Stage IB2-IVA Cervical Cancer Research Articles

Clinical outcomes of three vs four fractions of MRI-guided brachytherapy in cervical cancer

PURPOSEMRI-guided brachytherapy (MRgBT) is essential in the management of locally advanced cervical cancer. This study compares disease and toxicity outcomes in cervical cancer patients treated with 24 Gy/3 fractions (Fr) versus the conventional 28 Gy/4 Fr. METHODS AND MATERIALSThis retrospective study included 241 consecutive patients with FIGO 2018 stage IB-IVA cervical cancer treated with definitive chemoradiation between April 2014 - March 2021. Disease-free survival (DFS) was estimated using the Kaplan-Meier method and compared using the log-rank test. Cumulative incidence of local failure (LF), distant failure (DF) and G2+ gastrointestinal (GI), urinary (GU) and vaginal toxicity were estimated using the cumulative incidence function with death as a competing risk and compared using the Gray's test. RESULTSOf the 241 patients, 42% received 24 Gy/3 Fr and 58% received 28 Gy/4 Fr. With a median follow up of 3.2 (range 0.2-9.2) years, there were 14 local, 41 regional nodal and 51 distant failures in 63 (26%) patients. No significant differences were found between the 24 Gy/3 Fr vs 28 Gy/4 Fr group in 3-year DFS (77% vs 68%, P = 0.21), 3-year cumulative incidence of LF (5% vs 7%, P = 0.57), DF (22% vs 25%, P = 0.86), G2+ GI toxicity (11% vs 20%, P = 0.13), or G2+ vaginal toxicity (14% vs 17%, P = 0.48), respectively. The 3-year cumulative G2+ urinary toxicity rate was lower in the 24 Gy/3 Fr group (9% vs 23%, P = 0.03). CONCLUSIONCervical cancer patients treated with 24 Gy/3 Fr had similar DFS, LF, DF, GI and vaginal toxicity rates, and a trend towards lower G2+ urinary toxicity rate compared to those treated with 28 Gy/4 Fr. A less resource-intensive brachytherapy fractionation schedule of 24 Gy/3 Fr is a safe alternative to 28 Gy/4 Fr for definitive treatment of cervical cancer.

The Prognostic Value of the Systemic Immune-Inflammation Index (SII) and Red Cell Distribution Width (RDW) in Patients with Cervical Cancer Treated Using Radiotherapy.

There is growing interest in the prognostic value of routinely performed pre-treatment blood test indices, such as the RDW or SII, with the latter combining the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR). These indices were shown to be prognostic for survival in some malignancies. The purpose of this study was to evaluate the association between pre-treatment RDW and SII, and OS in patients treated with radiotherapy for primary localised cervical cancer. This retrospective analysis included patients treated with definitive CRT between 2011 and 2017 for histopathologically confirmed FIGO 2018 stage IB2-IVA cervical cancer. Statistical analysis was performed using the Kaplan-Meier method, two-sided log-rank tests, and Cox proportional hazards models, with the AIC serving as a prediction error estimator. The study group included 249 patients with a median age of 57.2 years and a median follow-up of 75.8 months. The majority were diagnosed with squamous cell carcinoma (237; 95.2%) and had FIGO stage III (211; 84.7%). Approximately half of the patients (116; 46.4%) had regional lymph node metastases. Patients with a low RDW (≤13.4%) and low SII (≤986.01) had a significantly longer OS (p = 0.001 and p = 0.002). The RDW remained as an independent prognostic factor in the multivariable model (high vs. low; HR = 2.04; 95% CI: 1.32-3.16; p = 0.001). Including RDW in the model decreased the Akaike Information Criterion from 1028.25 to 1018.15. The RDW is a cheap and widely available index that is simultaneously an independent prognostic factor for survival and could be used to improve pre-treatment prognosis assessments in patients with cervical cancer undergoing CRT. Available data encourage assessing the RDW as a prognostic factor in prospective trials to aid the identification of candidates for treatment escalation.

Serum Levels of Intercellular Adhesion Molecule 1 and Vascular Cell Adhesion Molecule 1 as Biomarkers to Predict Radiotherapy Sensitivity in Cervical Cancer.

Cervical cancer is a significant global health burden, and individualized treatment approaches are necessary due to its heterogeneity. Radiotherapy is a common treatment modality; however, the response varies among patients. The identification of reliable biomarkers to predict radiotherapy sensitivity is crucial. A cohort of 189 patients with stage IB2-IVA cervical cancer, treated with radiotherapy alone or concurrent chemoradiotherapy, was included. Serum samples were collected before treatment, and intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) concentrations were determined. Patients were categorized into radiotherapy-sensitive (RS) and radiotherapy-resistant (RR) groups based on treatment response. Clinicopathological characteristics and survival rates were analyzed. The analysis of clinicopathological characteristics showed that age, family history of cervical cancer and post-menopausal status did not significantly differ between RS and RR groups. Tumor size demonstrated a borderline significant association with radiotherapy response, while differentiation degree was significantly associated. Serum ICAM-1 and VCAM-1 concentrations were significantly higher in the RR group compared to the RS group. Combined detection of ICAM-1 and VCAM-1 improved the predictive ability for radiotherapy sensitivity. Higher serum ICAM-1 and VCAM-1 levels were observed in patients with lower tumor differentiation. Five-year overall survival rates differed significantly between patients with high and low ICAM-1 and VCAM-1 levels. Serum ICAM-1 and VCAM-1 levels show potential as predictive biomarkers for radiotherapy sensitivity in cervical cancer.

