Radiation Oncology

Assessing intra- and interfraction motion and its dosimetric impacts on cervical cancer adaptive radiotherapy based on 1.5T MR-Linac

The purpose of this study was to quantify the intra- and interfraction motion of the target volume and organs at risk (OARs) during adaptive radiotherapy (ART) for uterine cervical cancer (UCC) using MR-Linac and to identify appropriate UCC target volume margins for adapt-to-shape (ATS) and adapt-to-position (ATP) workflows. Then, the dosimetric differences caused by motion were analyzed. Thirty-two UCC patients were included. Magnetic resonance (MR) images were obtained before and after each treatment. The maximum and average shifts in the centroid of the target volume and OARs along the anterior/posterior (A/P: Y axes), cranial/caudal (Cr/C: Z axes), and right/left (R/L: X axes) directions were analyzed through image contours. The bladder wall deformation in six directions and the differences in the volume of the organs were also analyzed. Additionally, the motion of the upper, middle and lower rectum was quantified. The correlation between OAR displacement/deformation and target volume displacement was evaluated. The planning CT dose distribution was mapped to the MR image to generate a plan based on the new anatomy, and the dosimetric differences caused by motion were analyzed. For intrafraction motion, the clinical tumor volume (CTV) range of motion along the XYZ axes was within 5 mm; for interfraction motion, the range of motion along the X axis was within 5 mm, and the maximum distances of motion along the Y axis and Z axis were 7.45 and 6.59 mm, respectively. Additionally, deformation of the superior and anterior walls of the bladder was most noticeable. The largest magnitude of motion was observed in the upper segment of the rectum. Posterior bladder wall displacement was correlated with rectal and CTV centroid Y-axis displacement (r = 0.63, r = 0.50, P < 0.05). Compared with the interfractional plan, a significant decrease in the planning target volume (PTV) D98 (7.5 Gy, 7.54 Gy) was observed. However, there were no significant differences within the intrafraction. During ART for UCC patients using MR-Linac, we recommend an ATS workflow using isotropic PTV margins of 5 mm based on intrafraction motion. Based on interfraction motion, the recommended ATP workflow uses anisotropic PTV margins of 5 mm in the R/L direction, 8 mm in the A/P direction, and 7 mm in the Cr/C direction to compensate for dosimetric errors due to motion.

Health-related quality of life and patient-reported symptoms after postoperative proton beam radiotherapy of cervical and endometrial cancer: 2-year results of the prospective phase II APROVE-trial

Abstract Introduction The APROVE-trial investigated the tolerability of postoperative proton beam therapy in women with cervical or endometrial cancer. The present analysis evaluated the secondary endpoints of health-related quality of life (HRQOL) and patient-reported symptoms. Methods 25 patients were included in this prospective phase-II-trial and treated with postoperative radiotherapy using protons alone or in combination with chemotherapy. To attain general and gynecologic-specific HRQOL measures, the EORTC-QLQ-C30 questionnaires combined with -QLQ-CX24 for cervical and -QLQ-EN24 for endometrial cancer were assessed at baseline, at the end of RT and up to 2 years after radiotherapy. The results were compared to an age-matched norm reference population. Symptoms were assessed using Common Terminology Criteria for Adverse Events (CTCAE) and institutional patient-reported symptoms grading. Results Scores regarding global health status were markedly impaired at baseline (mean: 58.0 ± 20.1) compared to reference population data, but significantly (p = 0.036) improved and evened out to comparable norm values 2 years after proton therapy (mean: 69.9 ± 19.3). Treatment caused acute and long-term worsening of pain (p = 0.048) and gastrointestinal symptoms (p = 0.016) for women with endometrial cancer, but no higher-grade CTCAE ≥ 3° toxicity was observed. Dosimetric evaluation of rectum, sigmoid, large and small bowel showed no correlation with the reported gastrointestinal symptoms. After 2 years, fatigue had significantly improved (p = 0.030), whereas patients with cervical cancer experienced more often lymphedema (p = 0.017). Scores for endometrial cancer pertaining to sexual activity (p = 0.048) and body image (p = 0.022) had improved post treatment; in the latter this effect persisted after 2 years. Conclusion Proton beam therapy in the adjuvant setting was well tolerated with only low-grade side effects concerning gastrointestinal symptoms, lymphedema and pain. Overall quality of life was impaired at baseline, but patients were able to recover to values comparable to norm population 2 years after proton therapy. Larger studies are needed to confirm whether the benefit of proton therapy translates into a clinical effect. Sexual dysfunction remains an important issue. Trial registration: The trial was registered at https://clinicaltrials.gov (ClinicalTrials.gov Identifier: NCT03184350, 09th June 2017).

Dosimetric predictors of nephrotoxicity in patients receiving extended-field radiation therapy for gynecologic cancer

Abstract Purpose We sought dosimetric predictors of a decreasing estimated glomerular filtration rate (eGFR) in gynecological oncology patients receiving extended-field radiation therapy (EFRT). Materials and methods Between July 2012 and April 2020, 98 consecutive cervical or endometrial cancer patients underwent EFRT or whole-pelvis radiation therapy (WPRT) with concurrent cisplatin chemotherapy in our institution. To explore the effect of concurrent cisplatin chemotherapy on renal function, the renal function of the WPRT patients was examined. Of the 98 patients, 34 cervical or endometrial cancer patients underwent EFRT including extended-field intensity-modulated radiation therapy (EF-IMRT) and 64 cervical cancer patients underwent WPRT with cisplatin. Of the 34 EFRT patients, 32 underwent concurrent cisplatin chemotherapy. Excluding patients exhibiting recurrences within 6 months, 31 EFRT patients were analyzed in terms of the dose-volume kidney histograms (the percentages of kidney volumes receiving 12, 16, 20, and 24 Gy) and the post- to pre-treatment eGFR ratios. We calculated Pearson correlation coefficients between the renal dose volume and the percentage eGFR reductions of the 31 EFRT patients, and those treated via EF-IMRT. Renal dose constraint significance was evaluated using the Mann–Whitney U test. Results The eGFR value after WPRT with cisplatin remained largely unchanged for 12 months, unlike that after EFRT. In EFRT patients, a strong correlation was evident between the KV20Gy dose and the post- to pre-treatment eGFR ratio (correlation coefficients − 0.80 for all patients and − 0.74 for EF-IMRT patients). In EF-IMRT patients, the kidney volume receiving 20 Gy tended to correlate negatively with the eGFR reduction. The Mann–Whitney U test showed that patients with KV20Gy values &lt; 10% retained significantly better renal function than did patients with KV20Gy values &gt; 10% (P = 0.002). Conclusions Imposition of a severe kidney dose constraint during EF-IMRT may reduce nephrotic toxicity. Future prospective investigations of kidney-sparing EF-IMRT are required.

Retrospective analysis of the 18F-FDG PET/CT cutoff value for metabolic parameters was performed as a prediction model to evaluate risk factors for endometrial cancer

Abstract Purpose The study retrospectively analyzed the accuracy and predictive ability of preoperative integrated whole-body 18F-FDG PET/CT for the assessment of high-risk factors in patients with endometrial carcinoma (EC). Materials and methods A total of 205 patients with endometrial cancer who underwent preoperative PET/CT at Shanghai General Hospital from January 2018 to December 2021 were retrospectively evaluated and last follow-up was June 2023. Our study evaluated the ability and optimal cutoff values of three metabolic and volumetric parameters—standardized uptake value (SUV), metabolic tumor volume (MTV) and total lesion glycolysis (TLG)—to predict deep myometrial invasion (DMI), endocervical stroma invasion (ESI) and lymph node metastases (LNM) in endometrial cancer. The accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of PET/CT were used to assess the diagnostic performance for the prediction. Results Our study demonstrated a significant relationship between SUVmax (11.29, 17.38, 9.47), SUVmean (5.20, 6.12, 4.49), MTV (38.15, 36.28, 33.79 ml), and TLG (199.30, 225.10, 156.40 g) on PET/CT and histologically confirmed DMI, ESI and LNM in endometrial carcinoma (EC), with sensitivity, specificity, accuracy, PPV, and NPV of 100%/100%/100%, 96.53%/98.89%/87.14%, 97.56%/99.02%/91.22%, 92.42%/92.85%/78.31%, and 100%/100%/100%, respectively. Our study showed a risk model based on optimal cutoff values for MTV and TLG of 19.6 ml/126.3 g, 20.54 ml/84.80 g and 24 ml/49.83 g to preoperatively predict DMI, ESI, and LNM, respectively, in endometrial carcinoma. The 4-year OS (HR) for Stage IA, IB, II, III and IV according to 2009 FIGO was 98.00% (0.22), 95.20% (0.04), 83.90% (0.18), 90.50% (0.09) and 60% (0.51). Accordingly, estimated 4-year DFS (HR) for the stage IA-III was 98% (0.02), 95.20% (0.05), 76.90% (0.27) and 76.30% (0.35), all the patients in stage IV occurred recurrence and progression. Conclusion The present study showed patients with MTV &gt; = 19.6 ml of MI and PET- positive LN with MTV cutoff &gt; = 24 ml tended to predict poor OS and PFS in endometrial carcinoma. The cutoff of MTV and TLG in PET/CT assessment could be an independent prognostic factors to predict aggressive forms of EC. Graphic Abstract

Atlas-based auto-segmentation for postoperative radiotherapy planning in endometrial and cervical cancers

Abstract Background Since intensity-modulated radiation therapy (IMRT) has become popular for the treatment of gynecologic cancers, the contouring process has become more critical. This study evaluated the feasibility of atlas-based auto-segmentation (ABAS) for contouring in patients with endometrial and cervical cancers. Methods A total of 75 sets of planning CT images from 75 patients were collected. Contours for the pelvic nodal clinical target volume (CTV), femur, and bladder were carefully generated by two skilled radiation oncologists. Of 75 patients, 60 were randomly registered in three different atlas libraries for ABAS in groups of 20, 40, or 60. ABAS was conducted in 15 patients, followed by manual correction (ABASc). The time required to generate all contours was recorded, and the accuracy of segmentation was assessed using Dice’s coefficient (DC) and the Hausdorff distance (HD) and compared to those of manually delineated contours. Results For ABAS-CTV, the best results were achieved with groups of 60 patients (DC, 0.79; HD, 19.7 mm) and the worst results with groups of 20 patients (DC, 0.75; p = 0.012; HD, 21.3 mm; p = 0.002). ABASc-CTV performed better than ABAS-CTV in terms of both HD and DC (ABASc [n = 60]; DC, 0.84; HD, 15.6 mm; all p &lt; 0.017). ABAS required an average of 45.1 s, whereas ABASc required 191.1 s; both methods required less time than the manual methods (p &lt; 0.001). Both ABAS-Femur and simultaneous ABAS-Bilateral-femurs showed satisfactory performance, regardless of the atlas library used (DC &gt; 0.9 and HD ≤10.0 mm), with significant time reduction compared to that needed for manual delineation (p &lt; 0.001). However, ABAS-Bladder did not prove to be feasible, with inferior results regardless of library size (DC &lt; 0.6 and HD &gt; 40 mm). Furthermore, ABASc-Bladder required a longer processing time than manual contouring to achieve the same accuracy. Conclusions ABAS could help physicians to delineate the CTV and organs-at-risk (e.g., femurs) in IMRT planning considering its consistency, efficacy, and accuracy.

Moderately hypofractionated online adaptive radiotherapy (SWIFT-1) in cervical cancer patients: study protocol for a multi-centered, open-label, two-arm, phase III, randomized controlled study

External beam radiotherapy (EBRT) is an essential component of standard treatment for locally advanced cervical cancer. Moderately hypofractionated radiotherapy (MHRT) offers the potential to reduce treatment burden while compromising efficacy. Although various studies have investigated the safety and efficacy of MHRT, high-quality evidence remains inadequate. The lack of integration of modern radiotherapy techniques in many existing studies may lead to an overestimation of MHRT-associated toxicity. This prospective, multi-center, randomized controlled, non-inferiority phase III trial aims to evaluate the non-inferiority of moderately hypofractionated online adaptive radiotherapy (oART) compared to conventional fractionated radiotherapy (CFRT). A total of 440 participants will be enrolled and randomly assigned in a 1:1 ratio to either the MHRT or CFRT group. Both groups will receive concurrent chemoradiotherapy, and a subset of eligible patients will undergo immunotherapy. The prescribed EBRT dose for the MHRT group will be 43.35 Gy in 17 fractions, with a simultaneous integrated boost of 54.4 Gy in 17 fractions to positive lymph nodes. The CFRT group will receive 45 Gy in 25 fractions, with a simultaneous integrated boost of 60 Gy in 25 fractions to positive lymph nodes. The primary endpoint will be 3-year progression-free survival. Secondary endpoints will include the complete response rate, tumor regression following EBRT, overall survival, locoregional progression-free survival, metastasis-free survival, cervical cancer-specific survival, acute and late toxicity, and quality of life. This randomized controlled trial will prospectively investigate whether MHRT is non-inferior to conventional fractionation in terms of efficacy and safety. Furthermore, the trial will evaluate the potential of moderately hypofractionated oART as a clinically viable alternative to CFRT for the treatment of locally advanced cervical cancer. This trial was registered at ClincalTrials.gov (NCT06641635) on October 12, 2024.

