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Purpose: BIOEMBRACE was designed to study the impact of biomarkers in addition to clinicopathological factors on disease outcomes in patients treated with chemoradiation and magnetic resonance imaging (MRI)-guided brachytherapy (BT) for locally advanced cervical cancer in the EMBRACE study., Methods and Materials: Between 2018 and 2021, 8 EMBRACE-I sites contributed tumor tissue for the immunohistochemistry of p16, PD-L1, and L1CAM. These biomarkers and clinicopathological factors (International Federation of Gynecology and Obstetrics 2009 stage, nodal status, histology, and necrosis on MRI) were analyzed to predict poor response at BT (high-risk clinical target volume [HR-CTV] ≥ 40 cc) at BT) and 5-year local control, pelvic control, and disease-free survival. Interaction between p16, PD-L1, radiation therapy dose (HR-CTV D90), and disease outcomes was investigated. Univariable and multivariable analyses were performed., Results: Two hundred sixty-four patients were included. The median HR-CTV D90 was 89 Gy (86-95). P-16 positive status, PD-L1 > 1%, and L1CAM ≥ 10% was noted in 86.6%, 20.1%, and 17.8% of patients, respectively. P16 negative status (odds ratio, 2.0; 95% CI, 1.0-5.7; P = .04) and necrosis on MRI (odds ratio, 2.1; 95% CI, 1.1-4.3; P < .02) independently predicted for HR-CTV ≥ 40 cc, as did the International Federation of Gynecology and Obstetrics stage and tumor width >5 cm. PD-L1 > 1% was associated with reduced local (82% vs 94%; P = .02) and pelvic control (79% vs 89%; P = .02). HR-CTV D90 < 85 Gy was associated with inferior 5-year local control in p16-positive patients, especially if PD-L1 was coexpressed. On multivariable analysis, PD-L1 > 1% was the only independent factor for 5-year local control (hazard ratio, 3.3; P = .04) and L1CAM ≥ 50% for pelvic control (hazard ratio, 5.5; 95% CI, 1.3-23.3; P = .02)., Conclusions: P16 negative status and tumor necrosis on MRI are independently associated with poor response to chemoradiation, whereas PD-L1 > 1% and L1CAM ≥ 50% have an independent impact on local and pelvic control, suggesting an impact of biomarker expression on outcomes. Further validation is needed., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: Definitive pelvic intensity modulated radiation therapy (IMRT) in cervical cancer is susceptible to geographic miss due to daily positional and volumetric variations in target and organs at risk. Hence, despite evidence of reduced acute and late treatment-related toxicities, implementation of image-guided IMRT (IG-IMRT) with a reasonable safety margin to encompass organ motion is challenging., Methods and Materials: In this prospective, nonrandomized phase 2 study, patients with cervical cancer International Federation of Gynecology and Obstetrics (2009) stage IB2-IIIB between the ages of 18 and 65 years were treated with definitive pelvic chemoradiotherapy with a prespecified organ (bladder and rectum) filling protocol. Reproducibility of organ filling was assessed along with the implementation of daily comprehensive adaptive image-guided radiotherapy (IGRT), with a library of 3 IMRT (volumetric modulated arc therapy) plans with incremental expansions of clinical target volume (CTV) to planning target volume (PTV) (primary) margins (small, 0.7 cm; adequate, 1 cm; and large, 1.5 cm) and a backup motion robust 3-dimensional conformal radiotherapy plan; the appropriate plan is chosen based on pretreatment cone beam computed tomography (CBCT) ("plan of the day" approach)., Results: Fifty patients with a median age of 49 years (IQR, 45-56 years) received definitive radiation therapy (45-46 Gy in 23-25 fractions to pelvis, with simultaneous integrated boost to gross nodes in 15 patients) with the aforementioned IGRT protocol. In the analysis of 1171 CBCT images (in 1184 treatment sessions), the mean planning computed tomography (CT) and CBCT bladder volumes were 417 and 373 cc, respectively. Significant interfractional variation in bladder volume was noted with a mean absolute dispersion of 29.5% with respect to planning CT; significant influential random factors were postchemotherapy sessions (P ≤ .001), pre-CBCT protocol duration (P = .001), and grades of chemotherapy induced nausea vomiting (P = .001). Significantly higher variation in bladder filling was noted in patients with older age (P = .014) and larger