbiome is an immune defense against reproductive diseases and can serve as an important biomarker for cervical cancer. However, the intrinsic relationship between the recurrence and the vaginal microbiome in patients with cervical cancer before and after concurrent chemoradiotherapy is poorly understood. Here, we analyzed 125 vaginal microbial profiles from a patient cohort of stage IB-IVB cervical cancer using 16S metagenomic sequencing and deciphered the microbial composition and functional characteristics of the recurrent and non-recurrent both before and after chemoradiotherapy. We demonstrated that the abundance of beneficial bacteria and stability of the microbial community in the vagina decreased in the recurrence group, implying the unique characteristics of the vaginal microbiome for recurrent cervical cancer. Moreover, using machine learning, we identified Lactobacillus iners as the most important biomarker, combined with age and other biomarkers (such as Ndongobacter massiliensis, Corynebacterium pyruviciproducens ATCC BAA-1742, and Prevotella buccalis), and could predict cancer recurrence phenotype before chemoradiotherapy. This study prospectively employed rigorous bioinformatics analysis and highlights the critical role of vaginal microbiota in post-treatment cervical cancer recurrence, identifying promising biomarkers with prognostic significance in the context of concurrent chemoradiotherapy for cervical cancer. The role of L. iners in determining chemoradiation resistance in cervical cancer warrants further detailed investigation. Our results expand our understanding of cervical cancer recurrence and help develop better strategies for prognosis prediction and personalized therapy.

Biological treatment evaluation in thermoradiotherapy: application in cervical cancer patients.

BACKGROUND: Hyperthermia treatment quality is usually evaluated by thermal (dose) parameters, though hyperthermic radiosensitization effects are also influenced by the time interval between the two modalities. This work applies biological modelling for clinical treatment evaluation of cervical cancer patients treated with radiotherapy plus hyperthermia by calculating the equivalent radiation dose (EQDRT, i.e., the dose needed for the same effect with radiation alone). Subsequent analyses evaluate the impact of logistics. METHODS: Biological treatment evaluation was performed for 58 patients treated with 23-28 fractions of 1.8-2 Gy plus 4-5 weekly hyperthermia sessions. Measured temperatures (T50) and recorded time intervals between the radiotherapy and hyperthermia sessions were used to calculate the EQDRT using an extended linear quadratic (LQ) model with hyperthermic LQ parameters based on extensive experimental data. Next, the impact of a 30-min time interval (optimized logistics) as well as a 4­h time interval (suboptimal logistics) was evaluated. RESULTS: Median average measured T50 and recorded time intervals were 41.2 °C (range 39.7-42.5 °C) and 79 min (range 34-125 min), respectively, resulting in a median total dose enhancement (D50) of 5.5 Gy (interquartile range [IQR] 4.0-6.6 Gy). For 30-min time intervals, the enhancement would increase by ~30% to 7.1 Gy (IQR 5.5-8.1 Gy; p < 0.001). In case of 4­h time intervals, an ~ 40% decrease in dose enhancement could be expected: 3.2 Gy (IQR 2.3-3.8 Gy; p < 0.001). Normal tissue enhancement was negligible (< 0.3 Gy), even for short time intervals. CONCLUSION: Biological treatment evaluation is a useful addition to standard thermal (dose) evaluation of hyperthermia treatments. Optimizing logistics to shorten time intervals seems worthwhile to improve treatment efficacy.

Radiochemotherapy and interstitial brachytherapy for cervical cancer: clinical results and patient-reported outcome measures.