Re-irradiation in oligorecurrence and oligometastatic cervical cancer in modern radiotherapy era

Recurrent cervical cancer remains a therapeutic challenge despite advances in primary treatment. The emerging paradigm of oligorecurrence and oligometastasis has opened avenues for curative-intent local therapies, including re-irradiation. Modern radiotherapy techniques have enabled high-dose delivery with acceptable toxicity. This study aims to assess clinical outcomes and treatment-related toxicities in patients with oligorecurrent or oligometastatic cervical cancer treated with modern re-irradiation techniques. This retrospective study included 20 cervical cancer patients with oligorecurrence or synchronous/metachronous oligometastases (≤ 5 lesions) who underwent at least one course of re-irradiation. Survival outcomes including locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS), progression-free survival (PFS), and overall survival (OS) were estimated using Kaplan-Meier analysis. Genitourinary (GU), gastrointestinal (GI), and hematologic toxicities were assessed and graded based on CTCAE version 5.0. The median age was 53 years (range: 33-70), with 75% initially diagnosed at FIGO 2018 stage III. The predominant histologies were squamous cell carcinoma (50%) and adenocarcinoma (45%). Recurrences most commonly involved pelvic (30%) and para-aortic (30%) lymph nodes, with 50% occurring in-field. Stereotactic body radiotherapy (SBRT), volumetric modulated arc therapy (VMAT), and MR-guided adaptive brachytherapy (MR-GABT) were the most commonly used re-irradiation modalities, employed in 95% of patients. Median times to first and second recurrence were 11.1 months (IQR: 6.0-17.3) and 13.7 months (IQR: 5.6-21.7), respectively. At a median follow-up of 33.6 months, PFS, LRRFS, DMFS, and OS rates after the first recurrence were were 31.8%, 33.6%, 60.5%, and 84.2% respectively. Grade ≥ 2 genitourinary (GU), gastrointestinal (GI), and hematologic toxicities were observed in 40%, 25%, and 55% of patients, respectively. Grade 3 hematologic toxiciy was 25% and mostly occurred during chemotherapy administration. No grade ≥ 3 GU or GI toxicities were reported. The mean accumulated D0.03 cc after re-irradiation to bladder, rectum, sigmoid and bowel for in-fied/out-of-field were 83.8 ± 6.7/78.5 ± 7.5), 71.2 ± 3.9/69.5 ± 5.2, 68.0 ± 5.5/61.0 ± 5.3, and 62.9 ± 4.6/62.4 ± 7.1 GyEQD2 Re-irradiation with contemporary radiotherapy techniques appears to be a feasible and effective salvage option for selected patients with limited recurrent or metastatic cervical cancer, yielding favorable survival and acceptable toxicity profiles.

Pelvic target volume inter-fractional motion during radiotherapy for cervical cancer with daily iterative cone beam computed tomography

Abstract Background Tumor regression and organ movements indicate that a large margin is used to ensure target volume coverage during radiotherapy. This study aimed to quantify inter-fractional movements of the uterus and cervix in patients with cervical cancer undergoing radiotherapy and to evaluate the clinical target volume (CTV) coverage. Methods This study analyzed 303 iterative cone beam computed tomography (iCBCT) scans from 15 cervical cancer patients undergoing external beam radiotherapy. CTVs of the uterus (CTV-U) and cervix (CTV-C) contours were delineated based on each iCBCT image. CTV-U encompassed the uterus, while CTV-C included the cervix, vagina, and adjacent parametrial regions. Compared with the planning CTV, the movement of CTV-U and CTV-C in the anterior-posterior, superior-inferior, and lateral directions between iCBCT scans was measured. Uniform expansions were applied to the planning CTV to assess target coverage. Results The motion (mean ± standard deviation) in the CTV-U position was 8.3 ± 4.1 mm in the left, 9.8 ± 4.4 mm in the right, 12.6 ± 4.0 mm in the anterior, 8.8 ± 5.1 mm in the posterior, 5.7 ± 5.4 mm in the superior, and 3.0 ± 3.2 mm in the inferior direction. The mean CTV-C displacement was 7.3 ± 3.2 mm in the left, 8.6 ± 3.8 mm in the right, 9.0 ± 6.1 mm in the anterior, 8.4 ± 3.6 mm in the posterior, 5.0 ± 5.0 mm in the superior, and 3.0 ± 2.5 mm in the inferior direction. Compared with the other tumor (T) stages, CTV-U and CTV-C motion in stage T1 was larger. A uniform CTV planning treatment volume margin of 15 mm failed to encompass the CTV-U and CTV-C in 11.1% and 2.2% of all fractions, respectively. The mean volume change of CTV-U and CTV-C were 150% and 51%, respectively, compared with the planning CTV. Conclusions Movements of the uterine corpus are larger than those of the cervix. The likelihood of missing the CTV is significantly increased due to inter-fractional motion when utilizing traditional planning margins. Early T stage may require larger margins. Personal radiotherapy margining is needed to improve treatment accuracy.

Study on the ability of 3D gamma analysis and bio-mathematical model in detecting dose changes caused by dose-calculation-grid-size (DCGS)

Abstract Objective To explore the efficacy and sensitivity of 3D gamma analysis and bio-mathematical model for cervical cancer in detecting dose changes caused by dose-calculation-grid-size (DCGS). Methods 17 patients’ plans for cervical cancer were enrolled (Pinnacle TPS, VMAT), and the DCGS was changed from 2.0 mm to 5.0 mm to calculate the planned dose respectively. The dose distribution calculated by DCGS = 2.0 mm as the “reference” data set (RDS), the dose distribution calculated by the rest DCGS as the“measurement”data set (MDS), the 3D gamma passing rates and the (N) TCPs of the all structures under different DCGS were obtained, and then analyze the ability of 3D gamma analysis and (N) TCP model in detecting dose changes and what factors affect this ability. Results The effect of DCGS on planned dose was obvious. When the gamma standard was 1.0 mm, 1.0 and 10.0%, the difference of the results of the DCGS on dose-effect could be detected by 3D gamma analysis (all p value &lt; 0.05). With the decline of the standard, 3D gamma analysis’ ability to detect this difference shows weaker. When the standard was 1.0 mm, 3.0 and 10.0%, the p value of &gt; 0.05 accounted for the majority. With DCGS = 2.0 mm being RDS, ∆gamma-passing-rate presented the same trend with ∆(N) TCPs of all structures except for the femurs only when the 1.0 mm, 1.0 and 10.0% standards were adopted for the 3D gamma analysis. Conclusions The 3D gamma analysis and bio-mathematical model can be used to analyze the effect of DCGS on the planned dose. For comparison, the former’s detection ability has a lot to do with the designed standard, and the latter’s capability is related to the parameters and calculated accuracy instrinsically.

Comparison of CTVHR and organs at risk contours between TRUS and MR images in IB cervical cancers: a proof of concept study

Abstract Purpose To compare CTVHR and OAR dimensions and inter-rater agreement between magnetic resonance (MR) and trans-rectal ultrasound (TRUS) images in IB cervical cancer patients. Methods IB cervical cancer patients treated with (chemo)radiotherapy plus MR-guided brachytherapy (BT) were prospectively enrolled in this study. Radiation oncologists contoured CTVHR and OARs in pre-BT MR images (MRI) and intra-operative TRUS images. These contours were subsequently compared in regard to volume and dimension. Contour inter-rater agreement analysis was also investigated using kappa index (KI). Stata 15.0 was used for statistical analysis and a p-value &lt; 0.05 was considered statistically significant. Results TRUS CTVHR volumes were statistically smaller than the respective MRI contoured volumes. TRUS CTVHR thickness was found to be consistently smaller than MRI contours in all patients. No statistical difference was seen in width and height between the two different imaging modalities. MRI contours had a median KI of 0.66 (range: 0.56–0.77) while TRUS-based contours had a median KI of 0.64 (range: 0.47–0.77). Bladder and rectum had very satisfactory KI in both imaging modalities. Vaginal contours had moderate agreement in MR (0.52) and in TRUS images (0.58). Conclusion TRUS images allow good visualization of CTVHR and OARs in IB cervical cancer patients. Inter-rater contour variability was comparable between TRUS and MR images. TRUS is a promising modality on its own for image-guided BT.

DCE-MRI of locally-advanced carcinoma of the uterine cervix: Tofts analysis versus non-model-based analyses

Abstract Background Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) may provide biomarkers of the outcome of locally-advanced cervical carcinoma (LACC). There is, however, no agreement on how DCE-MR recordings should be analyzed. Previously, we have analyzed DCE-MRI data of LACC using non-model-based strategies. In the current study, we analyzed DCE-MRI data of LACC using the Tofts pharmacokinetic model, and the biomarkers derived from this analysis were compared with those derived from the non-model-based analyses. Methods Eighty LACC patients given cisplatin-based chemoradiotherapy with curative intent were included in the study. Treatment outcome was recorded as disease-free survival (DFS) and overall survival (OS). DCE-MRI series were analyzed voxelwise to produce Ktrans and ve frequency distributions, and ROC analysis was used to identify the parameters of the frequency distributions having the greatest potential as biomarkers. The prognostic power of these parameters was compared with that of the non-model-based parameters LETV (low-enhancing tumor volume) and TVIS (tumor volume with increasing signal). Results Poor DFS and OS were associated with low values of Ktrans, whereas there was no association between treatment outcome and ve. The Ktrans parameters having the greatest prognostic value were p35-Ktrans (the Ktrans value at the 35 percentile of a frequency distribution) and RV-Ktrans (the tumor subvolume with Ktrans values below 0.13 min− 1). Multivariate analysis including clinical parameters and p35-Ktrans or RV-Ktrans revealed that RV-Ktrans was the only independent prognostic factor of DFS and OS. There were significant correlations between RV-Ktrans and LETV and between RV-Ktrans and TVIS, and the prognostic power of RV-Ktrans was similar to that of LETV and TVIS. Conclusions Biomarkers of the outcome of LACC can be provided by analyzing DCE-MRI series using the Tofts pharmacokinetic model. However, these biomarkers do not appear to have greater prognostic value than biomarkers determined by non-model-based analyses.

Evaluation of plan quality and robustness of IMPT and helical IMRT for cervical cancer

Abstract Background Both plan quality and robustness were investigated through comparing some dosimetric metrics between intensity modulated proton therapy (IMPT) and helical tomotherapy based intensity modulated radiotherapy (IMRT) for cervical cancer. Methods Both a spot-scanning robust (SRO) IMPT plan and a helical tomotherapy robust (TRO) IMRT plan were generated for each of 18 patients. In order to evaluate the quality of nominal plans without dose perturbations, planning scores (PS) on clinical target volume (CTV) and five organs at risk (OARs) based on clinical experience, and normal tissue complication probabilities (NTCP) of rectum and sigmoid were calculated based on Lyman-Kutcher-Burman (LKB) model. Dose volume histogram bands width (DVHBW) were calculated in 28 perturbed scenarios to evaluate plan robustness. Results Compared with TRO, the average scores of SRO nominal plans were higher in target metrics [V46.8Gy, V50Gy, Conformity and Homogeneity](16.5 vs. 15.1), and in OARs metrics (60.9 vs. 53.3), including bladder [V35,V45, Dmean,D2cc], rectum [V40,V45,D2cc,Dmax], bowel [V35,V40,V45, Dmax], sigmoid [V40,Dmax] and femoral heads [V30,Dmax]. Meanwhile, NTCP calculation showed that the toxicities of rectum and sigmoid in SRO were lower than those in TRO (rectum: 2.8% vs. 4.8%, p &lt; 0.05; sigmoid: 5.2% vs. 5.7%, p &lt; 0.05). DVHBW in target coverage for the SRO plan was smaller than that for the TRO plan (0.6% vs. 2.1%), which means that the SRO plan generated a more robust plan in target. Conclusion Better CTV coverage and OAR Sparing were obtained in SRO nominal plan. Based on NTCP calculation, SRO was expected to allow a small reduction in rectal toxicity. Furthermore, SRO generated a more robust plan in CTV target coverage.

A retrospective study on the analysis of influencing factors of neutropenia in endometrial cancer with adjuvant chemoradiotherapy

Abstract Objective This retrospective study aimed to investigate the factors influencing the occurrence of neutropenia in patients with endometrial cancer (EC) following adjuvant chemoradiotherapy (CRT). Methods Retrospective analysis of EC patients who underwent adjuvant CRT from January 2012 to June 2023 in the Department of Gynecology and Oncology of the First Affiliated Hospital of Shandong First Medical University. Neutropenia was defined as an Absolute Neutrophil Count (ANC) of peripheral blood neutrophils below 2 × 109/L. Factors affecting neutropenia in EC patients treated with CRT using Generalized Estimating Equation (GEE), and Logistic regression was used to further analyze the effect of adding radiotherapy to different chemotherapy cycles on neutropenia, so that patients receive optimal adjuvant CRT while the risk of neutropenia is appropriately controlled. Results A total of 144 patients met the inclusion criteria. They underwent 330 cycles of adjuvant chemotherapy, of whom 96 (66.7%) developed neutropenia, which occurred 140 times. The results of one-way GEE analysis showed that before CRT, White Blood Cell (WBC) (OR = 0.827; 95%CI, 0.701–0.976), ANC (OR = 0.749; 95%CI, 0.586–0.957), Absolute Monocyte Count (AMC) (OR = 0.047; 95%CI, 0.008–0.283), Blood Urea Nitrogen (BUN) (OR = 0.857; 95%CI, 0.741–0.991), platinum and docetaxel (platinum/docetaxel) dosing regimen (OR = 2.284; 95%CI, 1.130–4.618) were associated with neutropenia with adjuvant CRT for EC (p &lt; 0.05), results of multifactorial GEE analysis showed that before adjuvant CRT ANC (OR = 0.552; 95%CI, 0.973–2.231), AMC (OR = 0.047; 95%CI, 0.004–0.052), platinum/docetaxel (OR = 2.437; 95%CI, 1.087–5.464) were an independent influence on neutropenia in adjuvant CRT for EC (p &lt; 0.05). Multifactorial Logistic regression shows addition of radiotherapy to the first cycle of chemotherapy (OR = 4.413; 95%CI, 1.238–18.891) was an independent influence of neutropenia (p &lt; 0.05). Conclusions Patients with low pre-CRT ANC and AMC, platinum/docetaxel dosing regimens need to be closely monitored during each cycle of CRT. Also, the concurrent addition of radiotherapy should be avoided during the first cycle of chemotherapy.