Less than whole uterus irradiation for patients with locally advanced cervical cancer

IntroductionCurrent consensus guidelines for definitive cervical cancer intensity modulated radiation therapy (IMRT) recommend inclusion of the entire uterus within the clinical target volume, however this is debated. We aimed to evaluate outcomes of patients with cervical cancer who were treated with less than whole uterus irradiation. MethodsWe identified 109 patients with FIGO Stage IB-IVA cervical cancer treated definitively with concurrent chemoradiation, including IMRT and brachytherapy, from 2010 to 2022 at a single institution where the practice was to include the gross cervix tumor with an internal target volume with differences in bladder filing accounted for, plus additional 5 mm planning target volume (PTV) margin. Local, regional, and distant recurrences were analyzed using competing risk methods, and a Wilcoxon rank sum test was performed to assess differences in dose to organs at risk based on the proportion of the uterus included in the PTV, with the median proportion of the uterus included (75 %) used as the cut-point. ResultsThe median follow-up time was 65 months (range 3–352 months). The 2-year cumulative incidence of LR for the entire cohort was 4.2 % (95 % confidence interval [CI] 1.3–9.7). Compared with patients who had ≥ 75 % of the uterus included in the PTV, patients who had < 75 % of the uterus included in the PTV had significantly lower bowel D200cc (p = 0.02). The cumulative incidence of local failure (LR) was not significantly different between the two groups. ConclusionsIncluding less than the whole uterus for definitive cervix cancer IMRT does not seem to compromise local control. Less than whole uterus irradiation could be considered for carefully selected cervix cancer patients to decrease bowel dose and possible treatment-related toxicity.

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.

Updated Trends in the Utilization of Brachytherapy in Cervical Cancer in the United States: A Surveillance, Epidemiology, and End-Results Study

BackgroundA previous Surveillance, Epidemiology, and End Results (SEER) study revealed a concerning decline in brachytherapy utilization in the United States between 1988-2009. This study evaluates recent trends in brachytherapy utilization in cervical cancer, and identifies factors and survival benefit associated with the use of brachytherapy treatment. Methods and MaterialsUsing SEER data, 8500 patients with FIGO 2009 stage IB2-IVA cervical cancer treated with external beam radiotherapy (EBRT) between 2000-2020 were identified. Logistic regression analysis was performed on potential factors associated with brachytherapy use: age, marital status, race, ethnicity, income, metropolitan status, year of diagnosis, SEER region, histology, grade and stage. To adjust for differences between patients who received brachytherapy and those who did not, propensity-score matching was used. Multivariable Cox regression analysis assessed the association of brachytherapy use with cervical cancer-specific mortality (CSM) and all-cause mortality (ACM) in the matched cohort. ResultsSixty-four percent of the 8500 women received brachytherapy in combination with EBRT; 36% received EBRT alone. The brachytherapy utilization rate declined sharply in 2003/2004 (lowest rate 44% in 2003), and then gradually improved especially in 2018-2020 (76%). Factors associated with higher odds of brachytherapy use included younger age, married (versus single), later years of diagnosis, certain SEER regions and earlier stage. In the propensity-score matched cohort, brachytherapy treatment was associated with lower 4-year cumulative incidence of cancer death (32.1% vs 43.4%, P<.001) and better overall survival (OS, 64.0% vs 51.4%, P<.001). Brachytherapy treatment was independently associated with lower CSM (hazard ratio [HR] 0.70, 95% CI 0.64-0.76; P<.001) and ACM (HR 0.72, 95% CI 0.67-0.78; P<.001). ConclusionBrachytherapy utilization among SEER regions has improved since 2004 in patients with stage IB2-IVA cervical cancer. Brachytherapy use remains independently associated with significantly lower CSM and ACM, and an essential component of treatment for patients with locally advanced cervical cancer.