OBJECTIVE: To evaluate clinical results and long-term patient-reported outcome measures (PROMs) on quality of life in cervical cancer patients following radiochemotherapy (RCT) and brachytherapy (BT) as definitive treatment. MATERIALS AND METHODS: Between 2003 and 2023, a total of 132 patients with advanced cervical cancer were evaluated for possible treatment. Patients treated by postoperative RCT, palliative radiotherapy, and those treated for recurrent disease were excluded. Thus, 46 patients receiving standard RCT and BT as their curative treatment were included in this study. PROMs were assessed prospectively by patients' self-completion of the EORTC-QLQ-C30 and EORTC-QLQ-CX24 questionnaires. RESULTS: Five-year overall survival (OS), distant metastases-free survival (DMFS), and pelvic tumor-free survival rates (PTFS) were 53%, 54%, and 83%, respectively. A significant impact on OS was seen for FIGO (International Federation of Gynecologic Oncology) stage (IIB-IIIA: 79% vs. IIIB-IVA: 33%, p = 0.015), for overall treatment time (OTT; 50-65 d: 64% vs. > 65 d: 38%, p = 0.004), and for rectal D2cc (≤ 73 Gy: 50% vs. > 73 Gy: 38%, p = 0.046). The identical parameters were significantly associated with DMFS (FIGO stage: p = 0.012, OTT: p = 0.008, D2cc: p = 0.024). No parameters with a significant influence on PTFS were seen. In multivariate analysis, an impact of FIGO stage on OS (p = 0.05) and DMFS (p = 0.014) was detected, and of rectal D2cc on DMFS (p = 0.031). The overall QoL score was 63/100. Cognitive function was the least impaired (84/100), while role functioning was the worst (67/100). On the symptom scale, insomnia (46/100), fatigue (41/100), dyspnea (32/100), pain (26/100), and financial difficulties (25/100) were scored the worst. According to EORTC-QLQ-CX24, peripheral neuropathy (36/100) and lymphedema (32/100) occurred most frequently. Impaired sexual/vaginal functioning (32/100) and body image (22/100) were also frequently recorded. CONCLUSION: In patients with advanced cervical cancer, a combination of RCT and BT remains an excellent treatment option. In terms of patient-reported long-term quality of life, specific support is needed to alleviate symptoms including lymphedema, peripheral neuropathy, and impaired sexual activity.

Provision of cervical cancer services for women living with HIV, Uganda.

Objective: To describe the scale-up of cervical cancer screening and treatment for women living with human immunodeficiency virus (HIV), aged 25-49 years in Uganda, and to analyse the programme data. Methods: The health ministry targeted existing HIV clinics in a 2-year scale-up of cervical cancer screening services from October 2020. In preparation, we trained health workers to assess women attending HIV clinics for screening eligibility, provided either by human papillomavirus (HPV) testing and/or visual inspection with acetic acid. Clinic staff treated women with precancerous cervical lesions with thermocoagulation or referred women with suspected cancer to external services. We analysed data reported every 6 months for the number of clinics offering screening, screening uptake, the number of positive diagnoses and the number of women who received treatment. Findings: The number of HIV clinics offering cervical cancer screening services increased from 11, before the programme launch, to 1571. During the programme, screening uptake increased from 5.0% (6506/130 293) to 107.3% (151 872/141 527) of targets. The cumulative proportion of positive diagnoses was 5.9% (23 970/407 323) overall, but was much lower for screening offering visual inspection only compared with clinics offering HPV testing. Although the proportion of women receiving treatment if positive increased from 12.8% (53/413) to 84.3% (8087/9592), the World Health Organization target of 90% was not reached. Conclusion: We demonstrated marked increases, potentially replicable by other countries, in screening and treatment. These increases could be improved further by expanding HPV testing and same-day treatment of precancerous lesions.

Development and validation of a 18F-FDG PET/CT radiomics nomogram for predicting progression free survival in locally advanced cervical cancer: a retrospective multicenter study.

BACKGROUND: The existing staging system cannot meet the needs of accurate survival prediction. Accurate survival prediction for locally advanced cervical cancer (LACC) patients who have undergone concurrent radiochemotherapy (CCRT) can improve their treatment management. Thus, this present study aimed to develop and validate radiomics models based on pretreatment 18Fluorine-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)-computed tomography (CT) images to accurately predict the prognosis in patients. METHODS: The data from 190 consecutive patients with LACC who underwent pretreatment 18F-FDG PET-CT and CCRT at two cancer hospitals were retrospectively analyzed; 176 patients from the same hospital were randomly divided into training (n = 117) and internal validation (n = 50) cohorts. Clinical features were selected from the training cohort using univariate and multivariate Cox proportional hazards models; radiomic features were extracted from PET and CT images and filtered using least absolute shrinkage and selection operator and Cox proportional hazard regression. Three prediction models and a nomogram were then constructed using the previously selected clinical, CT and PET radiomics features. The external validation cohort that was used to validate the models included 23 patients with LACC from another cancer hospital. The predictive performance of the constructed models was evaluated using receiver operator characteristic curves, Kaplan Meier curves, and a nomogram. RESULTS: In total, one clinical, one PET radiomics, and three CT radiomics features were significantly associated with progression-free survival in the training cohort. Across all three cohorts, the combined model displayed better efficacy and clinical utility than any of these parameters alone in predicting 3-year progression-free survival (area under curve: 0.661, 0.718, and 0.775; C-index: 0.698, 0.724, and 0.705, respectively) and 5-year progression-free survival (area under curve: 0.661, 0.711, and 0.767; C-index, 0.698, 0.722, and 0.676, respectively). On subsequent construction of a nomogram, the calibration curve demonstrated good agreement between actually observed and nomogram-predicted values. CONCLUSIONS: In this study, a clinico-radiomics prediction model was developed and successfully validated using an independent external validation cohort. The nomogram incorporating radiomics and clinical features could be a useful clinical tool for the early and accurate assessment of long-term prognosis in patients with LACC patients who undergo concurrent chemoradiotherapy.