planning CT bladder volume (P ≤ .001). Time trend analysis of fraction-wise bladder volume revealed an absolute systemic reduction of 16.3% in bladder volume means from the first to the fifth week. Variation in rectal diameter was much less pronounced, with 19.2% mean dispersion and without any significant factors affecting it. Although in 19% and 2% of sessions large IMRT PTV and 3-dimensional conformal radiotherapy were necessary to cover the primary target, respectively, reduction in treated volume was possible in 43% of sessions with small PTV selection instead of standard adequate PTV (36% sessions). Plan of the day selection had a moderate to strong correlation with nonabsolute dispersion of bladder filling (Spearman ρ =0.4; P = .001) and a weak (but significant) correlation with grades of acute toxicities. The planned protocol was well tolerated with no radiation-induced local grade 3 toxicity., Conclusions: Interfractional variation in organ filling (especially bladder) is inevitable despite fixed pretreatment protocol in definitive settings (intact cervix). Despite the logistical challenges, adaptive IGRT in the form of plan of the day based on incremental CTV-to-PTV margins is a relatively simple and feasible strategy to minimize geometric uncertainties in radical IG-IMRT of cervical cancer., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: Variations in the levels of systemic inflammatory biomarker levels have been linked with outcomes in various malignancies including cervical cancer. In this study, we investigated prognostic implications of pretreatment hematological factors/indices in locally advanced cervical cancers treated with radical radio(chemo)therapy., Methods and Materials: Electronic medical records of 1051 patients with cervical cancer of FIGO (International Federation of Gynecology and Obstetrics) stage IB2-IVA treated in various prospective trials at our institute between 2003 and 2017 were reviewed. All clinical parameters such as age (dichotomized at the median), stage (IB2-IIB vs III-IVA), histologic type (squamous vs others), and hematological parameters (hemoglobin, platelets, absolute neutrophil count, absolute lymphocyte count, absolute monocyte count) were recorded. Neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and prognostic nutritional index (PNI; defined as 10 × albumin concentration [g/dL] + 0.005 × total lymphocyte count [μL]) were calculated. Univariate and multivariate (Cox regression) analyses were performed to evaluate these factors with disease-free survival (DFS) and overall survival (OS)., Results: With a median follow-up of 69 months, the 5-year DFS and OS were 65% and 69%, respectively. On multivariate analysis, FIGO stage (hazard ratio [HR], 1.9; P = .000) and PLR (HR, 1.002; P = .008) significantly affected DFS while FIGO stage (HR, 1.804; P = .000), LMR (HR, 0.92; P = .018), PNI (HR, 0.96; P = .013), and PLR (HR, 1.002; P = .006) significantly affected OS. Apart from FIGO stage, PLR significantly affected both DFS and OS. This correlation of hematological parameters is stronger in stage IIIB cervical cancer., Conclusions: Hematological indices, including PNI, PLR, and LMR, can serve as reliable prognostic indicators for patients with cervical cancer. By incorporating these indices into routine assessment and monitoring, clinicians can better stratify patients, personalize treatment plans, and more accurately predict outcomes, ultimately improving patient care and management., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: In patients with recurrent or metastatic cervical cancer, the median survival time is 13 to 24 months based on the choice of palliative systemic chemotherapy. Evolving evidence suggests that the addition of radiation may lead to improved survival., Methods and Materials: Consecutive patients treated with radiation with or without systemic chemotherapy for oligometastatic or oligorecurrent disease within the period from 2017 to 2020 were included. All patients received systemic chemotherapy consultation and radiation to relapsed or metastatic sites. Progression-free survival (PFS) was determined as the period between diagnosis of relapse or metastasis and the last progression of the disease. Overall survival (OS) was defined as the time between the date of diagnosis of relapse or metastasis and follow-up or death. The effect of various prognostic