Weekly Image Guidance in Patients with Cervical Cancer Treated with Intensity Modulated Radiation Therapy: Results of a Large Cohort Study

Given the motion of the cervix, uterus, and organs at risk, image guidance is recommended for patients undergoing intensity modulated radiation therapy (IMRT) for cervical cancer. However, daily image guidance can be resource intensive, particularly in developing countries. In this study, we evaluated the feasibility of a weekly image-guidance pattern and analyzed the long-term outcomes in a large cohort of patients. The study enrolled patients with stage IB-IVA cervical cancer who received concurrent chemotherapy between 2005 and 2015. IMRT was delivered at a dose of 50.4 Gy in 28 fractions, with weekly cone-beam CT scans for image guidance. Following the image guidance, physicians would advise patients on the suitability of rectum and bladder preparation to help them prepare on non-imaging days. When significant tumor regression was observed, a second CT simulation and re-planning were performed. Intracavitary brachytherapy was delivered at a dose of 30 Gy in 5 fractions. The concurrent chemotherapy regimen consisted of weekly cisplatin. A total of 1,433 patients were included in the study. The median follow-up periods for all patients and surviving patients were 63 months (ranging from 2 to 125 months) and 70 months (ranging from 3 to 125 months), respectively. The 5-year overall survival (OS), disease-free survival (DFS), and local control (LC) rates were 79.6%, 73.2%, and 86.5%, respectively. The estimated 8-year OS, DFS, and LC rates were 75.6%, 69.2%, and 85.2%, respectively. For patients with stage IB1, IB2, IIA, IIB, IIIA, IIIB, and IVA diseases (according to the 2014 FIGO staging system), the 5-year OS and DFS rates were 90.2% and 86.7%, 95.1% and 86.5%, 87.9% and 79.8%, 82.2% and 75.5%, 64.3% and 58.2%, 61.8% and 57.4%, and 43.8% and 19.4%, respectively. For patients with squamous cell carcinoma and adenocarcinoma, the 5-year DFS rates were 75.1% and 57.3%, respectively. For patients with positive regional lymph nodes, the 5-year OS and DFS rates were 64.1% and 57.8%, respectively. A total of 66 patients (4.6%) experienced grade 3-5 chronic toxicities, including 38 patients (2.7%) with gastrointestinal toxicities and 36 patients (2.5%) with genitourinary toxicities. IMRT with weekly image guidance resulted in high survival rates and acceptable toxicities. This indicates that weekly image guidance is acceptable in countries with limited medical resources.

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.

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.

The Value of Progression-Free Survival at Three Years as a Primary Endpoint for Studies on Radiotherapy in Patients with Locally Advanced Cervical Cancer: Individual Patient Data and Validation From 27 Randomized Trials

A traditional endpoint for locally advanced cervical cancer (LACC) clinical trials is overall survival (OS) with five years of follow-up. At present, many clinical trials evaluating concurrent chemoradiotherapy combined with immunotherapy for LACC are underway in worldwide. The use of a shorter-term endpoint could significantly speed the translation of research findings into practice. The primary hypothesis was that PFS with three years of follow-up (PFS36) is an appropriate primary endpoint to replace OS with five years of follow-up (5-year OS). The primary hypothesis was developed from our individual data, was further investigated using phase III randomized controlled trials (RCTs), and then externally validated by phase II trials and retrospective studies up to 2022. Correlation analysis at the treatment-arm level was performed between 2-, 3-, 4-, and 5-year PFS rates and 5-year OS, using the Pearson correlation coefficient r in weighted linear regression, with weight equal to patient size. The MEDLINE, Embase, and PubMed databases, together with the Cochrane Central Register of Controlled Trials, were searched from January 1, 1999, to February 2, 2023. Articles eligible for inclusion contained complete survival data. A total of 613 patients with histologically confirmed, FIGO 2009 stage IB-IVA cervical cancer who underwent radiotherapy at our institute from January 2010 to December 2013 were eligible. Individual patient data were pooled to explore the correlation between PFS and the OS trend. The recurrence rates for years 1 through 5 were 12.9%, 7.3%, 3%, 2.3%, and 1.8%, respectively. The median recurrence time was 13 months and the median time from recurrence to death was 12.2 months. Within all the recurrence, 47.3% of recurrences occurred during the first year, 71.4% in the first two years, and 85% in the first three years. Patients who did not achieve PFS36 had a 5-year OS rate of 30.3%. In contrast, a 5-year OS rate of 98.2% was observed in patients who achieved PFS36. Further data were extracted from 27 RCTs on locally advanced cervical cancer. The trials included 57 arms, with a pooled sample size of 7,692 patients. Formal measures of surrogacy were satisfied. Quality control was performed, where studies with a high risk of bias were excluded. In trial-level surrogacy, PFS36 (r2, 0.778) was associated with 5-year OS. The correlation between PFS36 and OS was externally validated using independent phase II trials and retrospective data. In total, 23 studies representing 5,174 patients were included. PFS36 (r2, 0.719) was found to be associated with OS. The patients who achieved PFS36 had excellent outcomes, whereas patients that experienced earlier progression had poor survival. A significant correlation was found between PFS36 and 5-year OS in clinical trials on patients with locally advanced cervical cancer. These results suggest that PFS36 is an appropriate endpoint for LACC clinical trials of radiotherapy-based regimens.

The impact of bone marrow sparing on organs at risk dose for cervical cancer: a Pareto front analysis.