Comparison of outcomes between early-stage cervical cancer patients without high-risk factors undergoing adjuvant concurrent chemoradiotherapy and radiotherapy alone after radical surgery.

PURPOSE: For patients with early-stage cervical cancer without high-risk factors, there is no consensus regarding the optimal postoperative treatment regimen and whether postoperative concurrent radiochemotherapy (CCRT) is superior to radiotherapy (RT) alone. PATIENTS AND METHODS: The medical records of patients with stage I-IIA cervical cancer, who underwent radical surgery and postoperative RT or CCRT between June 2012 and December 2017, were retrospectively reviewed. Patients with any high-risk factors, including positive pelvic lymph node(s), positive resection margin(s), and parametrial invasion, were excluded. Patients with large tumors (≥ 4 cm), deep stromal invasion (≥ 1/2), and lymphovascular space involvement were categorized as the intermediate-risk group. Patients without intermediate-risk factors were categorized as the low-risk group. RESULTS: A total of 403 patients were enrolled and divided into 2 groups according to postoperative treatment: RT alone (n = 105); and CCRT (n = 298). For risk stratification, patients were also divided into 2 groups: intermediate-risk (n = 350); and low-risk (n = 53). The median follow-up was 51.7 months. Patients in the intermediate-risk group and those with multiple intermediate-risk factors were more likely to undergo CCRT. For patients who underwent RT alone or CCRT in the intermediate-risk group, 5-year overall survival (OS) rates were 93.4% and 93.8% (p = 0.741), and 5-year disease-free survival (DFS) rates were 90.6% and 91.4%, respectively (p = 0.733). Similarly, for patients who underwent RT alone or CCRT in the low-risk group, the 5-year OS rates were 100.0% and 93.5% (p = 0.241), and 5-year DFS rates were 94.4% and 93.5%, respectively (p = 0.736). Adjuvant CCRT or RT were not independent risk factors for either OS or DFS. Patients who underwent CCRT appeared to develop a higher proportion of grade ≥ 3 acute hematological toxicities than those in the RT group (44.0% versus 11.4%, respectively; p < 0.001). There was no significant difference in grade ≥ 3 chronic toxicities of the urogenital and gastrointestinal systems between the CCRT and RT groups. CONCLUSION: There was no significant difference in 5-year OS and DFS rates between patients with early-stage cervical cancer without high-risk factors undergoing postoperative CCRT versus RT alone. Patients who underwent CCRT appeared to develop a higher proportion of grade ≥ 3 acute hematological toxicities than those who underwent RT alone.

Implementation of WHO guidelines for cervical cancer screening, diagnosis and treatment: knowledge and perceptions of health providers from Argentina.

