Chemoradiation For Cervical Cancer Research Articles

694: A systematic review of incidence of vaginal toxicities following chemoradiation in cervical cancer

694: A systematic review of incidence of vaginal toxicities following chemoradiation in cervical cancer

2896: Correlation between MR-Radiomics and Outcomes after Concurrent Chemoradiation in Cervical Cancer

2896: Correlation between MR-Radiomics and Outcomes after Concurrent Chemoradiation in Cervical Cancer

Clinical Validation of Human Papilloma Virus Circulating Tumor DNA for Early Detection of Residual Disease After Chemoradiation in Cervical Cancer

Clinical Validation of Human Papilloma Virus Circulating Tumor DNA for Early Detection of Residual Disease After Chemoradiation in Cervical Cancer

The Value of Patient-Reported Outcomes to Predict Symptom Burden and Health-Related Quality of Life After Chemoradiation for Cervical Cancer: A Prospective Study

Patients with cervical cancer undergoing chemoradiation have high symptom burden. We performed an analysis of prospectively collected data on patient-reported outcomes to determine characteristics predictive of poor treatment experience. Between 2021 and 2023, we prospectively collected data on patient-reported outcomes from patients with cervical cancer undergoing definitive chemoradiation. The European Organization for Research and Treatment of Cancer (EORTC)-Quality of Life Question-Core 30 and the EORTC-Quality of Life Question-Cervical Cancer module were completed at baseline (BL) and at the end of treatment (EOT). Poor treatment experience was defined as EOT poor health-related quality of life (HRQOL), low physical function, or significant overall symptom burden. Predictive factors analyzed included demographic, clinical, and disease-specific factors and BL financial toxicity, depression, social function, and emotional function. Receiver operating characteristic analysis provided appropriate predictive cutoff values. Univariable and multivariable (MVA) linear regression analyses were performed. Forty-nine patients completed BL and EOT questionnaires. Median age was 43 years (range, 18-85 years). Most patients (59%) had stage III disease. BL financial toxicity ≥66.7, depression ≥66.7, social function ≤50, and emotional function ≤58 on the EORTC linear transformed scale of 0 to 100 were significant predictors for poor treatment experience (p ≤ .04) based on receiver operating characteristic analysis. On MVA, poor BL social function was associated with reduced EOT HRQOL (β, -9.3; 95% CI, -16.1 to -2.6; p < .008), decreased physical function (β, -24.4; 95% CI, -36.3 to -12.6; p < .001), and high symptom burden (β, 26.9; 95% CI, 17.5-36.3; p < .001). Earlier disease stage predicted decreased symptom burden (β, -6.7; 95% CI, -13.1 to -0.3; p = .039). BL financial toxicity was a significant predictor in univariable analysis (p = .001-.044) and showed a significant interaction term on MVA (p = .024-.041) for all 3 domains of poor treatment experience. Demographic and treatment-related factors were not predictive. Patients with cervical cancer with poor BL social function or high financial toxicity were at risk for increased symptom burden and poor HRQOL. Screening for these factors provides an opportunity for early intervention to improve treatment experience.

Clinical Validation of Human Papilloma Virus Circulating Tumor DNA for Early Detection of Residual Disease After Chemoradiation in Cervical Cancer.