To quantify the increase in bladder and rectum dose of a bone marrow sparing (BMS) VMAT strategy for primary treatment of locally advanced cervical cancer (LACC). Twenty patients with stage IB-IVA cervical cancer were selected for this study. The whole Pelvic Bones (PB) was taken as substitute for bone marrow. For every patient, Pareto-optimal plans were generated to explore the trade-off between rectum, bladder, and PB mean dose. The PB mean dose was decreased in steps of 1 Gy. For each step, the increase in rectum and bladder mean dose was quantified. The increase in mean dose of other OAR compared to no BMS was constrained to 1 Gy. In total, 931 plans of 19 evaluable patients were analyzed. The average [range] mean dose of PB without BMS was 22.8 [20.7-26.2] Gy. When maximum BMS was applied, the average reduction in mean PB dose was 5.4 [3.0-6.8] Gy resulting in an average mean PB dose of 17.5 [15.8-19.8] Gy. For <1 Gy increase in both the bladder and the rectum mean dose, the PB mean dose could be decreased by >2 Gy, >3 Gy, >4 Gy, and >5 Gy for 19/19, 13/19, 5/19, and 1/19 patients, respectively. Based on the comprehensive three-dimensional Pareto front analysis, we conclude that 2-5 Gy BMS can be implemented without a clinically relevant increase in mean dose to other OAR. If BMS is too dominant, it results in a large increase in mean dose to other OAR. Therefore, we recommend implementing moderate BMS for the treatment of LACC patients with VMAT.

The value of progression-free survival at three years as a primary endpoint for studies on radiotherapy in patients with locally advanced cervical cancer: Individual patient data from Chinese National Cancer Center and validation from 27 global randomized trials.

5534 Background: A traditional endpoint for locally advanced cervical cancer (LACC) clinical trials is overall survival with five years of follow-up (5-year OS). The use of a shorter-term endpoint could significantly speed the translation of research findings into practice. The primary hypothesis was that PFS with three years of follow-up (PFS36) is an appropriate primary endpoint to replace 5-year OS. Methods: The primary hypothesis was developed from our individual data, was further investigated using phase III randomized controlled trials (RCTs), and then externally validated by phase II trials and retrospective studies up to 2022. Correlation analysis at the treatment-arm level was performed between 2-, 3-, 4-, and 5-year PFS rates and 5-year OS. Correlation analysis was performed using the Pearson correlation coefficient r in weighted linear regression, with weight equal to patient size. The MEDLINE, Embase, and PubMed databases, together with the Cochrane Central Register of Controlled Trials, were searched from January 1, 1999, to February 2, 2023. Articles eligible for inclusion contained complete survival data. Results: A total of 613 patients with histologically confirmed, FIGO 2009 stage IB–IVA cervical cancer who underwent radiotherapy at our institute from January 2010 to December 2013 were eligible. Individual patient data were pooled to explore the correlation between PFS and the OS trend. The recurrence rates for years 1 through 5 were 12.9%, 7.3%, 3%, 2.3%, and 1.8%, respectively. The median recurrence time was 13 months and the median time from recurrence to death was 12.2 months. Within all the recurrence, 47.3% of recurrences occurred during the first year, 71.4% in the first two years, and 85% in the first three years. Patients who did not achieve PFS36 had a 5-year OS rate of 30.3%. In contrast, a 5-year OS rate of 98.2% was observed in patients who achieved PFS36. Further data were extracted from 27 randomized phase III trials on LACC. The trials included 57 arms, with a pooled sample size of 7,692 patients. In trial-level surrogacy, PFS36 (r2, 0.778) was associated with 5-year OS. Sensitivity analysis demonstrated reasonable overall consistency. The correlation between PFS36 and OS was externally validated using independent phase II trials and retrospective data. In total, 23 studies representing 5,174 patients were included. PFS (r2, 0.719) was found to be associated with 5-year OS. Conclusions: A significant correlation was found between PFS36 and 5-year OS in clinical trials on patients with locally advanced cervical cancer. This correlation was found both within patients and across trials. These results suggest that PFS36 is an appropriate endpoint for LACC trials of radiotherapy-based regimens.

A retrospective study of locally advanced cervical cancer cases treated with CT-based 3D-IGBT compared with 2D-IGBT.