BACKGROUND: The 2021 World Health Organization (WHO) guidelines on cervical cancer screening and treatment provide countries with evidence-based recommendations to accelerate disease elimination. However, evidence shows that health providers' adherence to screening guidelines is low. We conducted a study in Argentina to analyze health providers' knowledge and perceptions regarding the 2021 WHO Guidelines. METHODS: A qualitative study was conducted based on individual, semi-structured interviews with health providers specializing in gynecology (n = 15). The themes explored were selected and analyzed using domains and constructs of the Consolidated Framework for Implementation Research. RESULTS: Although health providers perceive WHO as a reliable institution, they do not know the 2021 guidelines, its supporting evidence, and its elaboration process. Their clinical practice is mainly guided by local recommendations developed by national professional medical associations (PMAs). For interviewees, WHO guidelines should be disseminated through health authorities and national PMAs, mainly through in-service training. Health providers had a positive assessment regarding WHO Recommendation 1 (screen, triage, and treatment for women aged 30 + with HPV-testing every 5 to 10 years) and perceived a favorable climate for its implementation. HPV-testing followed by triage was considered a low-complexity practice, enabling a better detection of HPV, a better selection of the patients who will need diagnosis and treatment, and a more efficient use of health system resources. However, they suggested adapting this recommendation by removing screening interval beyond 5 years. WHO Recommendation 2 (screen-and-treat approach with HPV-testing for women aged 30 + every 5 to 10 years) was predominantly rejected by interviewees, was considered an algorithm that did not respond to women's needs, and was not adequate for the Argentinean context. Regarding the HPV-test modality, clinician-collected tests were the preferred mode. Health providers considered that HPV self-collection should be used primarily among socially vulnerable women to increase screening coverage. CONCLUSION: WHO guidelines should be widely disseminated among health providers, especially in settings that could benefit from a screen-and-treat approach. Identifying areas of partnership and collaboration with PMAs in implementing WHO guidelines is essential.

Dose escalation of tolinapant (ASTX660) in combination with standard radical chemoradiotherapy in cervical cancer : a study protocol for a phase 1b TiTE-CRM clinical trial (CRAIN) in UK secondary care centres.

BACKGROUND: Cervical cancer is the fourth most common cancer in women, with an estimated 342,000 deaths worldwide in 2020. Current standard of care in the UK for locally advanced cervical cancer is concurrent chemoradiotherapy with weekly cisplatin, yet 5-year overall survival rates are only 65% with a distant relapse rate of 50%. Inhibitors of Apoptosis Proteins (IAPs) are often overexpressed in cancer cells and associated with tumour progression and resistance to treatment. Tolinapant, developed by Astex Pharmaceuticals, is an IAP antagonist with an additional mechanism of action via down-regulation of NF-kB, an important regulator in cervical cancer. Preclinical studies performed using tolinapant in combination with cisplatin and radiotherapy showed inhibition of tumour growth and enhanced survival. There is therefore a strong rationale to combine tolinapant with chemoradiotherapy (CRT). METHODS: CRAIN is a phase Ib open-label, dose escalation study to characterise the safety, tolerability and initial evidence for clinical activity of tolinapant when administered in combination with cisplatin based CRT. Up to 42 patients with newly diagnosed cervix cancer will be recruited from six UK secondary care sites. The number of participants and the duration of the trial will depend on toxicities observed and dose escalation decisions, utilising a TiTE-CRM statistical design. Treatment will constist of standard of care CRT with 45 Gy external beam radiotherapy given in 25 daily fractions over 5 weeks with weekly cisplatin 40mg/m2. This is followed by brachytherapy for which common schedules will be 28 Gy in 4 fractions high-dose-rate or 34 Gy in 2 fractions pulsed-dose-rate. Tolinapant will be administered in fixed dose capsules taken orally daily for seven consecutive days as an outpatient on alternate weeks (weeks 1, 3, 5) during chemoradiation. Dose levels for tolinapant which will be assessed are: 60 mg; 90 mg (starting level); 120 mg; 150 mg; 180 mg. Escalation will be guided by emerging safety data and decisions by the Safety Review Committee. DISCUSSION: If this trial determines a recommended phase II dose and shows tolinapant to be safe and effective in combination with CRT, it would warrant future phase trials. Ultimately, we hope to provide a synergistic treatment option for these patients to improve outcome. TRIAL REGISTRATIONS: EudraCT Number: 2021-006555-34 (issued 30th November 2021); ISRCTN18574865 (registered 30th August 2022).

Sociodemographic characteristics and their association with survival in women with cervical cancer.