Most cervical cancers are caused by human papilloma virus (HPV), and HPV circulating tumor DNA (ctDNA) may identify patients at highest risk of relapse. Our pilot study using digital polymerase chain reaction (dPCR) showed that detectable HPV ctDNA at the end of chemoradiation (CRT) is associated with inferior progression-free survival (PFS) and that a next-generation sequencing approach (HPV-seq) may outperform dPCR. We aimed to prospectively validate HPV ctDNA as a tool for early detection of residual disease. This prospective, multicenter validation study accrued patients with stage IB-IVA cervical cancer treated with CRT between 2017 and 2022. Participants underwent phlebotomy at baseline, end of CRT, 4-6 weeks post-CRT, and 3 months post-CRT for HPV ctDNA levels. Plasma HPV genotype-specific DNA levels were quantified using both dPCR and HPV-seq. The primary end point was 2-year PFS. With a median follow-up of 2.2 (range, 0.5-5.5) years, there were 24 PFS events among the 70 patients with HPV+ cervical cancer. Patients with detectable HPV ctDNA on dPCR at the end of CRT, 4-6 weeks post-CRT, and 3 months post-CRT had significantly worse 2-year PFS compared with those with undetectable HPV ctDNA (77% v 51%, P = .03; 82% v 15%, P < .001; and 82% v 24%, P < .001, respectively); the median lead time to recurrence was 5.9 months. HPV-seq showed similar results as dPCR. On multivariable analyses, detectable HPV ctDNA on dPCR and HPV-seq remained independently associated with inferior PFS. Persistent HPV ctDNA after CRT is independently associated with inferior PFS. HPV ctDNA testing can identify, as early as at the end of CRT, patients at high risk of recurrence for future treatment intensification trials.

Clinical Validation of HPV ctDNA for Early Detection of Residual Disease Following Chemoradiation in Cervical Cancer

Despite chemoradiation (CRT), 30-40% of patients with locally advanced cervical cancer relapse. Most cases are caused by human papilloma virus (HPV), and HPV circulating tumor DNA (ctDNA) may identify patients at highest risk of relapse. Our previous pilot study showed that detectable HPV ctDNA at the end of CRT is associated with inferior progression-free survival (PFS) using digital polymerase chain reaction (dPCR), and that a next generation sequencing approach (HPV-seq) may outperform dPCR. We hypothesized that HPV ctDNA may identify cervical cancer patients at increased risk of relapse following CRT and aimed to prospectively validate HPV ctDNA as a tool for early detection of residual disease. This prospective, multicenter validation study accrued 70 patients with HPV+ stage IB-IVA cervical cancer treated with definitive CRT from 2017-2022. Patients underwent phlebotomy at baseline, end of, 4-6 weeks and 3 months post CRT for HPV ctDNA levels. HPV genotyping was performed on the baseline plasma sample using HPV-seq. HPV genotype-specific DNA levels in plasma were quantified using both dPCR and HPV-seq. PFS was estimated using the Kaplan-Meier method and compared using the log rank test. Multivariable Cox regression analyses incorporating stage and HPV ctDNA detectability assessed independent prognostic factors associated with PFS. At the time of abstract, results for 67 patients were available. The majority had squamous histology (84%) and stage IIB (36%) or IIIC1 (25%) disease. HPV genotyping using HPV-seq revealed 54% (36/67) of cases harboring HPV-16, and 46% harboring other HPV types: 15 HPV-18; 5 HPV-59; 2 HPV-31; 2 HPV-33; 2 HPV-52; 1 each HPV-39, HPV-45, HPV-53, HPV-58, and HPV-82. With a median follow up of 2.2 (range 0.4 - 5.2) years, there were 21 PFS events. Most recurrences (14/21) were distant and/or paraaortic; 4 local and nodal/distant; 2 pelvic nodal; and 1 local. Patients with detectable HPV ctDNA on dPCR at the end of, 4-6 weeks and 3 months post CRT had significantly worse 2-year PFS compared to those with undetectable HPV ctDNA (78 vs 52%, p = 0.04; 82 vs 26%, p < 0.001; and 80 vs 23%, p = < 0.001, respectively). HPV-seq showed similar results (87 vs 55%, p = 0.02; 81 vs 45%, p = 0.003; and 84 vs 31%, p = < 0.001, respectively). On multivariable analyses, detectable HPV ctDNA on dPCR and HPV-seq remained independently associated with inferior PFS (see table). HPV-seq enables HPV genotyping directly from plasma in locally advanced cervical cancer. Persistent HPV ctDNA following CRT is independently associated with inferior PFS in this prospective validation study. HPV ctDNA testing can be used to identify, as early as at the end of CRT, patients at high risk of recurrence in future treatment intensification trials.