and predictive factors was estimated using the Kaplan-Meier method and log-rank test., Results: Fifty-eight consecutive patients were included. The median time to relapse was 18 months (8-205 months). At the time of first relapse, 34.4% of patients (n = 20) had locoregional relapse, 32.8% (n = 19) had distant nodal metastases, and 32.8% (n = 19) had visceral metastases. The relapse was within previously irradiated portals in 34.5% (n = 20), out of field in 50% (n = 29), and both in 15.5% (n = 9) of patients. Overall, 56% of patients (n = 33) received systemic chemotherapy. The radiation therapy dose in equivalent doses of 2 Gy at the time of retreatment was 44 Gy (31-68 Gy). The median PFS and OS from the date of first relapse were 16 (12-19) and 28 months (2-108), respectively. Grade ≥3 toxicity was observed in 19% of patients. No patient- or treatment-related factor was identified as predictive of OS on univariate analysis., Conclusions: The use of potentially radical doses of radiation, including reirradiation at locoregional or distant oligorelapse or metastasis, is associated with encouraging PFS and OS in patients with cervical cancer., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: Pelvic irradiation leads to substantial dose to the pelvic girdle. However, bone density loss as a function of radiation therapy dose and time has not been investigated. This study was undertaken to evaluate such a dose-response relationship., Methods and Materials: Women undergoing pelvic radiation therapy for cervix cancer within a phase 3 trial were included. The study necessitated 2 computed tomography imaging sets acquired at least 12 months apart in patients with no evidence of relapse. All images were transferred to the treatment planning system to determine radiation dose and Hounsfield unit (HU). Across the entire lumbopelvic region (lumbar 1-5 [L1-5] vertebrae, pubic symphysis, femur, acetabulum, greater trochanter, and anterior-superior iliac spine) multiple regions were defined to measure radiation therapy dose and HU. Bone health was categorized as normal if >130 HU, osteopenic at 110 to 130 HU, and osteoporotic <110 HU at baseline and follow-up. Univariate analysis was performed to test the effect of various factors on HU. Further interaction among radiation therapy dose, time, and HU was assessed using a linear mixed model., Results: Overall, 132 of 300 patients were eligible. The median age was 49 (42-56) years. With a prescription dose of 50 Gy, the L1 and L2 vertebrae received a median dose of 1.2 and 4 Gy, respectively, and L3-5 received 10 to 50 Gy. At 24 months, median HU loss at L4-5 was 45 HU (interquartile range, 34-77 HU). Out of the 132 patients, at baseline 96% had normal bone health. However, at the last follow-up, 3% of patients had normal bone health, 12% developed osteopenia, and 85% developed osteoporosis (P < .001). There were no patient- or treatment-related factors predicted for HU loss on univariate analysis. HU loss >60 to 70 was observed at >45 Gy at L5 vertebra (60-70 HU, P < .02) and >15 Gy at L4 vertebra (33 HU; P = .04)., Conclusions: Dose-response relationship is observed between radiation dose and bone mineral density loss. Prospective studies are needed to corroborate these observations and design future interventions., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: Reirradiation (re-RT) is a suitable and potentially curative treatment option for in-field locoregional recurrences in gynecological malignancies. Lack of clear guidelines on prescription, dose-response relationship, and clinical outcomes limits its clinical use. This clinical narrative describes the methodology for integration of deformable image registration (DIR) for cumulative dose assessment in the setting of re-RT for gynecologic malignancies, using the tools available within a commercial treatment planning system., Methods and Materials: Four patients who received re-RT for locoregional recurrence or second cancer within previously irradiated areas for a gynecologic primary were identified. Patient-specific DIR for deformable dose mapping and accumulation was retrospectively performed using intensity-based algorithm provided by the Varian Medical Systems Velocity AI version 4.1. Cumulative equivalent doses in 2 Gy fractions (EQD2) delivered to overlapping targets and organs at risk were generated and compared with the physically