BACKGROUND: In 2020, the highest incidence and mortality from cervical cancer (CC) were detected in low and middle-income countries. CC remains a health problem for women living in them. In Mexico, CC ranks second in cancer incidence and mortality in women. The main characteristics of this population are low income, low educational level, and inadequate medical coverage. The present study characterized the Mexican population by CC, and the sociodemographic variables that impacted overall survival (OS) were identified. METHODS: A retrospective study that included a cohort of patients with a confirmed diagnosis of CC at the Instituto Nacional de Cancerologia between 2003 and 2016. Information was collected on sociodemographic variables related to the disease and OS. RESULTS: Four thousand six hundred thirty-one patients were included. The median age was 51 years, 78.5% were unemployed, 44.4% lived in a rural/suburban area, 50.8% had a partner when collecting this information, and 74.3% were classified as having low socioeconomic status. Age, living in a rural/suburban area, more advanced stages of the disease, and not receiving cancer treatment were associated with lower OS. CONCLUSION: CC continues to affect mainly women with minimal resources, low educational levels, and living in marginalized areas. These characteristics influence the OS. Prevention and timely detection programs, education, and training focused on this population and with broader coverage are required to identify patients with CC at earlier stages.

[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. METHODS: In 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. RESULTS: All 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. CONCLUSIONS: Low 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.

Neoadjuvant chemotherapy followed by surgery versus concurrent chemoradiotherapy in patients with stage IIB cervical squamous cell carcinoma: a retrospective cohort study.

PURPOSE: This study aims to compare treatment outcomes between neoadjuvant chemotherapy (NACT) followed by surgery and concurrent chemoradiotherapy (CCRT) in patients with stage IIB cervical squamous cell carcinoma (CSCC). MATERIALS AND METHODS: We conducted a retrospective cohort study involving patients with stage IIB CSCC treated at Guangxi Medical University Cancer Hospital between June 2012 and June 2019. We compared overall survival (OS), locoregional-free survival (LRFS), and distant metastasis-free survival (DMFS) between the NACT + surgery and CCRT groups. RESULTS: A total of 257 patients were enrolled: 165 underwent NACT + surgery and 92 received CCRT. Before propensity score matching, the NACT + surgery group exhibited lower 5-year OS (68.2% vs. 85.6%; hazard ratio [HR] = 2.50, 95% confidence interval [CI]: 1.26-4.96; P = 0.009), LRFS (85.2% vs. 96.9%; HR = 5.88, 95% CI: 1.33-25.94; P = 0.019), and DMFS (81.9% vs. 97.4%; HR = 6.65, 95% CI: 1.51-29.23; P = 0.012) compared to the CCRT group. After propensity score matching, OS, LRFS, and DMFS remained worse in the NACT + surgery group compared to the CCRT group. CONCLUSION: NACT followed by surgery is associated with decreased OS, LRFS, and DMFS compared to CCRT among patients with stage IIB CSCC.

Efficacy and safety of different chemotherapy regimens concurrent with radiotherapy in the treatment of locally advanced cervical cancer.

BACKGROUND: Evaluate the efficacy and safety of different chemotherapy regimens concurrent with radiotherapy in treating locally advanced cervical cancer (LACC). METHODS: Retrospective data was collected from LACC patients who were treated at our institution. These patients were categorized into three groups: the single-agent cisplatin (DDP) chemoradiotherapy group, the paclitaxel plus cisplatin (TP) chemoradiotherapy group, and the nanoparticle albumin-bound (nab-) paclitaxel combined with cisplatin (nPP) chemoradiotherapy group. The primary endpoints were overall survival (OS) and progression-free survival (PFS) and the secondary endpoints were objective response rate (ORR) and incidence of adverse events (AEs). RESULTS: A total of 124 patients were enrolled (32 in the DDP group, 41 in the TP group, and 51 in the nPP group). There were differences in OS (P = 0.041, HR 0.527, 95% CI 0.314-0.884) and PFS (P = 0.003, HR 0.517, 95% CI 0.343-0.779) between the three groups. Notably, the 2-year OS rate was significantly higher in the nPP group compared to the DDP group (92.2% vs. 85.4%, P = 0.012). The 2-year PFS rates showed a marked increase in the TP group (78.0% vs. 59.4%, P = 0.048) and the nPP group (88.2% vs. 59.4%, P = 0.001) relative to the DPP group, with multiple comparisons indicating that the 2-year PFS rate was significantly superior in the nPP group versus the DDP group (88.2% vs. 59.4%, P = 0.001). Moreover, the ORR was also significantly higher in the nPP group than in the DDP group (P = 0.013); and no statistically significant differences were found in the incidence of AEs among the groups (P > 0.05). CONCLUSIONS: In LACC treatment, the two cisplatin-based doublet chemotherapy regimens are associated with better outcomes, with the nab-paclitaxel plus cisplatin regimen showing better efficacy than the paclitaxel plus cisplatin regimen. Furthermore, the AEs associated with these regimens were deemed tolerable. These findings could provide a reference for the clinical treatment of LACC. However, further prospective studies are needed to verify it.