A prospective single-arm study on the relationship between dose-volume parameters of pelvic functional bone marrow and acute hematological toxicities during intensity-modulated radiotherapy with or without concurrent chemotherapy for uterine cervical/endometrial cancer

Abstract Background FLT-PET/CT can accurately identify and locate functional bone marrow (FBM) with hematopoietic capability, the FBM were divided into two levels as FBM1 (strongest hemopoietic ability region)and FBM2 (moderate hemopoietic ability region) via FLT-PET/CT. The purpose of this study was to explore the relationship between dose-volume parameters of pelvic FBM and hematologic toxicity (HT) during radiotherapy with or without concurrent chemotherapy for uterine cervical/endometrial cancer. Methods From December 2016 to September 2021, ninety-seven uterine cervical/endometrial cancer patients received intensity-modulated radiation therapy were prospectively recruited in this single-arm, prospective, phase II trial. Blood counts were reviewed weekly during radiotherapy. Single- and multifactor regression methods were used to analyze the relationships between dose-volume parameters of FBM1/2 and grade ≥ 2 HT. ROC curves were used to determine the cutoff values for the dose-volume parameters of FBM1/2. Results The incidence of grade ≥ 2 leukopenia, neutropenia, thrombocytopenia and anemia in patients during radiotherapy was 63.9%, 45.4%, 19.6% and 38.8% respectively, and the median occurrence time was the 29th, 42th, 35th and 31th day, respectively. Multivariate regression analysis showed that the Dmax of FBM1 was significantly related to grade ≥ 2 leukopenia (OR = 1.277 95% CI 1.067–1.528, P = 0.008), Dmean of FBM2 was significantly related to grade ≥ 2 thrombocytopenia (OR = 1.262 95% CI 1.066–1.494, P = 0.007), and V10 of FBM1 was significantly related to grade ≥ 2 anemia (OR = 1.198 95% CI 1.003–1.431, P = 0.046). The incidence of grade ≥ 2 leukopenia for patients with FBM1 Dmax &lt; 53 Gy was lower than that for patients with FBM1 Dmax ≥ 53 Gy (53.4% vs. 95.8%, P &lt; 0.001). The incidence of grade ≥ 2 thrombocytopenia in patients with FBM2 Dmean &lt; 33 Gy was lower than that in patients with FBM2 Dmean ≥ 33 Gy (0 vs. 28.4%, P &lt; 0.001). The incidence of grade ≥ 2 anemia for patients with FBM1 V10 &lt; 95% was lower than that in patients with FBM1 V10 ≥ 95% (24.4% vs. 57.1%, P = 0.003). Conclusions Grade ≥ 2 HT usually occurs in the 4th week of radiotherapy for patients with uterine cervical/endometrial cancer. The Dmax and V10 of FBM1 and the Dmean of FBM2 were significantly associated with the occurrence of grade ≥ 2 HT. The recommended optimal dose constraints were FBM1 Dmax &lt; 53 Gy, V10 &lt; 95%, and FBM2 Dmean &lt;33 Gy.

Impact of adjuvant radiotherapy on the survival of women with optimally resected stage III endometrial cancer in the era of modern radiotherapy: a retrospective study

Abstract Background The optimal adjuvant treatment for stage III endometrial cancer in the era of modern radiotherapy remains undefined. We investigated the benefit of adjuvant radiotherapy for women who underwent optimal resection for stage III endometrial cancer in the era of modern radiotherapy. Methods We retrospectively reviewed patients with endometrial cancer who were treated between 2010 and 2018. Adjuvant treatment included radiotherapy by modern radiotherapy techniques (intensity-modulated or volumetric modulated arc radiotherapy), chemotherapy, or both. Recurrence-free survival (RFS) and overall survival (OS) were calculated using the Kaplan-Meier method and analyzed via multivariate Cox proportional hazards models. Results One hundred sixty-one patients were initially included (52, 9, and 100 with stages IIIA, IIIB, and IIIC cancer, respectively); 154 patients (96%) received adjuvant therapy. Such adjuvant treatment was associated with improved RFS (p = 0.014) and OS (p = 0.044) over surgery alone. Adjuvant radiotherapy by modern radiotherapy techniques led to low incidence of acute (25%) and chronic (7%) grade ≥ 2 gastrointestinal toxicity. On univariate analysis, non-endometrioid histology and grade 3 status were associated with higher risks of tumor recurrence and death, whereas adjuvant radiotherapy alone or in combination chemotherapy reduced their risks. On multivariate analysis, non-endometrioid histology was associated with increased recurrence (hazard ratio [HR], 2.95; p = 0.009), whereas adjuvant radiotherapy alone or with chemotherapy was associated with lower recurrence (HR, 0.62; p = 0.042). Patients &gt; 60 years of age (p = 0.038) as well as those with endometrioid histology (p = 0.045), lymphovascular space invasion (p = 0.031), and ≥ 2 positive lymph nodes (p = 0.044) benefited most from adjuvant radiotherapy. Conclusions Modern adjuvant radiotherapy (intensity-modulated or volumetric modulated arc radiotherapy) alone or with chemotherapy should be considered for women with optimally resected stage III endometrial cancer. Trial registration ClinicalTrials.gov, NCT04251676. Registered 24 January 2020. Retrospectively registered.

Longitudinal dynamic MRI radiomic models for early prediction of prognosis in locally advanced cervical cancer treated with concurrent chemoradiotherapy

To investigate the early predictive value of dynamic magnetic resonance imaging (MRI)-based radiomics for progression and prognosis in locally advanced cervical cancer (LACC) patients treated with concurrent chemoradiotherapy (CCRT). A total of 111 LACC patients (training set: 88; test set: 23) were retrospectively enrolled. Dynamic MR images were acquired at baseline (MRI Compared with single-sequence models, multisequence models exhibited superior performance. MRI We built machine learning models from dynamic features in longitudinal images and found that the ΔMRI

Automatic cervical tumors segmentation in PET/MRI by parallel encoder U-net

Automatic segmentation of cervical tumors is important in quantitative analysis and radiotherapy planning. A parallel encoder U-Net (PEU-Net) integrating the multi-modality information of PET/MRI was proposed to segment cervical tumor, which consisted of two parallel encoders with the same structure for PET and MR images. The features of the two modalities were extracted separately and fused at each layer of the decoder. Res2Net module on skip connection aggregated the features of various scales and refined the segmentation performance. PET/MRI images of 165 patients with cervical cancer were included in this study. U-Net, TransUNet, and nnU-Net with single or multi-modality (PET or/and T2WI) input were used for comparison. The Dice similarity coefficient (DSC) with volume data, DSC and the 95th percentile of Hausdorff distance (HD95) with tumor slices were calculated to evaluate the performance. The proposed PEU-Net exhibited the best performance (DSC The networks with multi-modality input outperformed those with single-modality images as input. The results showed that the proposed PEU-Net could use multi-modality information more effectively through the redesigned structure and achieved competitive performance.

Feasibility study of automatic radiotherapy treatment planning for cervical cancer using a large language model

Radiotherapy treatment planning traditionally involves complex and time-consuming processes, often relying on trial-and-error methods. The emergence of artificial intelligence, particularly Large Language Models (LLMs), surpassing human capabilities and existing algorithms in various domains, presents an opportunity to automate and enhance this optimization process. This study seeks to evaluate the capacity of LLMs to generate radiotherapy treatment plans comparable to those crafted by human medical physicists, focusing on target volume conformity and organs-at-risk (OARs) dose sparing. The goal is to automate the optimization process of radiotherapy treatment plans through the utilization of LLMs. Multiple LLMs were employed to adjust optimization parameters for radiotherapy treatment plans, using a dataset comprising 35 cervical cancer patients treated with volumetric modulated arc therapy (VMAT). Customized prompts were applied to 5 patients to tailor the LLMs, which were subsequently tested on 30 patients. Evaluation metrics included target volume conformity, dose homogeneity, monitor units (MU) value, and OARs dose sparing, comparing plans generated by various LLMs to manual plans. With the exception of Gemini-1.5-flash, which faced challenges due to hallucinations, Qwen-2.5-max and Llama-3.2 produced acceptable VMAT plans in 16.3 ± 5.0 and 9.8 ± 2.1 min, respectively, outperforming an experienced human physicist's time cost of about 20 min. The average conformity index (CI) for Qwen-2.5-max plans, Llama-3.2 plans, and manual plans on the test set were 0.929 ± 0.007, 0.928 ± 0.007, and 0.926 ± 0.007, respectively. The average homogeneity index (HI) was 0.058 ± 0.006, 0.059 ± 0.005, and 0.065 ± 0.006, respectively. While there was a significant difference in target volume conformity between LLM plans and manual plans, OARs dose sparing showed no significant variations. In lateral comparisons among different LLMs, no statistically significant differences were observed in the PTV dose, OARs dose sparing, and target volume conformity between Qwen-2.5-max and Llama-3.2 plans. Through an assessment of LLM-generated plans and clinical plans in terms of target volume conformity and OARs dose sparing, this study provides preliminary evidence supporting the viability of LLMs for optimizing radiotherapy treatment plans. The implementation of LLMs demonstrates the potential for enhancing clinical workflows and reducing the workload associated with treatment planning.

Risk stratification of node-positive early-stage cervical cancer treated with radical hysterectomy followed by chemoradiotherapy: a retrospective single-center study

Limited data exist on the effectiveness of concurrent chemoradiotherapy (CRT) using intensity-modulated radiation therapy (IMRT) after radical surgery in patients with node-positive early-stage cervical cancer. This study aimed to identify prognostic factors and categorize patients into risk groups for personalized adjuvant therapy. The study included consecutive patients with pathologically confirmed node-positive cervical cancer who underwent radical hysterectomy and lymphadenectomy followed by CRT from January 2013 to October 2024 at our institute. Patients with parametrial invasion or positive resection margins were excluded. All patients received modern volumetric-modulated arc therapy with platinum-based concurrent chemotherapy. Data on clinicopathologic features, treatment details, and oncologic outcomes were collected. Univariate and multivariate Cox regression analyses were conducted to identify factors associated with disease-free survival (DFS) and overall survival (OS). Patients were further stratified into distinct risk categories for recurrence based on identified prognostic factors. A total of 160 patients were included, with a median age of 44 years. The median number of lymph nodes retrieved was 33, and 11 patients presented with para-aortic lymph node metastasis (LNM). Over a median follow-up period of 39.7 months, 31 patients experienced disease progression, and 12 succumbed to the disease, yielding 3-year DFS and OS rates of 81.3% and 93.7%, respectively. Multivariate analysis identified non-squamous histotype (hazard ratio [HR]: 1.526, 95% confidence interval [CI]: 1.044-2.232, p = 0.029) and LNM ≥ 4 (HR: 1.521, 95% CI: 1.027-2.252, p = 0.036) as independent predictors of poorer DFS. Utilizing these prognostic factors for DFS, a risk stratification system was developed, categorizing patients into low-risk (no risk factors, n = 108) and high-intermediate risk (one or two risk factors, n = 52) groups. The high-intermediate-risk group exhibited significantly inferior DFS and OS compared to the low-risk group (3-year DFS: 67.4% versus 87.3%, HR: 1.697, 95% CI: 1.192-2.417, p = 0.002; 3-year OS: 82.5% versus 98.8%, HR: 3.577, 95% CI: 1.668-7.667, p < 0.001, respectively). Node-positive early-stage cervical cancer exhibits heterogeneous outcomes following radical hysterectomy and postoperative CRT. In patients with non-SCC histotype or ≥ 4 LNM, consolidation chemotherapy does not confer an additional survival benefit, indicating a need for innovative therapeutic strategies.

Prognostic implications of tumor volume reduction during radiotherapy in locally advanced cervical cancer: a risk-stratified analysis

This study aimed to identify key risk factors in locally advanced cervical cancer (LACC) patients receiving radical radiotherapy and to evaluate the prognostic significance of MRI-determined tumor volume regression (TVR) among varying risk groups. We retrospectively analyzed a cohort of 176 cervical cancer patients (stages IIA-IVA) treated with intensity-modulated radiotherapy from January 2012 to December 2020. Three-dimensional MRI scans were utilized to measure TVR and lymph node volume regression (NVR). Kaplan-Meier analysis was employed to assess overall survival (OS), progression-free survival (PFS), local relapse-free survival (LRFS), and distant metastasis-free survival (DMFS). Prognostic factors were further analyzed using Cox proportional hazards models. A tumor TVR of ≥ 94% was significantly associated with improved 5-year overall survival (OS; 82.7% vs. 49.8%, p < 0.001) and progression-free survival (PFS; 82.5% vs. 51.1%, p < 0.001). Patients with TVR ≥ 94% also demonstrated superior LRFS and DMFS compared to those with TVR < 94% (p < 0.001 and p = 0.012, respectively). In the concurrent chemoradiotherapy (CCRT) subgroup, higher TVR correlated with better prognosis, whereas in patients receiving radiotherapy alone, an increased TVR did not significantly impact OS. Notably, the prognostic value of TVR was most evident in patients with CYFRA21-1 levels below 7.7 ng/ml. In the NVR ≥ 94% subgroup, OS, PFS, and LRFS were significantly better than in patients with NVR < 94% (p < 0.01), with a trend towards improved DMFS observed (p = 0.138). TVR serves as a pivotal prognostic marker in LACC patients with CYFRA21-1 levels below 7.7 ng/ml undergoing CCRT. Additionally, within the lymph node metastasis subgroup, patients achieving a NVR of ≥ 94% demonstrated a notably improved prognosis.

3D-printed brachytherapy in patients with cervical cancer: improving efficacy and safety outcomes

This study aims to evaluate the efficacy and safety of 3D printing technology in brachytherapy for cervical cancer, comparing its outcomes with conventional free hand implantation brachytherapy. A total of 50 cervical cancer patients treated at the First Affiliated Hospital of Gannan Medical College from January 2019 to July 2023 were included in this study. Patients were divided into two groups: 25 patients received intensity-modulated radiotherapy (IMRT) combined with 3D-printed brachytherapy, and 25 patients underwent IMRT combined with free hand brachytherapy implantation. Key indicators analyzed included short-term therapeutic effects, survival outcomes, operation times, the number of CT scans, the number of needles inserted, dosimetric parameters, and complications. The use of 3D-printed brachytherapy significantly improved the safety of radiation therapy operations, especially for large tumors (≥ 30 mm), by providing more precise dose distribution and reducing the radiation doses received by critical organs such as the bladder and rectum. Compared to the artificial implant group (88% prevalence), the 3D-printed brachytherapy group showed a significantly lower incidence of radiation enteritis (29.2% prevalence, p < 0.001). There were no significant differences in other complications between the two groups. For instance, the incidence of radiation cystitis was relatively high in the 3D-printed brachytherapy group (79.2% prevalence) compared to the artificial implant group (64% prevalence, p = 0.240). The median follow-up period in this study was 22.5 months [IQR 18-29]. Among the 49 patients included, 43 had cervical squamous carcinoma and 6 had cervical adenocarcinoma. Short-term therapeutic response rates were comparable, with no significant difference in overall survival observed between the two groups. 3D-printed brachytherapy offers a more effective and safer therapeutic option for patients with cervical cancer, particularly for those with large tumors or complex anatomical structures.