To retrospectively review locally advanced cervical cancer (CC) cases treated with three-dimensional image-guided brachytherapy (3D-IGBT) and two-dimensional (2D)-IGBT. Patients with Stage IB-IVa CC who underwent intracavitary irradiation between 2007 and 2021 were divided into the 3D-IGBT and 2D-IGBT groups. Local control (LC), distant metastasis-free survival (DMFS), progression-free survival (PFS), overall survival (OS), and gastrointestinal toxicity (G3 or more) were investigated at 2/3years post-treatment. Seventy-one patients in the 2D-IGBT group from 2007 to 2016 and 61 patients in the 3D-IGBT group from 2016-2021 were included in the study. The median follow-up period was 72.7 (4.6-183.9) months in the 2D-IGBT group and 30.0 (4.2-70.5) months in the 3D-IGBT group. The median age was 65.0 (40-93) years in the 2D-IGBT group and 60.0 (28-87) years in the 3D-IGBT group, but there was no difference in FIGO stage, histology, or tumor size between the groups. In treatment, the median A point dose was 56.1 (40.0-74.0) Gy in the 2D-IGBT group and 64.0 (52.0-76.8) Gy in the 3D-IGBT group (P < 0.0001), and the proportion of patients who underwent chemotherapy more than five times was 54.3% in the 2D-IGBT group and 80.8% in the 3D-IGBT group (P = 0.0004). The 2/3-year LC, DMFS, PFS, and OS rates were 87.3%/85.5%, 77.4%/65.0%, 69.9%/59.9%, and 87.9%/77.9% in the 2D-IGBT group, and 94.2%/94.2%, 81.8%/81.8%, 80.5%/80.5%, and 91.6%/83.0% in the 3D-IGBT group, respectively. A significant difference was observed in PFS (P = 0.02). There was no difference in gastrointestinal toxicity, but there were four intestinal perforations in the patients from the 3D-IGBT group, three of whom had a history of bevacizumab treatment. The 2/3-year LC of the 3D-IGBT group was excellent and PFS also tended to improve. Care should be taken with concomitant use of bevacizumab after radiotherapy.

Abstract 2375: Whole exome sequencing and immune profiling of cervical adenocarcinoma reveal a “cold” tumor-immune phenotype

Abstract Purpose: Cervical adenocarcinomas (CAC), a less common cervical cancer histology with poor prognosis as compared to squamous cell carcinoma (CSCC), disproportionally present at advanced stages in young women and incidence is increasing; however, the same chemoradiation (CRT) paradigm is used by clinicians for both histologies. Given the rarity of CAC, little is known about genomic pathways and tumoral immune factors that differentiate CAC from CSCC and could drive differences in patient outcomes. Objective: To identify distinctions in the mutational landscape and immune phenotype of CAC and CSCC tumors in patients undergoing CRT which may be potential therapeutic targets. Methods: 80 patients with FIGO stage IB-IVA cervical cancer who underwent definitive CRT were prospectively enrolled on an IRB approved clinical trial. Cervical tumor DNA (9 CAC patients; 58 CSCC patients) and cervical tumor microenvironment samples (13 CAC patients, 67 CSCC patients) were collected by a noninvasive swab technique at baseline, and after 1, 3, and 5 weeks of CRT. WES and neoantigen prediction were performed and tumor mutation burden (TMB) was calculated as the number of somatic coding mutations per megabase. Lymphocyte immunostaining was performed according to standard protocols and cells were analyzed using a LSRFortessa X-20 Flow Cytometer (BD Biosciences) and FlowJo 10.6.1. Statistical comparison of mean values was performed by t-test. Results: Baseline mean TMB and tumor neoantigen was lower in CAC compared to CSCC (1.1±0.14 vs 5.2±3.5 respectively for TMB, p&amp;lt;0.01; 6.0±8.5 vs 455.3±472.5 respectively for neoantigen, p&amp;lt;0.01) and persisted during CRT. The top 3 most frequently altered genes unique to CAC were GPR98, SLC12A3, and TP53. The baseline mutational profile of CAC tumors was most similar to other adenocarcinomas including prostate and pancreatic cancer in TCGA. There was a significant reduction for CAC in baseline CD4+ T-cell infiltration in CAC compared to CSCC (p=0.01) which persisted through the course of CRT (p=0.02 at week 3). There was a trend toward decreased CD4+ T-cell activation, including co-expressing CD69 (p=0.17) and Ki67 (p=0.06), decreased CD8+ T-cell infiltration (p=0.19), and decreased Ki67+CD8+ T-cells as compared to CSCC (p=0.02). Conclusions: In contrast to CSCC, immune profiling of the CAC tumor microenvironment suggests a reduction in immune cell infiltrate and absence of or failed T-cell activation. Similarly, unique genetic alterations were detected between histologies, and CAC tumors displayed reduced TMB and loss of tumor neoantigen expression. These findings are consistent with an “immune cold” phenotype in CAC. These patients may be less likely to benefit from immunotherapy. Future investigation into molecularly targeted therapies or strategies that help mobilize peritumoral T-cells in response to CRT may better potentiate improved CRT response in CAC. Citation Format: Julianna Bronk, Xiaogang Wu, Rui Wang, Ananta Yanamandra, Tatiana Karpinets, Chike Abana, Molly El Alam, Katarina Tomasic, Daniel Lin, Erica Lynn, David Lo, Timothy Harris, Xingzhi Song, Andrew Futreal, Jianhua Zhang, Jagannadha Sastry, Ann Klopp, Lauren Colbert. Whole exome sequencing and immune profiling of cervical adenocarcinoma reveal a “cold” tumor-immune phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2375.

Survival effect of pre-RT PET-CT on cervical cancer: Image-guided intensity-modulated radiation therapy era.