Pre-Brachytherapy Diffusion-Weighted Magnetic Resonance Imaging (DW-MRI) Response as Predictor of Local Control in the Definitive Treatment of Cervical Cancer

Chemoradiation consisting of external beam radiotherapy (EBRT) followed by brachytherapy (BT) is the standard of care for Stage IB2-IVA cervical cancer (CC). Multi-parametric MRI (mpMRI) is a valuable tool for initial staging, treatment planning and response assessment. In this study, we aim to explore the potential of mpMRI, in particular DW-MRI, to predict overall tumor control following chemoradiation in CC. We identified 78 consecutive patients treated with chemoradiation for FIGO IB2-IVA CC between 2012-2020, who had an MRI at baseline (MRb) and post-EBRT prior to brachytherapy boost (MRpb) that included DW-MRI (b-value = 0 and 800 s/mm2). Median age was 53 years, most patients had squamous cell carcinoma (76.9%) and advanced-stage disease (56.4% stage IIIA-IVA). Median time from completion of EBRT to MRpb was 3 days. Regions of interest (ROI) in primary tumor were delineated on DW image (b = 0 s/mm2) using ITK-SNAP software. DW-MRI data were fitted to a monoexponential model to calculate apparent diffusion coefficient (ADC) values using in-house software platform (MRI-QAMPER). MRpb mean ADC values (n = 78) and relative changes (%) in mean ADC values between MRb and MRpb (n = 64) were correlated with outcomes, including local failure (LF), regional or distant failure (RDF), and failure at any site (FAS), with death without failure as a competing risk. Median follow-up time was 45 months (95% CI 38, 53). At first post treatment assessment, 72 patients (92.3%) had a complete response (CR) in the cervix and 68 patients (87.2%) had CR in all disease sites. Of patients who had CR in the cervix (n = 72), only 1 patient had local recurrence. Of patients who had CR in all disease sites, 10 later recurred (1 LF only, 1 LF&RDF, 8 RDF only). Overall, 7 patients (9%) had LF, and 19 patients (24.4%) had FAS. A higher mean ADC value in MRpb was associated with LF (HR 4.3, 95% CI 1.32, 14.6; P = 0.016), but not with RDF (P = 0.4) or FAS (P = 0.5). A higher relative change in the mean ADC value between MRb and MRpb was associated with a lower risk of LF (HR 0.94, 95% CI 0.90, 0.98; P = 0.002), but not with RDF (P = 0.8) or FAS (P = 0.4). Treatment response as measured on prebrachytherapy DW-MRI is a significant predictor of local control in patients undergoing chemoradiation for stage IB2-IVA CC. ADC values, a quantitative imaging biomarker on MRpb may be instrumental in dose intensification/de-escalation efforts in CC.

Comparison of Survival of Radical hysterectomy and chemoradiation for cervical cancer with an absence of Parametrial involvement and suspicious lymph node metastasis (SURPRISE): Gynecologic Oncology Research Investigators coLLborAtion study (GORILLA-1002) (1199)

Comparison of Survival of Radical hysterectomy and chemoradiation for cervical cancer with an absence of Parametrial involvement and suspicious lymph node metastasis (SURPRISE): Gynecologic Oncology Research Investigators coLLborAtion study (GORILLA-1002) (1199)

109 Clinical Validation of HPV CTDNA for Early Detection of Residual Disease Following Chemoradiation in Cervical Cancer

109 Clinical Validation of HPV CTDNA for Early Detection of Residual Disease Following Chemoradiation in Cervical Cancer

Association of Cell Death Markers With Tumor Immune Cell Infiltrates After Chemo-Radiation in Cervical Cancer.