Development and validation of an automated Tomotherapy planning method for cervical cancer

Abstract Purpose This study aimed to develop an automated Tomotherapy (TOMO) planning method for cervical cancer treatment, and to validate its feasibility and effectiveness. Materials and methods The study enrolled 30 cervical cancer patients treated with TOMO at our center. Utilizing scripting and Python environment within the RayStation (RaySearch Labs, Sweden) treatment planning system (TPS), we developed automated planning methods for TOMO and volumetric modulated arc therapy (VMAT) techniques. The clinical manual TOMO (M-TOMO) plans for the 30 patients were re-optimized using automated planning scripts for both TOMO and VMAT, creating automated TOMO (A-TOMO) and automated VMAT (A-VMAT) plans. We compared A-TOMO with M-TOMO and A-VMAT plans. The primary evaluated relevant dosimetric parameters and treatment plan efficiency were assessed using the two-sided Wilcoxon signed-rank test for statistical analysis, with a P-value &lt; 0.05 indicating statistical significance. Results A-TOMO plans maintained similar target dose uniformity compared to M-TOMO plans, with improvements in target conformity and faster dose drop-off outside the target, and demonstrated significant statistical differences (P+ &lt; 0.01). A-TOMO plans also significantly outperformed M-TOMO plans in reducing V50Gy, V40Gy and Dmean for the bladder and rectum, as well as Dmean for the bowel bag, femoral heads, and kidneys (all P+ &lt; 0.05). Additionally, A-TOMO plans demonstrated better consistency in plan quality. Furthermore, the quality of A-TOMO plans was comparable to or superior than A-VMAT plans. In terms of efficiency, A-TOMO significantly reduced the time required for treatment planning to approximately 20 min. Conclusion We have successfully developed an A-TOMO planning method for cervical cancer. Compared to M-TOMO plans, A-TOMO plans improved target conformity and reduced radiation dose to OARs. Additionally, the quality of A-TOMO plans was on par with or surpasses that of A-VMAT plans. The A-TOMO planning method significantly improved the efficiency of treatment planning.

Apparent diffusion coefficient values predict response to brachytherapy in bulky cervical cancer

Abstract Background Diffusion-weighted magnetic resonance imaging (DWI) provides a measurement of tumor cellularity. We evaluated the potential of apparent diffusion coefficient (ADC) values obtained from post-external beam radiation therapy (EBRT) DWI and prior to brachytherapy (BT) to predict for complete metabolic response (CMR) in bulky cervical cancer. Methods Clinical and DWI (b value = 500 s/mm 2 ) data were obtained from patients undergoing interstitial BT with high-risk clinical target volumes (HR-CTVs) &gt; 30 cc. Volumes were contoured on co-registered T2 weighted images and 90th percentile ADC values were calculated. Patients were stratified by CMR (defined by PET-CT at three months post-BT). Relation of CMR with 90th percentile ADC values and other clinical factors (International Federation of Gynecology and Obstetrics (FIGO) stage, histology, tumor and HR-CTV size, pre-treatment hemoglobin, and age) was assessed both in univariate and multivariate logistic regression analyses. Youden’s J statistic was used to identify a threshold value. Results Among 45 patients, twenty-eight (62%) achieved a CMR. On univariate analysis for CMR, only 90th percentile ADC value was significant ( p  = 0.029) while other imaging and clinical factors were not. Borderline significant factors were HR-CTV size ( p =  0.054) and number of chemotherapy cycles ( p =  0.078). On multivariate analysis 90th percentile ADC ( p &lt;  0.0001) and HR-CTV size ( p &lt;  0.003) were highly significant. Patients with 90th percentile ADC values above 2.10 × 10 − 3 mm 2 /s were 5.33 (95% CI, 1.35–24.4) times more likely to achieve CMR. Conclusions Clinical DWI may serve to risk-stratify patients undergoing interstitial BT for bulky cervical cancer.

The safety and efficacy of volumetric modulated Arc therapy combined with computer tomography-guided adaptive brachytherapy for locally advanced cervical cancer: a single institution experience

Abstract Background Volumetric modulated arc therapy (VMAT) is a novel form of IMRT, which can deliver more accurate dose distribution and shorten treatment time. Compared to MRI-guided adaptive brachytherapy, which is recommended as gold standard imaging for cervical cancer contours, CT-guided adaptive brachytherapy (CTGAB) is more available, more widespread, and more affordable in many centers. This study aims to retrospectively analyze the efficacy and the safety of VMAT combined with CTGAB for patients with locally advanced cervical cancer. Methods and materials This study retrospectively analyzed 102 patients with locally advanced cervical cancer who underwent VMAT and CTGAB. Clinical outcomes including local control (LC), overall survival (OS) and progression-free survival (PFS), tumor response to treatment evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.1), and toxicities including gastrointestinal toxicity, urinary toxicity and hematologic toxicity evaluated by the Common Terminology Criteria for Adverse Events (CTCAE) (version 5.0) were analyzed. The Kaplan-Meier method was used to calculate LC, OS, and PFS. Results Median follow-up time was 19 months. Complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) occurred in 68 (66.7%), 24 (23.5%), 4 (3.92%), and 6 (5.88%), respectively. The 2-year and 3-year OS were 89.6% and 83%, respectively. The 2-year and 3-year PFS were 84.2% and 74.3%, respectively. The 2-year and 3-year LC were 90.1% and 79.3%, respectively. The average cumulative D2cm3 in the rectum, the bladder, the colon, and the small intestine were 78.07 (SD: 0.46) Gy, 93.20 (SD: 0.63) Gy, 63.55 (SD: 1.03) Gy and 61.07 (SD: 0.75) Gy, respectively. The average cumulative D90% of the high-risk clinical target volume (HR-CTV) was 92.26 (SD: 0.35) Gy. Grade ≥ 3 gastrointestinal and urinary toxicities occurred in 4.9% and 0.98%, respectively. 1.96% of patients were observed grade ≥ 4 gastrointestinal toxicities and none of the patients observed grade ≥ 4 urinary toxicities. Conclusion VMAT combined with CTGAB for locally advanced cervical cancer was an effective and safe treatment method, which showed satisfactory LC, OS, PFS, and acceptable toxicities.

125I seed brachytherapy for non-central pelvic recurrence of cervical cancer after external beam radiotherapy

Abstract Objective To investigate the efficacy of 125I seed brachytherapy for non-central pelvic recurrence of cervical cancer after external beam radiotherapy, and to analyze the clinical influential factors. Methods Between June 2015 and April 2022, 32 patients with 41 lesions were treated with 125I seed brachytherapy. The seeds were implanted under the guidance of CT and/or 3D-printed template images at a median dose of 100 Gy (range, 80–120 Gy), and the local control rate (LCR) and survival rates were calculated. We used multivariate logistic regression to identify prognosis predictors, and receiver operating characteristic (ROC) curve analysis to determine the optimal cut-off values. Results The median follow-up was 48.52 months (range, 4–86 months), and the 6-, 12-, and 24-month LCR was 88.0%, 63.2%, and 42.1%, respectively. The 1- and 2-year survival rates were 36% and 33%, respectively, and the median survival time was 13.26 months. No significant adverse events occurred. Multivariate regression analysis showed that tumor diameter, tumor stage, and LCR were independent factors influencing survival. ROC curve analysis showed that the area under the curve for tumor diameter and D90 were 0.765 and 0.542, respectively, with cut-off values of 5.3 cm and 108.5 Gy. Conclusions The present findings indicate that 125I seed brachytherapy is feasible for treating non-central pelvic recurrence of cervical cancer after external beam radiotherapy. Further, tumor diameter &lt; 5.3 cm and immediate postoperative D90 &gt; 108.5 Gy were associated with better efficacy.

Effects of bone marrow sparing radiotherapy on acute hematologic toxicity for patients with locoregionally advanced cervical cancer: a prospective phase II randomized controlled study

Abstract Objective To evaluate effects of bone marrow sparing (BMS) radiotherapy on decreasing the incidence of acute hematologic toxicity (HT) for locoregionally advanced cervical cancer (LACC) patients treated by pelvic irradiation. Materials and methods LACC patients were recruited prospectively from May 2021 to May 2022 at a single center and were evenly randomized into the BMS group and the control group. All patients received pelvic irradiation with concurrent cisplatin (40 mg/m2 weekly), followed by brachytherapy and BM V40 &lt; 25% in the BMS group was additionally prescribed. Acute HT was assessed weekly. Binary logistic regression model and receiver operating characteristic (ROC) curve were used for predictive value analysis. The trial was registered with Chinese clinical trial registry (ChiCTR2200066485). Results A total of 242 patients were included in the analysis. Baseline demographic, disease and treatment characteristics were balanced between the two groups. In the intention-to-treat population, BMS was associated with a lower incidence of grade ≥ 2 and grade ≥ 3 acute HT, leukopenia and neutropenia s(72.70% v 90.90%, P  &lt; 0.001*; 16.50% vs. 65.30%, P  &lt; 0.001*; 66.10% vs. 85.10%, P  = 0.001*; 13.20% vs. 54.50%, P  &lt; 0.001*; 37.20% vs. 66.10%, P  &lt; 0.001*; 10.70% vs. 43.80%, P  &lt; 0.001*). BMS also resulted in decreased dose delivered to the organs at risk (OARs) including rectum, bladder and left and right femoral head. Univariate and multivariate analyses showed that BM V40 was an independent risk factor for grade ≥ 3 acute HT (odds ratio [OR] = 2.734, 95% confidence interval [CI] = 1.959–3.815, P  &lt; 0.001*). Cutoff value was 25.036% and area under the curve (AUC) was 0.786. The nomogram was constructed, which was rigorously evaluated and internally cross-validated, showing good predictive performance. Conclusions Receiving BMS pelvic irradiation could reduce the incidence of acute HT in LACC patients, and BM V40 &lt; 25% may be a significant factor in reducing the risks of acute HT.

Prospects for daily online adaptive radiotherapy for cervical cancer: Auto-contouring evaluation and dosimetric outcomes

Abstract Background Training senior radiation therapists as “adapters” to manage influencers and target editing is critical in daily online adaptive radiotherapy (oART) for cervical cancer. The purpose of this study was to evaluate the accuracy and dosimetric outcomes of automatic contouring and identify the key areas for modification. Methods A total of 125 oART fractions from five postoperative cervical cancer patients and 140 oART fractions from five uterine cervical cancer patients treated with daily iCBCT-guided oART were enrolled in this prospective study. The same adaptive treatments were replanned using the Ethos automatic contours workflow without manual contouring edits. The clinical target volume (CTV) was subdivided into several separate regions, and the average surface distance dice (ASD), centroid deviation, dice similarity coefficient (DSC), and 95% Hausdorff distance (95% HD) were used to evaluate contouring for the above portions. Dosimetric results from automatic oART plans were compared to supervised oART plans to evaluate target volumes and organs at risk (OARs) dose changes. Results Overall, the paired CTV had high overlap rates, with an average DSC value greater than 0.75. The uterus had the largest consistency differences, with ASD, centroid deviation, and 95% HD being 2.67 ± 1.79 mm, 17.17 ± 12 mm, and 10.45 ± 5.68 mm, respectively. The consistency differences of the lower nodal CTVleft and nodal CTVright were relatively large, with ASD, centroid deviation, and 95% HD being 0.59 ± 0.53 mm, 3.6 ± 2.67 mm, and 5.41 ± 4.08 mm, and 0.59 ± 0.51 mm, 3.6 ± 2.54 mm, and 4.7 ± 1.57 mm, respectively. The automatic online-adapted plan met the clinical requirements of dosimetric coverage for the target volume and improved the OAR dosimetry. Conclusions The accuracy of automatic contouring from the Ethos adaptive platform is considered clinically acceptable for cervical cancer, and the uterus, upper vaginal cuff, and lower nodal CTV are the areas that need to be focused on in training.

Evaluation of PTV margins with daily iterative online adaptive radiotherapy for postoperative treatment of endometrial and cervical cancer: a prospective single-arm phase 2 study

Abstract Background To determine the optimal planning target volume (PTV) margins for adequate coverage by daily iterative cone-beam computed tomography (iCBCT)-guided online adaptive radiotherapy (oART) in postoperative treatment of endometrial and cervical cancer and the benefit of reducing PTV margins. Methods Fifteen postoperative endometrial and cervical cancer patients treated with daily iCBCT-guided oART were enrolled in this prospective phase 2 study. Pre- and posttreatment iCBCT images of 125 fractions from 5 patients were obtained as a training cohort, and clinical target volumes (CTV) were contoured separately. Uniform three-dimensional expansions were applied to the PTVpre to assess the minimum margin required to encompass the CTVpost. The dosimetric advantages of the proposed online adaptive margins were compared with conventional margin plans (7–15 mm) using an oART emulator in another cohort of 125 iCBCT scans. A CTV-to-PTV expansion was verified on a validation cohort of 253 fractions from 10 patients, and further margin reduction and acute toxicity were studied. Results The average time from pretreatment iCBCT to posttreatment iCBCT was 22 min. A uniform PTV margin of 5 mm could encompass nodal CTVpost in 100% of the fractions (175/175) and vaginal CTVpost in 98% of the fractions (172/175). The margin of 5 mm was verified in our validation cohort, and the nodal PTV margin could be further reduced to 4 mm if ≥ 95% CTV coverage was predicted to be achieved. The adapted plan with a 5 mm margin significantly improved pelvic organ-at-risk dosimetry compared with the conventional margin plan. Grade 3 toxicities were observed in only one patient with leukopenia, and no patients experienced acute urinary toxicity. Conclusion In the postoperative treatment of endometrial and cervical cancer, oART could reduce PTV margins to 5 mm, which significantly decrease the dose to critical organs at risk and potentially lead to a lower incidence of acute toxicity.

Dose prediction for cervical cancer VMAT patients with a full-scale 3D-cGAN-based model and the comparison of different input data on the prediction results

Hypoxic tumor cell-derived small extracellular vesicle miR-152-3p promotes cervical cancer radioresistance through KLF15 protein

Abstract Background Radiotherapy is widely used in treating cervical cancer patients, however, radioresistance unavoidably occurs and seriously affects the treatment effect. It is well known that hypoxia plays an important role in promoting radioresistance in tumor microenvironment, yet our understanding of the effect of small extracellular vesicles miRNA on cervical cancer radiosensitivity in hypoxic environment is still limited. Methods Small extracellular vesicles extracted from hypoxic and normoxic cultured cervical cancer cells were evaluated for their effects on radioresistance. miR-152-3p was found to be a potential effector in hypoxia-derived extracellular vesicles by searching the GEO database. Its downstream substrate was confirmed by double luciferase report, which was KLF15. The role of miR-152-3p and KLF15 in regulating cervical cancer radioresistance was detected by cell activity assays. The findings were confirmed in vivo by animal models. The expression of miR-152-3p was quantified by qRT-PCR and its prognostic significance was evaluated. Results Hypoxic environment promoted the secretion of small extracellular vesicles, and reduced the apoptosis and DNA damage caused by radiation, accompanied by increased expression of small extracellular vesicles miR-152-3p from hypoxic cervical cancer cells. Furthermore, small extracellular vesicles miR-152-3p promoted Hela xenograft growth and reduced the radiosensitivity vivo. Mechanism studies revealed that KLF15 protein was the downstream target of miR-152-3p in regulating radioresistance. Conclusion Our findings suggest that small extracellular vesicles miR-152-3p affects the therapeutic effect of radiotherapy and holds potential as a biomarker or therapeutic target for cervical cancer prognosis and improving radiotherapy.