No large-scale, well-designed randomized study with a long-term follow-up has evaluated the survival effect of pretreatment 18-fluorodeoxyglucose positron emission tomography-computed tomography (18FDG-PET-CT) on patients with stage IB-IVA cervical cancer receiving image-guided intensity-modulated radiation therapy (IG-IMRT). This is the first head-to-head propensity score-matched, nationwide population-based cohort study evaluating this survival effect. The results revealed that pretreatment 18FDG-PET-CT might be associated with longer survival in patients with stage IB-IVA cervical cancer receiving radiotherapy or concurrent chemoradiotherapy, especially in the IG-IMRT era. No large-scale, well-designed randomized study with a long-term follow-up has evaluated the survival effect of pretreatment 18-fluorodeoxyglucose positron emission tomography-computed tomography (18FDG-PET-CT) on patients with stage IB-IVA cervical cancer receiving image-guided intensity-modulated radiation therapy (IG-IMRT). Therefore, in this propensity score-matched, population-based cohort study, we investigated these survival effects. We included 4167 patients with stage IB-IVA cervical cancer receiving radiotherapy (RT) or concurrent chemoradiotherapy (CCRT) through the IG-IMRT technique. The patients were categorized into two 1:2 propensity score-matched groups depending on whether they underwent pretreatment 18FDG-PET-CT, and their outcomes were compared. We included 2778 and 1389 patients with cervical cancer in the nonpretreatment and pretreatment PET-CT groups, respectively. Univariable and multivariable analyses revealed an association between pretreatment PET-CT and improved survival in the patients (in the adjusted model, the adjusted hazard ratio [aHR] was 0.88; 95% confidence interval [CI], 0.80-0.97: P = 0.010). Regardless of the cancer stage (early or advanced), pretreatment PET-CT was significantly superior to nonpretreatment PET-CT in terms of all-cause death (aHR, 0.78; 95% CI, 0.60-0.92; P = 0.013 and aHR, 0.90; 95% CI, 0.81-0.99; P = 0.039 for the early [IB-IIA] and advanced stages [IIB-IVA], respectively). Pretreatment 18FDG-PET-CT might be associated with longer survival in patients with stage IB-IVA cervical cancer receiving RT or CCRT, especially in the era of IG-IMRT.

Importance of radiographic tumor regression during radiotherapy in squamous cell versus adenocarcinoma of the uterine cervix as assessed by MRI and cone beam CT

The purpose of this study was to evaluate the kinetics of tumor regression in cervical squamous cell carcinoma (SCC) and adenocarcinoma (AC) using computed tomography (CT) and magnetic resonance imaging (MRI), and to correlate rate of regression and residual tumor with progression and survival. Thirty-two patients with stage IB2-IVA cervical cancer were randomly selected from an institutional database with a 2:1 ratio of SCC to AC. All available on-treatment weekly cone beam CT (CBCT) and pre- and post-external beam MRIs were utilized to generate largest two-dimensional area of tumor and tumor gross tumor volumes (GTV), respectively. Tumor volume regression velocity and percent residual tumor were correlated to 5-year progression-free survival (PFS) and disease-specific survival (DSS) using threshold regression modeling. Kaplan-Meier and Fine-Grey estimators were used for survival and cumulative incidence analysis, respectively. With a median follow-up of 2.9 years, 32 patients were included, 22 (69%) with SCC and 10 (31%) with AC. All received concurrent chemoradiation followed by brachytherapy. The 2-year cumulative incidence (CI) of local progression for both SCC and AC was 10%, and 2-year CI of distant progression was 9% vs. 57% (p = 0.02). Deaths occurred in 3/22 (14%) with SCC and 7/10 (70%) with AC, with a 2-year DSS of 90% versus 60%, respectively. Extent and rate of regression on CBCTs were not correlated with progression or survival; however, consistent rates of tumor regression for both SCC and AC. Thresholds of ≥20% residual disease on post-external beam pre-brachytherapy MRI and regression velocity ≤1.8%/day were associated with worse PFS and DSS. This study showed cervical AC is associated with higher rates of distant progression and worse overall survival than SCC. Cervical AC tends to have a higher initial and residual tumor burden. Our identified thresholds of ≥20% residual tumor and tumor regression of ≤1.8%/day may help identify cases warranting dose escalation.

Comparing dosimetry of locally advanced cervical cancer patients treated with 3 versus 4 fractions of MRI-guided brachytherapy

PURPOSETo demonstrate the feasibility of treating cervical cancer patients with MRI-guided brachytherapy (MRgBT) using 24 Gy in 3 fractions (F) versus a standard, more resource-intensive regimen of 28 Gy in 4F, and its ability to meet EMBRACE II planning aims. METHODS AND MATERIALSA retrospective review of 224 patients with FIGO Stage IB–IVA cervical cancer treated with 28 Gy/4F (n = 91) and 24 Gy/3F (n = 133) MRgBT between 2016-2021 was conducted. Multivariable linear regression models were fitted to compare dosimetric parameters between the two groups, adjusting for CTVHR and T stage. RESULTSMost patients had squamous cell carcinoma, T2b disease, and were treated with intracavitary applicator plus interstitial needles (96%). The 28 Gy/4F group had higher CTVHR (median 28 vs. 26 cm3, p = 0.04), CTVIR D98% (mean 65.5 vs. 64.5 Gy, p = 0.03), rectum D2cm3 (mean 61.7 vs. 59.2 Gy, p = 0.04) and bladder D2cm3 (81.3 vs. 77.9 Gy, p = 0.03). There were no significant differences in the proportion of patients meeting the EMBRACE II OAR dose constraints and planning aims, except fewer patients treated with 28 Gy/4F met rectum D2cm3 < 65 Gy (73 vs. 85%, p = 0.027) and ICRU rectovaginal point < 65 Gy (65 vs. 84%, p = 0.005). CONCLUSIONSCervical cancer patients treated with 24 Gy/3F MRgBT had comparable target doses and lower OAR doses compared to those treated with 28 Gy/4F. A less-resource intense fractionation schedule of 24 Gy/3F is an alternative to 28 Gy/4F in cervix MRgBT.