Irradiation induces distinct cellular responses such as apoptosis, necroptosis, iron-dependent cell death (a feature of ferroptosis), senescence, and mitotic catastrophe. Several of these outcomes are immunostimulatory and may represent a potential for immunogenic type of cell death (ICD) induced by radiotherapy triggering abscopal effects. The purpose of this study is to determine whether intra-tumoral ICD markers can serve as biomarkers for the prediction of patient’s outcomes defined as the metastasis status and survival over a 5-year period. Thirty-eight patients with locally advanced cervical cancer, treated with neoadjuvant chemoradiotherapy using cisplatin were included in this study. Pre-treatment tumor biopsy and post-treatment hysterectomy samples were stained for cell death markers and danger associated molecular patterns (DAMPs): cleaved caspase-3 (apoptosis), phosphorylated mixed lineage kinase domain like pseudokinase (pMLKL; necroptosis), glutathione peroxidase 4 (GPX4; ferroptosis) and 4-hydroxy-2-noneal (4-HNE; ferroptosis), high mobility group box 1 (HMGB1) and calreticulin. Although these markers could not predict the patient’s outcome in terms of relapse or survival, many significantly correlated with immune cell infiltration. For instance, inducing ferroptosis post-treatment seems to negatively impact immune cell recruitment. Measuring ICD markers could reflect the impact of treatment on the tumor microenvironment with regard to immune cell recruitment and infiltration.One Sentence SummaryCell death readouts during neoadjuvant chemoradiation in cervical cancer

PD-0909 Outcome of multiple high-risk factors on overall survival in adjuvant cervical cancer chemoradiation

PD-0909 Outcome of multiple high-risk factors on overall survival in adjuvant cervical cancer chemoradiation

Correlation of skeletal muscle depletion with acute toxicities for cervical cancer patients undergoing concurrent chemoradiation: A prospective study.

Pelvic radiation with concurrent chemotherapy is associated with toxicities that worsen the cachectic state of the patient. : The aim of this study is to quantify skeletal muscle changes on computed tomography (CT) images helps in assessing the same which could be correlated with the toxicities. The study design was s prospective study. Forty-one patients were treated with chemoradiation followed by brachytherapy (BT) for cervical cancer. Preexternal beam and preBT CT scans were used to assess skeletal muscle index (SMI). The changes in the SMI were correlated with enteritis, dyselectrolytemia, and hematological toxicities. Paired t-test was used to compare pre- and post-treatment SMI. Chi-square test would be used to study the association between toxicity and SMI change. The mean SMI was 57.41 cm2/m2 (42.5-73) in the preexternal beam radiotherapy (EBRT) scans and 54.5 cm2/m2 (40.9-71.07) in the post-EBRT scans. Twenty-two patients (53.7%), 14 patients (34.1%), and five patients (12.2%) belonged to <5%, 5%-10%, and >10% loss in SMI groups, respectively. Grade III enteritis was seen in 31.7% of the patients, hyponatremia in 26.8% of the patients in the 4th week, and leukopenia and neutropenia were seen in 26.8% of cases in the 5th week. Enteritis correlated significantly with the change in SMI (P = 0.047). Patients with cancer cachexia are at higher risk for radiation enteritis during chemoradiation for cervical cancer.

The Incorporation of Immunotherapy and Targeted Therapy Into Chemoradiation for Cervical Cancer: A Focused Review.

In 2011 the Food and Drug Administration (FDA) approved anti-vascular endothelial growth factor (VEGF) therapy, bevacizumab, for intractable melanoma. Within the year, immunotherapy modulators inhibiting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) were approved in addition to programmed death-ligand 1 (PD-L1) antibodies in 2012. Since then, research showing the effectiveness of targeted therapies in a wide range of solid tumors has prompted studies incorporating their inclusion as part of upfront management as well as refractory or relapsed disease. For treatment of cervical cancer, which arises from known virus-driven oncogenic pathways, the incorporation of targeted therapy is a particularly attractive prospect. The current standard of care for locally advanced cervical cancer includes concurrent platinum-based chemotherapy with radiation therapy (CRT) including external beam radiation therapy (EBRT) and brachytherapy. Building upon encouraging results from trials testing bevacizumab or immunotherapy in recurrent cervical cancer, these agents have begun to be incorporated into upfront CRT strategies for prospective study. This article will review background data establishing efficacy of angiogenesis inhibitors and immunotherapy in the treatment of cervical cancer as well as results of prospective studies combining targeted therapies with standard CRT with the aim of improving outcomes. In addition, the role of immunotherapy and radiation on the tumor microenvironment (TME) will be discussed.