Definitive irradiation as a first treatment strategy for primary and metastatic sites of newly diagnosed IVB cervical cancer that presented with synchronous oligometastases

Abstract Background The present study identified survival and progression-free rates and evaluated prognostic factors for IVB stage cervical cancer in patients that presented with synchronous oligometastases (sync-oligometastases) who received definitive irradiation for primary and metastatic sites. Methods The study retrospectively included 60 patients with newly diagnosed stage IVB cervical cancer. Patients received definitive radiation for both primary and metastatic sites through Volumetric Modulated Arc Therapy (VMAT) or intensity modulated radiation therapy (IMRT) followed by three dimensional-intracavitary/interstitial brachytherapy at our institution between July 2014 to December 2020. All patients were staged based on the International Federation of Gynecology and Obstetrics (FIGO) 2018 guidelines. Overall survival (OS), progression-free survival (PFS), and patient prognostic factors were analyzed. Results The 60 patients who received curative-intent irradiation for primary and metastatic sites showed a 5-year OS rate of 51.4% and a 5-year PFS rate of 25.9%. The median PFS was 52.3 months, and the median OS had not been reached. Lymphatic metastases had a better OS compared with hematogenous metastases (3-year OS rates: 57.2% vs. 20%, p = 0.017). Patients with one metastasis site showed a more favorable prognosis than patients with ≥ 2 metastases sites (3-year OS rates: 60.4% vs. 20.6%, p = 0.003). Patients that presented with tumors larger than 4 cm in diameter before treatment demonstrated a poorer prognosis (5-year OS rates: 41.2% vs. 65.2%, p = 0.029; 5-year PFS rates: 10.4% vs. 53.7%, p = 0.021). Conclusion Definitive irradiation for both primary and oligo-metastatic sites for selected IVB patients is a feasible treatment strategy. Metastatic type, number of metastatic sites, and pre-treatment tumor diameter were significant prognostic factors. Neoadjuvant chemotherapy, the lymph nodal metastatic type (supraclavicular or inguinal), and number of lymphatic metastatic sites failed to reach statistical significance as prognostic factors.

Elective nodal irradiation versus involved-field irradiation for stage II–IV cervical esophageal squamous cell carcinoma patients undergoing definitive concurrent chemoradiotherapy: a retrospective propensity study with 8-year survival outcomes

Abstract Background Definitive concurrent chemoradiotherapy (dCCRT) is suggested as the standard treatment for cervical esophageal squamous cell carcinoma (CESCC). This retrospective propensity study compared the 8-year survival outcomes and acute treatment toxicities of these patients treated with elective nodal irradiation (ENI) versus involved-field irradiation (IFI). Materials and methods Patients with stage II–IV CESCC treated with dCCRT at the Fourth Hospital of Hebei Medical University between January 1, 2007 and December 31, 2020 were enrolled in the study. All the patients were restaged according to the American Joint Commission 8th edition criteria. The propensity score matching (PSM) was used to minimize the effects of treatment selection bias and potential confounding factors including sex, age, ECOG score, clinical T stage, clinical N stage, clinical TNM stage and radiation dose between the ENI group and IFI group. Survival and the prognostic factors were evaluated. Results The 131 eligible patients underwent ENI (60 patients, 45.8%) or IFI (71 patients, 54.2%). The median follow-up time was 91.1 months (range, 23.8–182.0 months) for all the patients. The median OS, 1-, 3-, 5-, and 8-year OS rates were 44.4 months, 87.8%, 55.1%, 38.3%, and 27.2%, respectively. After PSM, there were 49 patients in each group. The median OS, 1-, 3-, 5-, and 8-year OS rates for ENI and IFI group were 32.0 months, 83.7%, 48.5%, 38.5% and 31.1% versus 45.2 months, 89.8%, 52.5%, 37.5%, 26.1%, respectively ( P  = 0.966; HR 0.99, 95% CI 0.61–1.61). Similar locoregional control was obtained in both groups. The tendency of leukocytopenia and neutropenia was higher in ENI than in IFI (59.2% vs. 38.8%; P  = 0.068 and 30.6% vs. 14.3%; P  = 0.089) at the end of dCCRT. Conclusion Cervical esophageal squamous cell carcinoma patients undergoing definitive concurrent chemoradiotherapy has a satisfactory prognosis with organ conservation. The involved-field irradiation might be a better alternative owing to similar overall survival outcomes and local control with less toxicity of myelosuppression.

Boost modalities in cervical cancer: dosimetric comparison between intracavitary BT vs. intracavitary + interstitial BT vs. SBRT.

Abstract Purpose / objective This study compares the dosimetric plans of three distinct boost modalities in cervical cancer (CC): intracavitary (IC) with tandem/ovoids brachytherapy (BT), IC + interstitial (IS) BT, and Stereotactic-Body-Radiotherapy (SBRT). The aim is to determine the dosimetric impact in terms of target coverage and organ at risk (OAR) doses. Materials and methods 24 consecutive IC + IS BT boost treatment plans were retrospectively identified. For each plan included, two additional plans were created: IC-BT and SBRT. Importantly, no planning target volume (PTV) or planning (organ at) risk volume (PRV) margins were generated, therefore all structures were identical for any boost modality. Two different normalizations were performed: (1) Normalization to the target: prescription of 7.1 Gy to the D90% (defined as the minimum dose covering 90%) of the high-risk clinical target volume (HR-CTV); (2) Normalization to the OARs. HR-CTV coverage and OARs sparing were compared. The equivalent doses in 2 Gy fractions (EQD2) of EBRT and BT for CTV-HR and OARs were calculated using the linear-quadratic model with α/β of 10 (EQD210) and 3 (EQD23), respectively Results A total of 72 plans were investigated. In the first normalization, the mean EQD23−D2cc (defined as the minimal dose of the 2 cc) of OAR was significantly higher in the IC-BT plans, and the bladder D2cc hard constraint could not be reached. IC + IS BT leads to a 1 Gy mean absolute decrease of bladder EQD23-D2cc (relative dose: -19%), allowing to reach the hard constraint. SBRT (without PTV) delivers the lowest EQD23-D2cc to the OAR. In the second normalization, IC-BT provides a significantly lower dose to the EQD210-D90% (6.62 Gy) and cannot achieve the coverage goal. SBRT (without PTV) yields the highest dose to the D90% of HR-CTV and a significantly lower EQD210-D50% and D30%. Conclusion The key dosimetric benefit of BT over SBRT without PTV is a significantly higher D50% and D30% in the HR-CTV, which increases the local and conformal dose to the target. IC + IS BT vs. IC-BT provides significantly better target coverage and a lower dose to the OARs, making it the preferred boost modality in CC.

Deep learning for segmentation of the cervical cancer gross tumor volume on magnetic resonance imaging for brachytherapy

Abstract Background Segmentation of the Gross Tumor Volume (GTV) is a crucial step in the brachytherapy (BT) treatment planning workflow. Currently, radiation oncologists segment the GTV manually, which is time-consuming. The time pressure is particularly critical for BT because during the segmentation process the patient waits immobilized in bed with the applicator in place. Automatic segmentation algorithms can potentially reduce both the clinical workload and the patient burden. Although deep learning based automatic segmentation algorithms have been extensively developed for organs at risk, automatic segmentation of the targets is less common. The aim of this study was to automatically segment the cervical cancer GTV on BT MRI images using a state-of-the-art automatic segmentation framework and assess its performance. Methods A cohort of 195 cervical cancer patients treated between August 2012 and December 2021 was retrospectively collected. A total of 524 separate BT fractions were included and the axial T2-weighted (T2w) MRI sequence was used for this project. The 3D nnU-Net was used as the automatic segmentation framework. The automatic segmentations were compared with the manual segmentations used for clinical practice with Sørensen–Dice coefficient (Dice), 95th Hausdorff distance (95th HD) and mean surface distance (MSD). The dosimetric impact was defined as the difference in D98 (ΔD98) and D90 (ΔD90) between the manual segmentations and the automatic segmentations, evaluated using the clinical dose distribution. The performance of the network was also compared separately depending on FIGO stage and on GTV volume. Results The network achieved a median Dice of 0.73 (interquartile range (IQR) = 0.50–0.80), median 95th HD of 6.8 mm (IQR = 4.2–12.5 mm) and median MSD of 1.4 mm (IQR = 0.90–2.8 mm). The median ΔD90 and ΔD98 were 0.18 Gy (IQR = -1.38–1.19 Gy) and 0.20 Gy (IQR =-1.10–0.95 Gy) respectively. No significant differences in geometric or dosimetric performance were observed between tumors with different FIGO stages, however significantly improved Dice and dosimetric performance was found for larger tumors. Conclusions The nnU-Net framework achieved state-of-the-art performance in the segmentation of the cervical cancer GTV on BT MRI images. Reasonable median performance was achieved geometrically and dosimetrically but with high variability among patients.

Utility of adjuvant whole abdominal radiation therapy in ovarian clear cell cancer (OCCC): a pragmatic cohort study of women with classic immuno-phenotypic signature

AbstractBackgroundTo evaluate the initial experience and clinical utility of first-line adjuvant intensity-modulated whole abdominal radiation therapy (WART) in women with ovarian clear cell cancer (OCCC) referred to an academic center.MethodsProgression-free and overall survival was analyzed in a pragmatic observational cohort study of histologically pure OCCC patients over-expressing HNF-1ß treated between 2013 and end-December 2018. An in-house intensity-modulated WART program was developed from a published pre-clinical model. Radiation dose-volume data was curated to American Association of Physics in Medicine (AAPM) Task Group 263 recommendations. A dedicated database prospectively recorded presenting characteristics and outcomes in a standardized fashion.ResultsFive women with FIGO (2018) stage IA to IIIA2 OCCC were treated with first-line WART. Median age was 58 years (range 47–68 years). At diagnosis CA-125 was elevated in 4 cases (median 56 kU/L: range 18.4–370 kU/L) before primary de-bulking surgery. Severe premorbid endometriosis was documented in 3 patients. At a median follow-up of 77 months (range 16–83 mo.), all patients remain alive and progression-free on clinical, biochemical (CA-125), and18Fluoro-deoxyglucose (FDG) PET/CT re-evaluation. Late radiation toxicity was significant (G3) in 1 case who required a limited bowel resection and chronic nutritional support at 9 months post-WART; 2 further patients had asymptomatic (G2) osteoporotic fragility fractures of axial skeleton at 12 months post-radiation treated with anti-resorptive agents (denosumab).ConclusionsThe clinical utility of intensity-modulated WART in OCCC over-expressing HNF-1β was suggested in this small observational cohort study. The hypothesis that HNF-1β is a portent of platinum-resistance and an important predictive biomarker in OCCC needs further confirmation. Curating multi-institutional cohort studies utilizing WART by means of “Big Data” may improve OCCC care standards in the future.

Online MR evaluation of inter- and intra-fraction uterus motions and bladder volume changes during cervical cancer external beam radiotherapy

Abstract Purpose/objective(s) The purpose of the study was to assess the uterus motions and bladder volume changes of fractional movements in cervical sites throughout the external beam radiotherapy (EBRT) treatment. Materials/methods A prospective online MR imaging tracking study was conducted in EBRT 43 patients with at least 4 scans during each treatment (before: ultrasound scan, MRI scan, CBCT scan, after: MRI scan) were included. In order to improve the treatment repeatability, each patient was instructed to empty the bladder and drink 500 ml water 1 h before CT simulation and each treatment. If the ultrasound scan result reached the CT simulation volume of bladder, the treatment began. Bladder was outlined on the T2 weighted axial sequence and CBCT image by the two observers to avoid the influence of contouring. The data of bladder volume and scanning time were accurately recorded. The bladder volumes, filling rates and uterus motion were retrospectively analyzed by MIM software. Results Inter-fraction variation of the bladder volume was significant (p &lt; 0.0001). Intra-fraction mean increase of the bladder volume was modest (30 cc) but significant (p &lt; 0.001). Both inter- and intra-fraction of the uterus motion were significant. The average time between the pre-and post-fraction MRI scans was 27.82 ± 7.12 min (range 10–55 min) for IMRT plans and 24.14 ± 5.86 min (range7-38 min) for VMAT plan. Average bladder filling rate was 3.43 ml/min. The bladder filling rate did not change significantly with the course of treatment, but the bladder was more intolerant. Conclusion This is the most detailed assessment of intra-fraction and inter-fraction motion during EBRT for cervical cancer. Finally, this study will inform appropriate treatment margins for online adaptive radiotherapy. We suggest that at least one image scan is needed before the EBRT. The portable US scanner provides a quick but unreliable measurement of the bladder volume. There is a significant statistical difference between the results of ultrasonic scanning and that of image scanning.

Intra-fractional dosimetric analysis of image-guided intracavitary brachytherapy of cervical cancer

Abstract Background To assess the intra-fractional dosimetric variations of image-guided brachytherapy of cervical cancer. Methods A total of 38 fractions (9 patients) undergoing brachytherapy for cervical cancer underwent a CT scanning for treatment planning (planning CT) and a Cone-beam CT (CBCT) scanning immediately prior to delivery (pre-delivery CBCT). The variations of volumes as well as the dosimetric impact from treatment planning to delivery (intra-application) were evaluated. The dose volume histogram parameters including volume, D90 of high-risk clinical target volume (HRCTV) and D2cc of organs at risk (OARs) were recorded. Results The relative differences (mean ± 1SD) of the volume and D90 HRCTV across the two scans were − 2.0 ± 3.3% and − 1.2 ± 4.5%, respectively. The variations of D2cc for bladder, rectum, sigmoid and small intestine are − 0.6 ± 17.1%, 9.3 ± 14.6%, 7.2% ± 20.5% and 1.5 ± 12.6%, respectively. Most of them are statistically nonsignificant except the D2cc for rectum, which showed a significant increase ( P  = 0.001). Using 5% and 10% uncertainty of physical dose for HRCTV at a 6 Gy × 5 high-dose-rate schedule, the possibility of total equivalent doses in 2 Gy fractions (EQD2) lower than 85 Gy is close to 0% and 3%, respectively. Performing similar simulation at 15% and 20% uncertainty of a 4 Gy physical dose for OARs, the possibility of total EQD2 dose exceeding 75 Gy is about 70%. Less than 1% of the total EQD2 of OARs would exceed 80 Gy. Conclusions Average intra-fractional dosimetric variation of HRCTV was small in an interval of less than 1 h, and the possibility of total EQD2 exceeding 85 Gy is higher than 97%. The intra-fractional dosimetric variations of OARs might result in an overdose for OARs in a single fraction or the whole treatment. It is necessary to detect unfavorable anatomical changes by re-imaging and take interventions to minimize applied doses and reduce the risk of complications.