Pegylated recombinant human granulocyte colony-stimulating factor for primary prophylaxis of neutropenia in patients with cervical cancer receiving concurrent chemoradiotherapy: a prospective study.

BACKGROUND: This study aimed to investigate the efficacy and safety of pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) for primary prophylaxis of neutropenia in patients with cervical cancer receiving concurrent chemoradiotherapy. METHODS: In this prospective, single-center, single-arm study, we enrolled patients (18-70 years) with 2018 International Federation of Gynecology and Obstetrics (FIGO) stage IIIC1r-IVA and IVB (distant metastasis only with inguinal lymph node metastasis) cervical cancer. Eligible patients should have normal function of the bone marrow (absolute neutrophil count (ANC) ≥ 2.0 × 109/L) and adequate hepatic and renal functions. Key exclusion criteria included: previous chemotherapy and/or radiotherapy; a history of bone marrow dysplasia or other hematopoietic abnormalities. All patients underwent radical radiotherapy (pelvic radiotherapy or extended-field irradiation) plus brachytherapy. The chemotherapy regimen included four cycles of 3-weekly paclitaxel and cisplatin. PEG-rhG-CSF was administered 48-72 h after each treatment cycle. Salvage granulocyte colony-stimulating factor (G-CSF) was only permitted in certain circumstances. The primary endpoint was the incidence of grade 3-4 neutropenia. The secondary endpoints included frequency of febrile neutropenia (FN), chemotherapy completion rate in cycles 2-4, time to complete radiotherapy, and safety. RESULTS: Overall, 52 patients were enrolled in this study from July 2019 to October 2020. The incidence of grade 3-4 neutropenia was 28.8%, with an average duration of grade 3-4 neutropenia persistence of 3.85 days (1-7 days). The incidence rate of FN was 3.8%. The chemotherapy completion rate was 94.2%, 82.7%, and 75.0% for cycles 2-4, respectively. The incidences of grade 3-4 neutropenia for cycles 1-4 were 9.6% (5/52), 8.2% (4/49), 14.0% (6/43), and 2.6% (1/39), respectively. All patients completed radiotherapy within 8 weeks (median, 48 days; range: 41-56 days), except one patient who withdrew consent and did not receive radiotherapy. Severe non-hematologic toxicity was not observed in any patient. CONCLUSION: PEG-rhG-CSF is an effective and safe prophylactic treatment for neutropenia in patients with cervical cancer undergoing concurrent chemoradiotherapy. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR1900024494. Date of Registration:13/July/2019.

The potential use of therapeutics and prophylactic mRNA vaccines in human papillomavirus (HPV).

Cervical cancer (CC) and other malignant malignancies are acknowledged to be primarily caused by persistent human papillomavirus (HPV) infection. Historically, vaccinations against viruses that produce neutralizing antibodies unique to the virus have been an affordable way to manage viral diseases. CC risk is decreased, but not eliminated, by HPV vaccinations. Since vaccinations have been made available globally, almost 90% of HPV infections have been successfully avoided. On the lesions and diseases that are already present, however, no discernible treatment benefit has been shown. As a result, therapeutic vaccines that elicit immune responses mediated by cells are necessary for the treatment of established infections and cancers. mRNA vaccines possess remarkable potential in combating viral diseases and malignancy as a result of their superior industrial production, safety, and efficacy. Furthermore, considering the expeditiousness of production, the mRNA vaccine exhibits promise as a therapeutic approach targeting HPV. Given that the HPV-encoded early proteins, including oncoproteins E6 and E7, are consistently present in HPV-related cancers and pre-cancerous lesions and have crucial functions in the progression and persistence of HPV-related diseases, they serve as ideal targets for therapeutic HPV vaccines. The action mechanism of HPV and HPV-related cancer mRNA vaccines, their recent advancements in clinical trials, and the potential for their therapeutic applications are highlighted in this study, which also offers a quick summary of the present state of mRNA vaccines. Lastly, we highlight a few difficulties with mRNA HPV vaccination clinical practice and provide our thoughts on further advancements in this quickly changing sector. It is expected that mRNA vaccines will soon be produced quickly for clinical HPV prevention and treatment.