Impact of three-dimensional chemoradiation on pelvic bone mineral density, low back pain, and disability in cervical cancer: a prospective study

ObjectiveTo prospectively analyze the effect of three-dimensional chemoradiation on the bone mineral density of pelvic bones and its association with low back pain and disability in patients with locally advanced...

A Phase 1 Trial Assessing the Safety and Tolerability of a Therapeutic DNA Vaccination Against HPV16 and HPV18 E6/E7 Oncogenes After Chemoradiation for Cervical Cancer

This study assessed the safety and tolerability of therapeutic immunization against the human papillomavirus (HPV) viral oncoproteins E6 and E7 in patients with cervical cancer after chemoradiation. MEDI0457 (INO-3112) is a DNA-based vaccine targeting E6 and E7 of HPV-16/18 that is coinjected with an IL-12 plasmid followed by electroporation with the CELLECTRA 5P device. At 2 to 4 weeks after chemoradiation, patients with newly diagnosed stage IB1-IVA (cohort 1) or persistent/recurrent (cohort 2) cervical cancers were treated with 4 immunizations of MEDI0457 every 4 weeks. The primary endpoints were incidence of adverse events and injection site reactions. Immune responses against HPV antigens were measured by ELISpot for interferon-γ (IFNγ), enzyme-linked immunosorbent assay for antibody responses and multiplexed immunofluorescence for immune cells in cervical biopsy specimens. Ten patients (cohort 1, n = 7; cohort 2, n = 3) with HPV16 (n = 7) or HPV18 (n = 3) cervical cancers received MEDI0457 after chemoradiation. Treatment-related adverse events were all grade 1, primarily related to the injection site. Eight of 10 patients had detectable cellular or humoral immune responses against HPV antigens after chemoradiation and vaccination: 6 of 10 patients generated anti-HPV antibody responses and 6 of 10 patients generated IFNγ-producing T cell responses. At the completion of chemoradiation and vaccination, cervical biopsy specimens had detectable CD8+ T cells and decreased PD-1+CD8+, PD-L1+CD8+, and PD-L1+CD68+ subpopulations. All patients cleared detectable HPV DNA in cervical biopsies by completion of chemoradiation and vaccination. Adjuvant MEDI0457 is safe and well tolerated after chemoradiation for locally advanced or recurrent cervical cancers, supporting further investigation into combining tumor-specific vaccines with radiation therapy.

Immunologic impact of chemoradiation in cervical cancer and how immune cell infiltration could lead toward personalized treatment.

We investigated the potential of tumor-infiltrating immune cells (ICs) as predictive or prognostic biomarkers for cervical cancer patients. In total, 38 patients treated with (chemo)radiotherapy and subsequent surgery were included in the current study. This unique treatment schedule makes it possible to analyze IC markers in pretreatment and posttreatment tissue specimens and their changes during treatment. IC markers for T cells (CD3, CD4, CD8 and FoxP3), macrophages (CD68 and CD163) and B cells (CD20), as well as IL33 and PD-L1, were retrospectively analyzed via immunohistochemistry. Patients were grouped in the low score or high score group based on the amount of positive cells on immunohistochemistry. Correlations to pathological complete response (pCR), cause-specific survival (CSS) and metastasis development during follow-up were evaluated. In analysis of pretreatment biopsies, significantly more pCR was seen for patients with CD8 = CD3, CD8 ≥ CD4, positive IL33 tumor cell (TC) scores, IL33 IC < TC and PD-L1 TC ≥5%. Besides patients with high CD8 scores, also patients with CD8 ≥ CD4, CD163 ≥ CD68 or PD-L1 IC ≥5% had better CSS. In the analysis of posttreatment specimens, less pCR was observed for patients with high CD8 or CD163 scores. Patients with decreasing CD8 or CD163 scores between pretreatment and posttreatment samples showed more pCR, whereas those with increasing CD8 or decreasing IL33 IC scores showed a worse CSS. Meanwhile, patients with an increasing CD3 score or stable/increasing PD-L1 IC score showed more metastasis during follow-up. In this way, the intratumoral IC landscape is a promising tool for prediction of outcome and response to (chemo)radiotherapy.