Evaluation of a highly refined prediction model in knowledge-based volumetric modulated arc therapy planning for cervical cancer

Abstract Background and purpose To explore whether a highly refined dose volume histograms (DVH) prediction model can improve the accuracy and reliability of knowledge-based volumetric modulated arc therapy (VMAT) planning for cervical cancer. Methods and materials The proposed model underwent repeated refining through progressive training until the training samples increased from initial 25 prior plans up to 100 cases. The estimated DVHs derived from the prediction models of different runs of training were compared in 35 new cervical cancer patients to analyze the effect of such an interactive plan and model evolution method. The reliability and efficiency of knowledge-based planning (KBP) using this highly refined model in improving the consistency and quality of the VMAT plans were also evaluated. Results The prediction ability was reinforced with the increased number of refinements in terms of normal tissue sparing. With enhanced prediction accuracy, more than 60% of automatic plan-6 (AP-6) plans (22/35) can be directly approved for clinical treatment without any manual revision. The plan quality scores for clinically approved plans (CPs) and manual plans (MPs) were on average 89.02 ± 4.83 and 86.48 ± 3.92 (p &lt; 0.001). Knowledge-based planning significantly reduced the Dmean and V18 Gy for kidney (L/R), the Dmean, V30 Gy, and V40 Gy for bladder, rectum, and femoral head (L/R). Conclusion The proposed model evolution method provides a practical way for the KBP to enhance its prediction ability with minimal human intervene. This highly refined prediction model can better guide KBP in improving the consistency and quality of the VMAT plans.

A novel knowledge-based prediction model for estimating an initial equivalent uniform dose in semi-auto-planning for cervical cancer

Abstract Background We developed a novel concept, equivalent uniform length (EUL), to describe the relationship between the generalized equivalent uniform dose (EUD) and the geometric anatomy around a tumor target. By correlating EUL with EUD, we established two EUD–EUL knowledge-based (EEKB) prediction models for the bladder and rectum that predict initial EUD values for generating quality treatment plans. Methods EUL metrics for the rectum and bladder were extracted and collected from the intensity-modulated radiotherapy therapy (IMRT) plans of 60 patients with cervical cancer. The two EEKB prediction models were built using linear regression to establish the relationships between EULr and EUDr (EUL and EUD of rectum) and EULb, and EUDb (EUL and EUD of bladder), respectively. The EE plans were optimized by incorporating the predicted initial EUD parameters for the rectum and bladder with the conventional pinnacle auto-planning (PAP) initial dose parameters for other organs. The efficiency of the predicted initial EUD values were then evaluated by comparing the consistency and quality of the EE plans, PAP plans (based on default PAP initial parameters), and manual plans (designed manually by different dosimetrists) for a sample of 20 patients. Results Linear regression analyses showed a significant correlation between EUL and EUD (R2 = 0.79 and 0.69 for EUDb and EUDr, respectively). In a sample of 20 patients, the average bladder V40 and V50 derived from the EE plans were significantly lower (V40: 30.00 ± 5.76, V50: 14.36 ± 4.00) than the V40 and V50 values derived from manual plans (V40: 36.03 ± 8.02, V50: 19.02 ± 5.42). Compared with the PAP plans, the EE plans produced significantly lower average V30 and Dmean values for the bladder (V30: 50.55 ± 6.33, Dmean: 31.48 ± 1.97 Gy). Conclusions Our EEKB prediction models predicted reasonable initial EUD values for the rectum and bladder based on patient-specific geometric EUL values, thereby improving optimization and planning efficiency.

Dosimetric evaluation of bone marrow sparing in proton radiotherapy for cervical cancer guided by MR functional imaging

Abstract Background To segment the pelvic active bone marrow (PABM) using magnetic resonance (MR) functional imaging and investigate the feasibility and dosimetric characteristics of cervical cancer proton radiotherapy for active bone marrow (ABM) sparing. Methods We collected CT and MR simulation images of 33 patients with cervical cancer retrospectively. The PBM was contoured on the MRI FatFrac images; the PBM was divided into high-active bone marrow (ABM-high) and low-active bone marrow based on the fat content of the PBM. Four radiotherapy plans were created for each patient, which included intensity-modulated photon therapy (IMRT), bone marrow sparing IMRT (IMRT-BMS), intensity-modulated proton therapy (IMPT), and bone marrow sparing IMPT (IMPT-BMS). The dosimetric differences among the four plans were compared. Results The ABM-high volume in the enrolled patients accounted for 45.2% of the total ABM volume. The target coverage was similar among the four radiotherapy plans. IMRT-BMS, IMPT, and IMPT-BMS reduced the Dmean of ABM-high by 16.6%, 14.2%, and 44.5%, respectively, compared to the Dmean of IMRT (p &lt; 0.05). IMPT-BMS had the best protective effect on the bone marrow. Compared to IMRT, the volume of ABM-high receiving an irradiation dose of 5–40 Gy decreased by 10.2%, 36.8%, 58.8%, 67.4%, 64.9%, and 44.5%, respectively (p &lt; 0.001). Conclusions The MR functional imaging technique helped in the grading and segmentation of PABM. MR functional image-guided proton radiotherapy for cervical cancer can achieve optimal BMS.

Radiobiological and dosimetric comparison of 60Co versus 192Ir high-dose-rate intracavitary-interstitial brachytherapy for cervical cancer

Abstract Background High-dose-rate (HDR) intracavitary-interstitial brachytherapy (IC-ISBT) is an effective treatment for bulky, middle, and advanced cervical cancer. In this study, we compared the differences between 60Co and 192Ir HDR IC-ISBT plans in terms of radiobiological and dosimetric parameters, providing a reference for clinical workers in brachytherapy. Methods A total of 30 patients with cervical cancer receiving HDR IC-ISBT were included in this study, and IC-ISBT plans for each individual were designed with both 60Co and 192Ir at a prescribed dose of CTV D90 = 6 Gy while keeping the dose to OARs as low as possible. Physical dose and dose–volume parameters of CTV and OARs were extracted from TPS. The EQD2, EUBED, EUD, TCP, and NTCP were calculated using corresponding formulas. The differences between the 60Co and 192Ir IC-ISBT plans were compared using the paired t-test. Results In each patient's 60Co and 192Ir IC-ISBT plan, the average physical dose and EQD2 of 60Co were lower than those of 192Ir, and there were statistically significant differences in D2cc and D1cc for the OARs (p &lt; 0.05); there were statistically significant differences in D0.1 cc for the bladder (p &lt; 0.05) and no significant differences in D0.1 cc for the rectum or intestines (p &gt; 0.05). The EUBED ratio (60Co/192Ir) at the CTV was mostly close to 1 when neither 60Co or 192Ir passed their half-lives or when both passed two half-lives, and the difference between them was not significant; at the OARs, the mean value of 60Co was lower than that of 192Ir. There was no statistical difference between 60Co and 192Ir in the EUD (93.93 versus 93.92 Gy, p &gt; 0.05) and TCP (97.07% versus 97.08%, p &gt; 0.05) of the tumors. The mean NTCP value of 60Co was lower than that of 192Ir. Conclusions Considering the CTV and OARs, the dosimetric parameters of 60Co and 192Ir are comparable. Compared with 192Ir, the use of 60Co for HDR IC-ISBT can ensure a similar tumor control probability while providing better protection to the OARs. In addition, 60Co has obvious economic advantages and can be promoted as a good alternative to 192Ir.

Deep learning in CT image segmentation of cervical cancer: a systematic review and meta-analysis

Abstract Background This paper attempts to conduct a systematic review and meta-analysis of deep learning (DLs) models for cervical cancer CT image segmentation. Methods Relevant studies were systematically searched in PubMed, Embase, The Cochrane Library, and Web of science. The literature on DLs for cervical cancer CT image segmentation were included, a meta-analysis was performed on the dice similarity coefficient (DSC) of the segmentation results of the included DLs models. We also did subgroup analyses according to the size of the sample, type of segmentation (i.e., two dimensions and three dimensions), and three organs at risk (i.e., bladder, rectum, and femur). This study was registered in PROSPERO prior to initiation (CRD42022307071). Results A total of 1893 articles were retrieved and 14 articles were included in the meta-analysis. The pooled effect of DSC score of clinical target volume (CTV), bladder, rectum, femoral head were 0.86(95%CI 0.84 to 0.87), 0.91(95%CI 0.89 to 0.93), 0.83(95%CI 0.79 to 0.88), and 0.92(95%CI 0.91to 0.94), respectively. For the performance of segmented CTV by two dimensions (2D) and three dimensions (3D) model, the DSC score value for 2D model was 0.87 (95%CI 0.85 to 0.90), while the DSC score for 3D model was 0.85 (95%CI 0.82 to 0.87). As for the effect of the capacity of sample on segmentation performance, no matter whether the sample size is divided into two groups: greater than 100 and less than 100, or greater than 150 and less than 150, the results show no difference (P &gt; 0.05). Four papers reported the time for segmentation from 15 s to 2 min. Conclusion DLs have good accuracy in automatic segmentation of CT images of cervical cancer with a less time consuming and have good prospects for future radiotherapy applications, but still need public high-quality databases and large-scale research verification.

A dual deep neural network for auto-delineation in cervical cancer radiotherapy with clinical validation

Abstract Background Artificial intelligence (AI) algorithms are capable of automatically detecting contouring boundaries in medical images. However, the algorithms impact on clinical practice of cervical cancer are unclear. We aimed to develop an AI-assisted system for automatic contouring of the clinical target volume (CTV) and organs-at-risk (OARs) in cervical cancer radiotherapy and conduct clinical-based observations. Methods We first retrospectively collected data of 203 patients with cervical cancer from West China Hospital. The proposed method named as SegNet was developed and trained with different data groups. Quantitative metrics and clinical-based grading were used to evaluate differences between several groups of automatic contours. Then, 20 additional cases were conducted to compare the workload and quality of AI-assisted contours with manual delineation from scratch. Results For automatic CTVs, the dice similarity coefficient (DSC) values of the SegNet trained with incorporating multi-group data achieved 0.85 ± 0.02, which was statistically better than the DSC values of SegNet independently trained with the SegNet(A) (0.82 ± 0.04), SegNet(B) (0.82 ± 0.03) or SegNet(C) (0.81 ± 0.04). Moreover, the DSC values of the SegNet and UNet, respectively, 0.85 and 0.82 for the CTV (P &lt; 0.001), 0.93 and 0.92 for the bladder (P = 0.44), 0.84 and 0.81 for the rectum (P = 0.02), 0.89 and 0.84 for the bowel bag (P &lt; 0.001), 0.93 and 0.92 for the right femoral head (P = 0.17), and 0.92 and 0.91 for the left femoral head (P = 0.25). The clinical-based grading also showed that SegNet trained with multi-group data obtained better performance of 352/360 relative to it trained with the SegNet(A) (334/360), SegNet(B) (333/360) or SegNet(C) (320/360). The manual revision time for automatic CTVs (OARs not yet include) was 9.54 ± 2.42 min relative to fully manual delineation with 30.95 ± 15.24 min. Conclusion The proposed SegNet can improve the performance at automatic delineation for cervical cancer radiotherapy by incorporating multi-group data. It is clinically applicable that the AI-assisted system can shorten manual delineation time at no expense of quality.

Whether individualized dose escalation should be recommended for lymph nodes with different sizes in the definitive radiotherapy of cervical cancer?

Abstract Background and purpose Dose escalation for positive node maybe improve the regional control of patients with node-positive cervical cancer, but the optimal dose for nodes of different sizes remains controversial. The purpose of this study was to explore the individualized dose escalation for lymph nodes (LNs) with different sizes in the definitive radiotherapy of cervical cancer. Methods A total of 1002 cervical cancer patients with the International Federation of Gynecology and Obstetrics (FIGO 2009) stage IB1–IVA, who were treated by definitively radiotherapy between September 2013 and December 2016 were enrolled. All LNs identified by computed tomography/magnetic resonance imaging (CT/MRI) were assigned into three groups according to the short diameters of &lt; 1 cm, 1–2 cm or ≥ 2 cm at pretreatment. Results In total, 580 patients with 1310 LNs were detected. The nodal control rate in groups of LNs &lt; 1 cm, 1–2 cm and ≥ 2 cm was 99.4%, 96%, and 75.9%, respectively (P = 0.000). Among LNs &lt; 1 cm, the control, overall survival (OS) and progression-free survival (PFS) rates did not significantly differ among three dose-based groups (≤ 50.4 Gy, 50.4–60 Gy, &gt; 60 Gy) (control rate, 99.4% vs. 99.3% vs. 100%, P = 0.647) (5-year OS, 76.2% vs. 79% vs. 81.6%, P = 0.682) (5-year PFS, 74.1% vs. 73.9% vs. 78.9% P = 0.713). Among LNs of 1–2 cm, the control and PFS rates were significantly higher in the group of dose ≥ 55 Gy than the group of dose &lt; 55 Gy (control rate, 98% vs. 93.6%, P = 0.028) (5-year PFS, 69.6% vs. 56.7%, P = 0.025). However, this did not cause a significant difference for 5-year OS rate (72.6% vs. 68.3%, P = 0.5). Among LNs ≥ 2 cm, the control, OS, and PFS rates were higher in the group of dose ≥ 55 Gy than the group of dose &lt; 55 Gy, while no significant difference was found (control rate, 82.1% vs. 63.2%, P = 0.107) (5-year OS, 60.6% vs. 37.5%, P = 0.141) (5-year PFS, 51.5% vs.37.5%, P = 0.232). Conclusions Radiation dose escalation is not necessary for LNs &lt; 1 cm, and dose escalation of 55 Gy is enough for LNs of 1–2 cm.