Importance of Radiographic Tumor Regression during Radiotherapy in Squamous Cell vs. Adenocarcinoma of the Uterine Cervix as Assessed by MRI, CT and Conebeam CT

<h3>Purpose/Objective(s)</h3> The purpose of this study was to evaluate the kinetics of tumor regression in cervical SCC and AC across the different imaging modalities used for patients undergoing radiotherapy, and to evaluate locoregional relapse (LRR), progression-free survival (PFS) and overall survival (OS) of each cohort and correlate these data with rate of regression of the primary tumor during treatment, and the percent of residual tumor after external beam. <h3>Materials/Methods</h3> Thirty-two patients with stage IB2-IVA cervical cancer were selected with all 3 imaging modalities from an institutional database with a 2:1 ratio of squamous cell carcinoma to adenocarcinoma. All available CT (113 scans), on-treatment weekly conebeam CT (CBCT; 100 scans) and MRIs (MRI₁ at diagnosis and MRI₂ prior to brachytherapy; 48 scans) were imported into planning software and tumor GTV volumes contoured (CT and MRI), or largest two-dimensional area of tumor delineated (CBCT). Volume regression over time curves were generated, and size and rate of regression, and the percent of residual tumor were correlated to disease progression and disease-specific survival (DSS), with receiver-operator curves and machine learning algorithms used to identify thresholds. Kaplan-Meier estimators were used for survival analysis. Fine-Grey analysis was used to estimate cumulative incidence of progression, using a competing risk of death. <h3>Results</h3> With a median follow-up of 2.9 years (yrs), 32 patients were included, 22 (69%) with SCC and 10 (31%) with AC. All were treated with concurrent chemoradiation with 45 Gy in 25 fractions with weekly cisplatin, followed by brachytherapy. The majority received 5 brachytherapy fractions (59%). 2/22 (9%) with SCC and 1/10 (10%) with AC had local progression. The 1- and 2-yr cumulative incidence (CI) of local progression for both SCC and AC was 10% at both time points. Distant progression was higher in AC (60%, 6/10) compared with SCC (9%, 2/22) For SCC vs AC, the 2-yr CI of distant progression was 9% vs 57% (p=0.02). Ten of 32 patients died (31%), 3/22 (14%) with SCC and 7/10 (70%) with AC. For SCC patients, 2-yr DSS was 90%, versus 60 % for AC. Extent and rate of regression on CT and CBCT data were not correlated with progression or survival in this cohort; however, these data showed consistent rates of tumor regression. A threshold of >20% residual on MRI₂ was identified and was correlated with worse 2-yr PFS (50% vs 90%, p=0.013) and 1-yr DSS (83% vs 100%, p<0.001). Median residual volume on MRI₂ trended toward significant between SCC and AC (55% vs 16%, p=0.052). <h3>Conclusion</h3> This study showed cervical AC is associated with higher rates of distant progression and worse overall survival than SCC. Cervical AC tends to have a higher residual tumor burden. Our identified threshold of >20% residual tumor on MRI₂ correlating with worse PFS and distant progression may help identify escalation of systemic therapy in select patients.

PO40 Presentation Time: 4:45 PM: Definitive Management of Cervical Cancer Patients at an Urban Institution During the COVID-19 Pandemic - Brachytherapy Treatment During the Surge