The role of additional hysterectomy after concurrent chemoradiation for patients with locally advanced cervical cancer

The standard treatment for cervical cancer is chemoradiation although some patients showed treatment resistance. The purpose of this study was to investigate the clinical efficacy of surgery after chemoradiation for cervical cancer. Patients with FIGO stage IB2 to IIB cervical cancer were included in the study between 2005 and 2015. A total of 50 patients who underwent surgery after neoadjuvant chemoradiation and 76 patients who received only chemoradiation were compared. Baseline differences between the two groups were adjusted with inverse probability of treatment weighting method using propensity scores composed of the following independent variables: age, stage, tumor size, lymph node metastasis, and histological subtypes. Median follow-up was 64.8 (range 4.8-143.9) months. After adjustment with inverse probability of treatment weighting, Kaplan-Meier curves showing adjusted progression-free survival and overall survival were significantly longer in the neoadjuvant chemoradiation compared with the chemoradiation-only group (p = 0.027 and p = 0.017, respectively). Moreover, in patients with squamous cell carcinoma, recurrence in previously irradiated field and recurrence both in and out of previously irradiated field were significantly decreased in the neoadjuvant chemoradiation compared with the chemoradiation-only group (3.1% and 18.4%, respectively; OR 0.142, p = 0.001]. Adverse events of surgery after chemoradiation were acceptable, although temporary hydronephrosis was frequently observed (23.1%). Surgery after chemoradiation reduced pelvic recurrence, and as a result, patients who underwent neoadjuvant chemoradiation showed more favorable survival outcomes compared with those who only underwent chemoradiation.

The role of PET/CT in surveillance after chemoradiation for cervical cancer

The role of PET/CT in surveillance after chemoradiation for cervical cancer

Predictors of acute hematologic toxicity in women receiving extended-field chemoradiation for cervical cancer

Predictors of acute hematologic toxicity in women receiving extended-field chemoradiation for cervical cancer

Volumetric assessment of apparent diffusion coefficient predicts outcome following chemoradiation for cervical cancer

ObjectiveTo determine the utility of volumetric diffusion weighted imaging (DWI) compared to other clinical factors for predicting recurrence and survival in cervical cancer patients treated with definitive chemoradiation. Methods and materialsWe retrospectively studied cervical cancer patients treated with definitive chemoradiation between 2009–2013 at a single institution with a baseline MRI with DWI and 18F-FDG positron emission tomography/computed tomography (FDG-PET) scan. To identify clinical and imaging metrics correlated with survival and recurrence endpoints, variable importance values were calculated from random forest models. To provide clinically relevant threshold values, recursive partitioning analysis dichotomized patients into potential risk groups based on selected metrics. Cox’s proportional hazard models assessed the effect of clinical and imaging factors on survival endpoints. ResultsNinety-three patients were included in the analysis (median age 50 years). At a median follow-up of 35.6 months, 32 patients (34%) had disease recurrence. In the best multivariate model including clinical and imaging parameters, 90th percentile ADC < 1.917 was the only significantly associated factor with worse progression free survival (PFS). Overall survival, PFS, and distant metastasis free survival (DMFS) were significantly different between patient groups divided on 90th percentile ADC with threshold of 1.917 × 10−3 mm2/s and MRI volume with threshold of 18.9 cc (P = 0.037, P = 0.0002, P = 0.001). High MRI volume and low ADC were associated with worse clinical outcomes. ConclusionsVolumetric 90th percentile ADC value of the primary tumor on pretreatment MRI was a significant predictor of PFS and DMFS in cervical cancer patients, independent of established clinical factors and SUV on FDG-PET.