Dosimetric parameters and absolute monocyte count can predict the prognosis of acute hematologic toxicity in cervical cancer patients undergoing concurrent chemotherapy and volumetric-modulated arc therapy

Abstract Purpose To explore clinical and dosimetric predictors of acute hematologic toxicity (HT) in cervical cancer patients treated with concurrent chemotherapy and volumetric-modulated arc therapy (VMAT). Methods and materials We retrospectively reviewed the clinical data of 184 cervical cancer patients who had concurrent chemotherapy and VMAT. Hematological parameters were collected during the treatment period. The total pelvic bone (TPB) was delineated retrospectively for dose-volume calculations. To compare the differences between two groups, the normality test findings were used to run a paired-samples t-test or Wilcoxon signed-rank test. Pearson's correlation analysis or Spearman's correlation was used to testing the correlation between the two variables. Binary logistic regression analysis was used to analyze associations between HT and possible risk factors. The receiver operating characteristic curve(ROC) was used to evaluate the best cut-off point for dosimetric planning constraints. Results The nadir of absolute monocyte count (AMC) was found to be positively correlated with the nadir of absolute white blood cells (WBC) count (r = 0.5378, 95% CI 0.4227–0.6357, P &lt; 0.0001) and the nadir of absolute neutrophil count(ANC) (r = 0.5000, 95% CI 0.3794–0.6039, P &lt; 0.0001). The AMC decreased and increased before the ANC and WBC. In multivariate logistic regression analysis, the chemotherapy regimens and the TPB_V20 were independent risk factors for developing grade ≥ 3 HT. The optimal TPB_V20 cut-off value identified by ROC curves and the Youden test was 71% (AUC = 0.788; 95% CI 0.722–0.845; P value &lt; 0.001). Conclusions The changing trend of AMC can be used as an effective predictor for the timing and severity of the ANC/WBC nadirs and prophylactic G-CSF administration. Maintain TPB_V20 &lt; 71% and selecting single-agent cisplatin or carboplatin could significantly reduce grade ≥ 3 HT in cervical cancer patients undergoing concurrent chemoradiotherapy.

Correlation between changes of pelvic bone marrow fat content and hematological toxicity in concurrent chemoradiotherapy for cervical cancer

Abstract Objectives To quantify the pelvic bone marrow (PBM) fat content changes receiving different radiation doses of concurrent chemoradiotherapy for cervical cancer and to determine association with peripheral blood cell counts. Methods The data of 54 patients were prospectively collected. Patients underwent MRI iterative decomposition of water and fat with echo asymmetrical and least squares estimation (IDEAL IQ) scanning at RT-Pre, RT mid-point, RT end, and six months. The changes in proton density fat fraction (PDFF%) at 5–10 Gy, 10–15 Gy, 15–20 Gy, 20–30 Gy, 30–40 Gy, 40–50 Gy, and &gt; 50 Gy doses were analyzed. Spearman’s rank correlations were performed between peripheral blood cell counts versus the differences in PDFF% at different dose gradients before and after treatment. Results The lymphocytes (ALC) nadirs appeared at the midpoint of radiotherapy, which was only 27.6% of RT-Pre; the white blood cells (WBC), neutrophils (ANC), and platelets (PLT) nadirs appeared at the end of radiotherapy which was 52.4%, 65.1%, and 69.3% of RT-Pre, respectively. At RT mid-point and RT-end, PDFF% increased by 46.8% and 58.5%, respectively. Six months after radiotherapy, PDFF% decreased by 4.71% under 5–30 Gy compared to RT-end, while it still increased by 55.95% compared to RT-Pre. There was a significant positive correlation between PDFF% and ANC nadirs at 5–10 Gy (r = 0.62, P  = 0.006), and correlation was observed between PDFF% and ALC nadirs at 5–10 Gy (r = 0.554, P  = 0.017). Conclusion MRI IDEAL IQ imaging is a non-invasive approach to evaluate and track the changes of PBM fat content with concurrent chemoradiotherapy for cervical cancer. The limitation of low-dose bone marrow irradiation volume in cervical cancer concurrent chemoradiotherapy should be paid more attention to.

Criteria-calibration approaches to deep learning-based cervical cancer radiation treatment auto-planning

Knowledge-Based Planning (KBP) pipelines, which integrate machine learning-based models to predict dose distribution, have gained popularity in clinical radiation therapy. However, for patients with specific requirements, the trained models may struggle to rapidly adjust to guide the automatic planning process. Therefore, the aim of this study was to calibrate the dose prediction model to improve the quality and accuracy of automatic planning for cervical cancer radiation therapy. We retrospectively collected a routine cervical cancer dataset (200 cases) to conduct the KBP pipelines for automatically generating radiation planning, and a small number of ovarian-protection and myelosuppressive datasets (21 cases) to calibrate and evaluate the dose prediction model. A total of three criteria-calibration approaches to solve the data imbalance problem in dose prediction were introduced and compared, including Prediction Tolerance function on uTPS (United Imaging Healthcare Co., Ltd., Shanghai), transfer learning, and mixture density network. The Prediction Tolerance function allowed for rapid optimization adjustments without model modification, which is suitable for patients with strong desires for ovary protection. The transfer learning approach required minimal training time and data to generate acceptable automatic planning results. The Mixture Density Network (MDN) approach, although the most time-consuming to train, achieved robust prediction results and facilitated dataset analysis. The MDN method showed the greatest consistency between predicted dose distribution and actual optimization outcomes, highlighting its potential as a reliable calibration method for dose prediction. This study demonstrated an automatic KBP workflow and compared three criteria-calibration approaches to address the data imbalance problem in dose prediction. These approaches can partially calibrate pre-existing models to accommodate newly added criteria and could be implemented according to specific requirements in different scenarios. Although there are trade-offs in various aspects, they all can generate feasible radiation treatment plans.

A novel external beam radiotherapy method for cervical cancer patients using virtual straight or bending boost areas; an in-silico feasibility study

Abstract Aim To investigate the potential role of a novel spatially fractionated radiation therapy (SFRT) method where heterogeneous dose patterns are created in target areas with virtual rods, straight or curving, of variable position, diameter, separation and alignment personalised to a patient’s anatomy. The images chosen for this study were CT scans acquired for the external beam part of radiotherapy. Methods Ten patients with locally advanced cervical cancer were retrospectively investigated with SFRT. The dose prescription was 30 Gy in 5 fractions to 90% target volume coverage. Peak-and-valley (SFRT_1) and peak-only (SFRT_2) strategies were applied to generate the heterogeneous dose distributions. The planning objectives for the target (CTV) were D90% ≥ 30 Gy, V45Gy ≥ 50–55% and V60Gy ≥ 30%. The planning objectives for the organs at risk (OAR) were: D2cm3 ≤ 23.75 Gy, 17.0 Gy, 19.5 Gy, 17.0 Gy for the bladder, rectum, sigmoid and bowel, respectively. The plan comparison was performed employing the quantitative analysis of the dose-volume histograms. Results The D2cm3 was 22.4 ± 2.0 (22.6 ± 2.1) and 13.9 ± 2.9 (13.2 ± 3.0) for the bladder and the rectum for SFRT_1 (SFRT_2). The results for the sigmoid and the bowel were 2.6 ± 3.1 (2.8 ± 3.0) and 9.1 ± 5.9 (9.7 ± 7.3), respectively. The hotspots in the target volume were V45Gy = 43.1 ± 7.5% (56.6 ± 5.6%) and V60Gy = 15.4 ± 5.6% (26.8 ± 6.6%) for SFRT_1 (SFRT_2). To account for potential uncertainties in the positioning, the dose prescription could be escalated to D90% = 33–35 Gy to the CTV without compromising any constraints to the OARs Conclusion In this dosimetric study, the proposed novel planning technique for boosting the cervix uteri was associated with high-quality plans, respecting constraints for the organs at risk and approaching the level of dose heterogeneity achieved with routine brachytherapy. Based on a sample of 10 patients, the results are promising and might lead to a phase I clinical trial.

Treatment planning comparison of volumetric modulated arc therapy employing a dual-layer stacked multi-leaf collimator and helical tomotherapy for cervix uteri

AbstractPurposeTo ascertain the dosimetric performance of a new delivery system (the Halcyon system, H) equipped with dual-layer stacked multi-leaf collimator (MLC) for risk-adapted targets in cervix uteri cancer patients compared to another ring-based system in clinical operation (Helical Tomotherapy, HT).MethodsTwenty patients were retrospectively included in a treatment planning study (10 with positive lymph nodes and 10 without). The dose prescription (45Gy to the primary tumour volume and a simultaneously integrated boost up to 55Gy for the positive patients) and the clinical planning objectives were defined consistently as recommended by an ongoing multicentric clinical trial. Halcyon plans were optimised for the volumetric modulated arc therapy. The plan comparison was performed employing the quantitative analysis of the dose-volume histograms.ResultsThe coverage of the primary and nodal target volumes was comparable for both techniques and both subsets of patients. The primary planning target volume (PTV) receiving at least 95% of the prescription isodose ranged from 97.2 ± 1.1% (node-negative) to 99.1 ± 1.2% (node-positive) for H and from 96.5 ± 1.9% (node-negative) to 98.3 ± 0.9% (node-positive) for HT. The uncertainty is expressed at one standard deviation from the cohort of patient per each group. For the nodal clinical target volumes, the dose received by 98% of the planning target volume ranged 55.5 ± 0.1 to 56.0 ± 0.8Gy for H and HT, respectively. The only significant and potentially relevant differences were observed for the bowels. In this case, V40Gyresulted 226.3 ± 35.9 and 186.9 ± 115.9 cm3for the node-positive and node-negative patients respectively for Halcyon. The corresponding findings for HT were: 258.9 ± 60.5 and 224.9 ± 102.2 cm3. On the contrary, V15Gyresulted 1279.7 ± 296.5 and 1557.2 ± 359.9 cm3for HT and H respectively for node-positive and 1010.8 ± 320.9 versus 1203.8 ± 332.8 cm3for node-negative.ConclusionThis retrospective treatment planning study, based on the dose constraints derived from the Embrace II study protocol, suggested the essential equivalence between Halcyon based and Helical Tomotherapy based plans for the intensity-modulated rotational treatment of cervix uteri cancer. Different levels of sparing were observed for the bowels with H better protecting in the high-dose region and HT in the mid-low dose regions. The clinical impact of these differences should be further addressed.

Pelvic bone marrow sparing intensity modulated radiotherapy reduces the incidence of the hematologic toxicity of patients with cervical cancer receiving concurrent chemoradiotherapy: a single-center prospective randomized controlled trial

Abstract Purpose To test the efficacy and feasibility of pelvic bone marrow sparing intensity modulated radiotherapy (PBMS-IMRT) in reducing grade 2 or higher hematological toxicity (HT2+) for patients with cervical cancer treated with concurrent chemoradiotherapy. Methods and materials A total of 164 patients with Stage Ib2–IIIb cervical cancer were prospectively enrolled from March 2018 to March 2019 at a single center and were randomly allocated into the PBMS group or the control group. The control group received weekly cisplatin concurrently with IMRT, followed by intracavitary brachytherapy. The PBMS group additionally received PBM dose constraint. The dosimetric parameters of the pelvic bone (PB) and the subsites including hip bone (HIP) and lumbosacral spine (LSS) and the corresponding bone marrow were recorded. The endpoint of the trial was acute hematologic or gastrointestinal toxicity. Receiver operating characteristic curves were used to derive optimal dosimetric planning constraints. Results Eighty-two patients in the PBMS group and 82 in the control group were enrolled for statistical analysis. The incidence of HT2+ in the PBMS group was 50.0%, significantly lower than the 69.5% incidence in the control group (P = 0.02). Patients with PB V40 ≥ 28% were more likely to experience HT2+ (OR = 2.85, P = 0.006), while the incidence of grade 2 or higher gastrointestinal toxicity (GT2+) events did not differ significantly between the two groups (P &gt; 0.05). Dosimetric parameters of LSS showed stronger associations with HT2+ than other subsites. The patients with LSS V10 ≥ 87% and LSS mean ≥ 39 Gy were more likely to experience HT2+ (OR = 3.13, P = 0.001;OR = 3.03, P = 0.002, respectively). Conclusion PBMS-IMRT reduced HT compared with IMRT alone. Efforts to maintain LSS V10 &lt; 87%, LSS mean &lt; 39 Gy and PB V40 &lt; 28% simultaneously may reduce the risk of HT2 +. Trial registration The trial was registered with Chinese clinical trial registry (ChiCTR1800015069).

Novel role of PAF1 in attenuating radiosensitivity in cervical cancer by inhibiting IER5 transcription

Abstract Background Radiosensitivity is limited in cervical cancer (CC) patients due to acquired radiation resistance. In our previous studies, we found that immediate-early response 5 (IER5) is upregulated in CC cells upon radiation exposure and decreases cell survival by promoting apoptosis. The details on the transcriptional regulation of radiation-induced IER5 expression are unknown. Studies in recent years have suggested that Pol II-associated factor 1 (PAF1) is a pivotal transcription factor for certain genes “induced” during tumor progression. In this study, we investigated the role of PAF1 in regulating IER5 expression during CC radiotherapy. Methods PAF1 expression in CC cells was measured by western blotting, immunohistochemistry, and qRT-PCR, and the localization of PAF1 and IER5 was determined by immunofluorescence. The effect of PAF1 and IER5 knockdown by siRNA in Siha and Hela cells was studied by western blotting, qRT-PCR, CCK-8 assay, and flow cytometry. The physical interaction of PAF1 with the IER5 promoter and enhancers was confirmed using chromatin immunoprecipitation and qPCR with or without enhancers knockout by CRISPR/Cas9. Results We confirmed that PAF1 was highly expressed in CC cells and that relatively low expression of IER5 was observed in cells with highly expressed PAF1 in the nucleus. PAF1 knockdown in Siha and Hela cells was associated with increased expression of IER5, reduced cell viability and higher apoptosis rate in response to radiation exposure, while simultaneous PAF1 and IER5 knockdown had little effect on the proportion of apoptotic cells. We also found that PAF1 hindered the transcription of IER5 by promoting Pol II pausing at the promoter-proximal region, which was primarily due to the binding of PAF1 at the enhancers. Conclusions PAF1 reduces CC radiosensitivity by inhibiting IER5 transcription, at least in part by regulating its enhancers. PAF1 might be a potential therapeutic target for overcoming radiation resistance in CC patients.