The interaction between social determinants of health and cervical cancer survival: A systematic review.

OBJECTIVE: This systematic review aimed to investigate what are the most relevant social determinants of health (SDH), how they are measured, how they interact among themselves and what is their impact on the outcomes of cervical cancer patients. METHODS: Search was performed in PubMed, Scopus, Web of Science, Embase, Cochrane, and Google Scholar databases from January 2001 to September 2022. The protocol was registered at PROSPERO (CRD42022346854). We followed the PICOS strategy: Population- Patients treated for cervical cancer in the United States; Intervention - Any SDH; Comparison- None; Outcome measures- Cancer treatment outcomes related to the survival of the patients; Types of studies- Observational studies. Two reviewers extracted the data following the PRISMA guidelines. Joanna Briggs Institute Critical Appraisal Checklist for Analytical Cross-Sectional Studies was used for risk of bias (ROB) assessment. RESULTS: Twenty-four studies were included (22 had low and 2 had moderate ROB). Most manuscripts analyzed data from public registries (83.3%) and only one SDH (54.17%). The SDH category of Neighborhood was not included in any study. Although the SDH were measured differently across the studies, not being married, receiving treatment at a low-volume hospital, and having public insurance (Medicaid or Medicare) or not being insured was associated with shorter survival of cervical cancer patients in most studies. CONCLUSIONS: There is a deficit in the number of studies comprehensively assessing the impact of SDH on cervical cancer treatment-related outcomes. Marital status, hospital volume and health insurance status are potential predictors of worse outcome.

A systematic review of stage IVA cervical cancer treatment: Challenges in the management of an understudied group.

OBJECTIVE: Stage IVA patients comprise a small proportion of participants in cervical cancer trials, yet survival outcomes are disproportionately poor. We aim to perform a systematic review evaluating stage IVA cervical cancer. METHODS: This systematic review was completed via PRISMA 2020 guidelines using two databases. Inclusion criteria comprised Phase III trials (2004-2024) assessing stage IVA cervical cancer including patients by stage. Searches had MeSH terms: ((cervical cancer) AND (stage IVA) AND (locally advanced)). 761 were articles identified, including books, trials, reviews, and meta-analyses. Of the articles identified, 12 met inclusion criteria. RESULTS: A total of 133 (3.8% of study populations) stage IVA and 818 (40% of study populations) stage III-IVA cervical cancer patients were analyzed. Two studies (stage IVA n = 15; 3.1%) established cisplatin as chemoradiotherapy agent of choice, while one study (stage IVA n = 2; 1%) showed no benefit with cisplatin versus radiotherapy alone. Four studies (stage IVA n = 32; 3.6%; stages IIIB-IVA n = 220; 24%) found no benefit with adjuvant chemotherapy, with one analyzing stage IIIB-IVA patients (progression-free survival (PFS) hazard ratio (HR) = 0.84; 95% confidence interval (CI): 0.57-1.23). Three studies (stage IVA n = 71; 5%) found no benefit adding immunomodulator (stage IVA overall survival HR = 3.48; 95% CI: 0.52-23.29), hypoxic cell sensitizer, or immunotherapy (stage III-IVA PFS HR = 0.71; 95% CI: 0.49-1.03) to chemoradiotherapy. One study (stages III-IVA n = 598; 56%) found benefit adding immunotherapy to chemoradiotherapy (stage III-IVA PFS HR = 0.58; 95% CI: 0.42-0.8). One study (stage IVA n = 13; 3.5%) showed benefit with induction chemotherapy. CONCLUSION: Trials have not included substantial IVA patients to draw reasonable conclusions. Despite mixed results for immunotherapy, adjuvant chemotherapy, and induction chemotherapy, the exact benefit for stage IVA patients remains unknown. Future clinical trials should include a greater number of stage IVA cervical cancer patients and analyze them individually.