<h3>Purpose</h3> Locally advanced cervical cancer was defined by an international consensus panel as a high priority malignancy during the COVID-19 pandemic, recommending prompt initiation of definitive treatment and completion of treatment (PMID 32563593). The objective of this study was to study the clinical outcomes of patients (pts) with cervical cancer treated with definitive chemoradiation (CRT) and brachytherapy (BT) at our institution in 2019 (pre-COVID) and in 2020 (peri-COVID). <h3>Materials and Methods</h3> This was a retrospective cohort study of pts with FIGO Stage IB2-IVA cervical cancer at our institutions from 1/1/2019 to 12/31/2020. Pts received CRT followed by intracavitary brachytherapy (IC) with two operative insertions one week apart, or interstitial (IS) BT with one operative insertion. BT treatment was planned using image-guided CT or MR delineation. Pre-COVID was defined by initiation of CRT in 1/2019-12/2019, and peri-COVID was defined by initiation in 1/2020-10/2020. Process changes peri-COVID included limited on-site staff (e.g., minimal OR staff, no trainees, remote physics team), universal implementation of COVID-19 testing prior to surgery, and CT instead of MR-delineation based treatment. Outcomes of interest were time to treatment initiation and completion and differences in treatment planning modality or dosimetry. Fisher's exact and Mann Whitney U tests were used with significance p<0.05. <h3>Results</h3> Thirty-one pts were included, with 18 patients undergoing treatment pre-COVID and 13 peri-COVID. The median age at diagnosis pre-COVID was 57.7 (range 23-77) and for peri-COVID, 45.5 (range 28-62, p=0.06). There were no differences in non-English speaking pts (44% vs 59%, p=0.71) or uninsured pts (11% vs 33%, p=0.184) between the two cohorts. Median time to initiation of treatment from biopsy diagnosis was 52 days (range 13-209) in 2019 and for peri-COVID, 55.5 (range 20-173, p=0.71). During COVID, four pts had delayed initiation to treatment >100 days: two related to fertility, and one due to fear of COVID-19. For this pt, tumor size progressed from 2.3 cm to 4.2 cm maximal dimension. One pt treated in 2020 tested positive following treatment and did not require hospital admission. All pts except one completed CRT with RT: 25 pts pelvic RT (45 Gy), 3 pelvic and para-aortic RT (45 Gy with 57.5 Gy concomitant boost to nodes), 8 pts pelvic RT (45Gy) with sequential parametrial boost (50.4-59.4 Gy) using IMRT with no dose differences between pre and peri-COVID (Table 1). No pts required treatment breaks and the median overall treatment time was 50 days (range 31-85) in 2019 vs 50 days (range 43-63) in 2020 (p=0.710). <h3>Conclusions</h3> Despite the significant burden of the COVID-19 pandemic on our health care system, all cervical cancer pts receiving CRT met standard of care including CRT and BT within the recommended time frame with no significant differences in dosimetric treatment parameters pre- and peri-COVID. Delays in treatment initiation of treatment initiation were seen in 30% of pts in the peri-COVID period, suggesting that patients may have had increased barriers to access care. More follow-up is needed to determine how the Covid pandemic impacted cervical cancer outcome measures.

Trends in IMRT Utilization for Definitive Treatment of Cervical Cancer, 2004-2018

<h3>Purpose/Objective(s)</h3> Intensity-modulated radiation therapy (IMRT) is an advanced radiotherapy technique that delivers conformal radiation to desired targets while minimizing dose to surrounding organs at risk. In the post-operative setting, IMRT is associated with reduced acute and late genitourinary and gastrointestinal side effects for patients with cervical cancer. However, no prospective randomized data exist for the use of IMRT in the setting of definitive treatment of intact cervical cancer. The objective of this study was to identify trends in IMRT use for this population. <h3>Materials/Methods</h3> Patients with stage IB2-IVA cervical cancer diagnosed from 2004-2018 who were treated with curative intent chemoradiation were identified in the National Cancer Database. Patients who underwent primary surgical management, did not receive external beam radiation to the pelvis or received radiation outside the pelvis, or received an unspecified technique or target of radiation were excluded. The primary outcome of interest was utilization of IMRT vs 3D conformal radiotherapy (3D-CRT) over time. A Cochrane-Armitage test was performed to assess trends over time. T-tests, chi-square tests, and multivariable logistic regression with propensity score matching were used to identify factors associated with receipt of IMRT. <h3>Results</h3> Overall, 13,974 patients met inclusion criteria; 4,590 (33%) received IMRT, and 9,384 (67%) received 3DCRT. In this cohort, 65% were non-Hispanic White, 45% were early stage (I-II), 80% were squamous histology, 62% received brachytherapy, and 28% had lymph node involvement. The utilization of IMRT increased from 30% in 2004 to 71% in 2018 (p<0.001). After adjustment for clinical and demographic variables, factors associated with IMRT use were: Hispanic ethnicity (adjusted odds ratio [aOR] 1.2, 95% confidence interval [CI] 1.0-1.5), treatment in the Western U.S. (aOR 1.4, CI 1.2-1.7) and the Southern U.S. (aOR 1.3, CI 1.1-1.5), living more than 50 miles from the treatment facility (aOR 1.2, CI 1.0-1.5), stage III disease (aOR 1.3, CI 1.1-1.5), and lymph node involvement (aOR 1.4, CI 1.3-1.6). Compared to an academic medical center, patients receiving care at a comprehensive community cancer center were less likely to receive IMRT (aOR 0.66, CI 0.59-0.72). There were no differences in IMRT use by age, insurance, or medical comorbidities. <h3>Conclusion</h3> Despite the lack of prospective efficacy data supporting the use of IMRT in patients with intact cervical cancer, IMRT has dramatically increased over the last fifteen years especially for patients with advanced-stage disease or lymph node involvement. More data on the optimal use of IMRT, including appropriate target volume margins and on-board imaging, are needed.