Magnetic resonance imaging features of tumor and lymph node to predict clinical outcome in node-positive cervical cancer: a retrospective analysis

Abstract Background Current chemoradiation regimens for locally advanced cervical cancer are fairly uniform despite a profound diversity of treatment response and recurrence patterns. The wide range of treatment responses and prognoses to standardized concurrent chemoradiation highlights the need for a reliable tool to predict treatment outcomes. We investigated pretreatment magnetic resonance (MR) imaging features of primary tumor and involved lymph node for predicting clinical outcome in cervical cancer patients. Methods We included 93 node-positive cervical cancer patients treated with definitive chemoradiotherapy at our institution between 2006 and 2017. The median follow-up period was 38 months (range, 5–128). Primary tumor and involved lymph node were manually segmented on axial gadolinium-enhanced T1-weighted images as well as T2-weighted images and saved as 3-dimensional regions of interest (ROI). After the segmentation, imaging features related to histogram, shape, and texture were extracted from each ROI. Using these features, random survival forest (RSF) models were built to predict local control (LC), regional control (RC), distant metastasis-free survival (DMFS), and overall survival (OS) in the training dataset (n = 62). The generated models were then tested in the validation dataset (n = 31). Results For predicting LC, models generated from primary tumor imaging features showed better predictive performance (C-index, 0.72) than those from lymph node features (C-index, 0.62). In contrast, models from lymph nodes showed superior performance for predicting RC, DMFS, and OS compared to models of the primary tumor. According to the 3-year time-dependent receiver operating characteristic analysis of LC, RC, DMFS, and OS prediction, the respective area under the curve values for the predicted risk of the models generated from the training dataset were 0.634, 0.796, 0.733, and 0.749 in the validation dataset. Conclusions Our results suggest that tumor and lymph node imaging features may play complementary roles for predicting clinical outcomes in node-positive cervical cancer.

High dose simultaneous integrated boost for node positive cervical cancer

Abstract Introduction Lymph node metastases presenting with locally advanced cervical cancer are poor prognostic features. Modern radiotherapy approaches enable dose escalation to radiologically abnormal nodes. This study reports the results of a policy of a simultaneous integrated boost (SIB) in terms of treatment outcomes. Materials and methods Patients treated with radical chemoradiation with weekly cisplatin for locally advanced cervical cancer including an SIB to radiologically abnormal lymph nodes were analysed. All patients received a dose of 45 Gy in 25 fractions and a SIB dose of 60 Gy in 25 fractions using intensity modulated radiotherapy/volumetric modulated arc therapy, followed by high dose rate brachytherapy of 28 Gy in 4 fractions. A control cohort with radiologically negative lymph nodes was used to compare impact of the SIB in node positive patients. Treatment outcomes were measured by overall survival (OS), post treatment tumour response and toxicities. The tumour response was based on cross sectional imaging at 3 and 12 months and recorded as local recurrence free survival (LRFS), regional recurrence free survival (RRFS) and distant recurrence free survival (DRFS). Results In between January 2015 and June 2017, a total of 69 patients with a median follow up of 30.9 months (23 SIB patients and 46 control patients) were identified. The complete response rate at 3 months was 100% in the primary tumour and 83% in the nodal volume receiving SIB. The OS, LRFS, RRFS and DRFS at 3 years of the SIB cohort were 69%, 91%, 79% and 77% respectively. High doses can be delivered to regional pelvic lymph nodes using SIB without excessive toxicity. Conclusion Using a SIB, a total dose of 60 Gy in 25 fractions chemoradiation can be delivered to radiologically abnormal pelvic nodes with no increase in toxicity compared to node negative patients. The adverse impact of positive nodal status may be negated by high dose deposition using SIB, but larger prospective studies are required to confirm this observation.

Mapping patterns of para-aortic lymph node recurrence in cervical cancer: a retrospective cohort analysis

Abstract Background To map anatomic patterns of para-aortic lymph node (PALN) recurrence in cervical cancer patients and validate currently available guidelines on PA clinical target volumes (CTV). Methods Cervical cancer patients who developed PALN recurrence were included. The PALNs were classified as left-lateral para-aortic (LPA), aorto-caval (AC), and right para-caval (RPC). Four PA CTVs were contoured for each patient to validate PALN coverage. CTV RTOG was contoured based on the Radiation Therapy Oncology Group guideline. CTV K was contoured as proposed by Keenan et al. CTV M was contoured by expanding symmetrical margins around the aorta and inferior vena cava of 7 mm up to the T12–L1 interspace. CTV new was created by modifying CTV RTOG to obtain better coverage. Results We identified 92 PALNs in 35 cervical cancer patients. 46.8% of the PALNs were at LPA, 38.0% were at AC, and 15.2% were at RPC areas. CTV RTOG , CTV K , and CTV M covered 87.0%, 88.0%, and 62.0% of all PALNs, respectively. PALN recurrence above the left renal vein was associated with PALN involvement at diagnosis ( p  = 0.043). Extending upper border to the superior mesenteric artery allowed the CTV new to cover 96.7% of all PALNs and all nodes in 91.4% of patients. Conclusion CTV RTOG and CTV K encompassed most PALN recurrences. For high-risk patients, such as those having PALN involvement at diagnosis, extending the superior border of CTV from the left renal vein to superior mesenteric artery could be considered.

Stereotactic ablative body radiotherapy boost for cervical cancer when brachytherapy boost is not feasible

Abstract Background The purpose of this study was to analyze the treatment efficacy and safety of stereotactic ablative body radiotherapy (SABR) boost for cervical cancer patients not amenable to brachytherapy. Methods A retrospective review of the medical records from single institution of 25 eligible patients was performed. The patients underwent pelvic radiotherapy (RT) in 25 or 28 fractions with a median dose of 45 Gy (range 44–50.4 Gy). SABR boost was delivered after pelvic RT, with a median dose of 25 Gy (range 20–33 Gy), and a median fraction number of 5 (range 4–6). 21 patients with a follow-up period of more than one year were included in the toxicity analysis, and hematuria and hematochezia that occurred later than 3 months after the RT were graded. Results The median follow-up period after radiotherapy was 2.85 years (range 0.33–6.60). The 3-year local control, locoregional control, disease-free survival, and overall survival rates were 80.9%, 75.8%, 40.9%, and 77.1%, respectively. 5 patients experienced grade 3 toxicity (3 genitourinary, 3 gastrointestinal), and no grade 4–5 toxicity was reported. Univariate analysis showed that cumulative D2cc in equivalent dose in 2 Gy fractions (EQD2) of rectum was marginally predictive for any grade of hematochezia (P = 0.051). Cumulative D2cc EQD2 of bladder was not predictive for hematuria. In the receiver operating characteristic (ROC) curve analysis, the optimal threshold of cumulative rectal D2cc EQD2 was 81.2 Gy for any grade of hematochezia. Conclusion SABR boost for cervical cancer was effective and tolerable. Although it cannot substitute brachytherapy, it can be a treatment option when brachytherapy is not possible.

Topographic distribution of lymph node metastasis in patients with stage IB1 cervical cancer: an analysis of 8314 lymph nodes

Abstract Background Systematic pelvic lymphadenectomy or whole pelvic irradiation is recommended for the patients with stage IB1 cervical cancer. However, the precise pattern of lymphatic tumor spread in cervical cancer is unknown. In the present study we evaluated the distribution of nodal metastases in stage IB1 cervical cancer to explore the possibilities for tailoring cancer treatment. Methods A total of 289 patients with cervical cancer of stage IB1, according to FIGO 2009, were retrospectively analyzed. All patients underwent laparoscopic radical hysterectomy (Querleu and Morrow type C2) and systematic pelvic lymphadenectomy with or without para-aortic lymphadenectomy (level 2 or level 3 according to Querleu and Morrow) from October 2014 to December 2017. Lymph nodes removed from 7 well-defined anatomical locations as well as other tissues were examined histopathologically, and typed, graded, and staged according to the WHO/IARC classification. Results Totally 8314 lymph nodes were analyzed with the average number of 31.88 ± 10.34 (Mean ± SD) lymph nodes per patient. Nodal metastases were present in 44 patients (15.22%). The incidence of lymphatic spread to different anatomic sites ranged from 0% (presacral) to 30.92% (obturator nodes). Tumor size above 2 cm, histologically proven lymphovascular space involvement (LVSI) and parametrial invasion were shown to be significantly correlated with the higher risk of lymphatic metastasis, while obesity (BMI ≥ 25) was independently negatively associated with lymphatic metastases. Conclusions The incidence of lymph node metastasis in patients with stage IB1 cervical cancer is low but prognostically relevant. Individual treatment could be considered for the selected low-risk patients who have smaller tumors and obesity and lack of the parametrial invasion or LVSI.

Adjuvant hysterectomy following primary chemoradiation for stage IB2 and IIA2 cervical cancer: a retrospective comparison of complications for open versus minimally invasive surgery

Abstract Background Adjuvant hysterectomy following chemoradiation for bulky, early stage cervical cancer has been shown to decrease local relapse rate. The objective of this study is to compare complications and recurrences between minimally invasive and open adjuvant hysterectomy for early stage cervical cancer. Methods Patients were identified who had undergone adjuvant hysterectomy following chemoradiation for 2009 FIGO stage IB2 and IIA2 cervical cancer from August 2006 to June 2018. Demographic information, treatment course, complications, recurrence data were retrospectively extracted from the medical record. Frequency of complications was compared with Fisher exact test or chi-square test as appropriate and inverse probability of treatment propensity score weighting was used to calculate the disease-free survival. Results Fifty-four patients met inclusion criteria with a median follow up time of 60.4 months (interquartile range 28.0–98.1 months). There were 24 (44%) open versus 30 (56%) minimally invasive hysterectomies performed. The overall grade 2 or worse complication rate was 43%. There were 8 (27%) patients with complications in the minimally invasive group compared to 4 (17%) in the open group (OR 1.82 (95% CI 0.5–7.0)). There were 9 vaginal cuff defects, dehiscences and/or fistulas in the minimally invasive group compared to 3 in the open group (OR 3.0 (95% CI 0.8–11.2)). There was no statistically significant difference between disease free survival and overall survival among the two groups, however there was a trend towards decreased disease-free survival in the minimally invasive group. Conclusions Among women undergoing adjuvant hysterectomy following chemoradiation for bulky, early stage cervical cancer, there was no difference in complication rates between an open or minimally invasive surgical approach. However, the overall complication rate was high, including a high rate of vaginal cuff defect, dehiscence and/or fistulas. Our findings suggest that an adjuvant hysterectomy should be reserved for patients in which chemoradiation is not anticipated to successfully treat the primary tumor and, if performed, an open approach should be considered.

Outcomes and prognostic factors in patients with locally advanced cervical cancer treated with concurrent chemoradiotherapy

Abstract Background To investigate the prognostic factors affecting long-term survival in locally advanced cervical cancer (LACC) patients treated with concurrent chemoradiotherapy (CCRT). Methods We retrospectively analyzed 192 naive LACC (stage IIB–IVA) patients who underwent intensity-modulated radiotherapy (IMRT) with concurrent platinum-based chemotherapy in Xiangya Hospital from January 2014 to June 2017. The clinicopathological factors of all patients were collected. To explore the relationship between factors and prognosis, survival rates were estimated by the Kaplan–Meier method. Univariate and multivariate Cox proportional hazards models were used to evaluate the effect of various factors on overall survival (OS) and progression-free survival (PFS). The nomogram and calibration curves were generated on the basis of survival analysis. Results The median follow-up time was 39.5 months. There-year rates of OS and PFS were 89.1% and 82.8%. LACC patients with non-squamous cell carcinoma [NSCC, including adenocarcinoma or adenosquamous carcinoma (AC/ASC)], advanced stage (IIIA-IVA), initially positive lymph node (pelvic or para-aortic lymph node, PLN/PALN), and a lower pretreatment hemoglobin (HGB) level (&lt; 126 g/L) had lower survival rates. In univariate analysis, patients with NSCC, advanced stage, PLN or PALN metastasis had worse OS. Patients with NSCC, advanced stage, PLN or PALN metastasis, and a lower pretreatment HGB level had worse PFS. In multivariate analysis, NSCC and PALN metastasis were independent prognostic parameters of OS. NSCC, PALN metastasis and a lower pretreatment HGB level were independent prognostic parameters of PFS. Conclusions NSCC and PALN metastasis were poor prognostic factors of OS and PFS, a lower pretreatment HGB level was an independent prognostic factor of PFS in LACC patients treated with CCRT.

The prognostic significance of pretreatment squamous cell carcinoma antigen levels in cervical cancer patients treated by concurrent chemoradiation therapy and a comparison of dosimetric outcomes and clinical toxicities between tomotherapy and volumetric modulated arc therapy

Abstract Background To analyze the prognostic factors associated with stage IB-IVA cervical cancer in patients who underwent concurrent chemoradiation therapy (CCRT) and to compare the clinical toxicities and dosimetric parameters of organs at risk between the different radiotherapy techniques. Methods This retrospective study enrolled 93 patients with stage IB-IVA cervical cancer who underwent definitive CCRT between April 2009 and December 2017. Nine patients (9.7%) received 3DCRT, 43 patients (46.2%) underwent VMAT, and 41 patients (44.1%) received tomotherapy, and all of them followed by brachytherapy using a 2D planning technique. The treatment outcomes and related prognostic factors were analyzed. We also compared the clinical toxicities and dosimetric parameters between the different techniques used for the last 30 patients. Results With a median follow-up of 52.0 months, the 5-year overall survival (OS), progression-free survival (PFS), locoregional recurrence–free survival (LRRFS), and distant metastases–free survival (DMFS) were analyzed. In a Cox proportional hazards regression model, pretreatment SCC Ag &gt; 10 ng/mL was a significant prognostic factor for PFS (hazard ratio [HR] 2.20; 95% confidence interval [CI] 1.03–4.70; P = 0.041), LRRFS (HR, 3.48; 95% CI 1.07–11.26; P = 0.038), and DMFS (HR 2.80; 95% CI 1.02–7.67; P = 0.045). Increasing the rectal volume receiving a radiation dose exceeding 30 Gy (V30 of rectum; odds ratio [OR] 1.15; 95% CI 1.10–1.30; P = 0.03) was associated with a higher possibility of ≥ Grade 2 acute radiation therapy (RT)-related diarrhea. The median rectal V30 values were 56.4%, 97.5%, and 86.5% for tomotherapy, 3-dimensional conformal radiation therapy (3DCRT), and volumetric modulated arc therapy (VMAT), respectively (P &lt; 0.001). In addition, the chance of experiencing ≥ Grade 2 acute diarrhea were 10.0%, 66.7%, and 54.5% for tomotherapy, 3DCRT, and VMAT, respectively (P = 0.029). Conclusions Patients with pretreatment SCC Ag ≤ 10 ng/mL have better PFS, LRRFS, and DMFS than those with pretreatment SCC Ag &gt; 10 ng/mL. The rectal V30 is a significant predictor of severe acute diarrhea. Tomotherapy significantly decreased the rectal V30, reducing the severity of acute RT-related diarrhea during external beam RT. Trial registration This study was approved by the institutional review board at Kaohsiung Medical University Hospital. The registration number is KMUHIRB-E(I)-20190054 and retrospectively registered on 2019/3.

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

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