summated doses. For both approaches, brachytherapy (BT) component was physically summated in cases where the BT applicator caused significant anatomic distortion., Results: The mean maximum cumulative overlapping target dose was 119.4 Gy 10 (range, 84.7 Gy10-144.9 Gy 10 ). The mean cumulative doses received by 2 cm 3 of bladder, rectum, sigmoid, and bowel were 114.6 Gy 3 (101.1-133.4 Gy 3 ), 98.7 Gy 3 (67-136.2 Gy 3 ), 92.5 Gy 3 (70.4-107 Gy 3 ), and 89.9 Gy 3 (81.1-102.8 Gy 3 ) , respectively. In the setting of in-field nodal recurrence, DIR-based dose summation was associated with lower cumulative organs at risk doses than those estimated with physical summation, except in one case with a higher bowel dose. In cases where re-RT was given for local recurrence/second primary, variation in sigmoid doses was observed between the 2 dose-summation strategies across all 3 cases, but it was inconsistent with bladder, rectum, or the bowel., Conclusions: DIR-based dose accumulation can be used to guide re-RT planning and can provide clinically relevant information, especially in cases with nodal recurrences. Registration of BT data sets remain challenging and requires an individualized assessment when applying these algorithms to clinical practice., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: The Radiation Therapy Oncology Group (RTOG) under NRG Oncology recently published updated contouring guidelines for intensity modulated radiation therapy in postoperative treatment for endometrial and cervical cancer. The present study was designed to evaluate the implications of newly published guidelines., Methods and Materials: We recruited 300 patients in a phase 3 randomized controlled trial of adjuvant chemoradiation therapy for cervical cancer (NCT01279135) to understand patterns of relapse. For those patients with pelvic relapse, we imported radiation therapy structure sets, treatment plans, and diagnostic images at relapse on the treatment planning system. We performed rigid registration with treatment planning images that contained the delineated planning target volume and radiation dose information. We delineated gross tumor volume at time of relapse on the diagnostic scans and superimposed it on the radiation therapy treatment scans. We categorized the site of pelvic relapse as "within field of old RTOG/[Postoperative Adjuvant Radiation in Cervical Cancer (PARCER)] target delineation guidelines" or "within field of new NRG/RTOG guidelines," or both, and compared proportions of recurrences contained within the 2 guidelines. We consider a P value of <.05 statistically significant. Additionally, we generated intensity modulated radiation therapy treatment plans based on the new guidelines for a limited set of patients to see if these new guidelines increased the organ at risk doses., Results: Most common form of relapse was distant metastasis (15%). Pelvic relapse rate in our study was 8%. Overall, 9 out of 19 relapses were encompassed in the contouring guidelines of the old RTOG/ Postoperative Adjuvant Radiation in Cervical Cancer (PARCER) trial, and 12 out of 19 were encompassed within the new RTOG 2021 contouring guidelines. This corresponded to a further 1% reduction in local relapses (P = .007). Dose to rectum was marginally increased with the new contouring, with no difference in other organs at risk. Salvage treatment was offered in 25 out of 60 patients who relapsed. Patients who received local treatment after relapse had a mean survival after relapse of 27.2 months compared with 8 months among those who received supportive care alone., Conclusions: Our study supports the use of newly published NRG/RTOG contouring guidelines in patients with cervical cancer who have undergone hysterectomy. Further data are needed to ascertain if anterior extension of the clinical target volume is needed as in the Postoperative Adjuvant Radiation in Cervical Cancer trial., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: The purpose was to evaluate patient- and treatment-related risk factors for physician-assessed and patient-reported gastrointestinal (GI) symptoms after radio(chemo)therapy and image guided adaptive brachytherapy in locally advanced cervical cancer., Methods and Materials: Of 1416 patients from the EMBRACE-I study, 1199 and 1002 were prospectively evaluated using physician-assessed (Common Terminology Criteria for Adverse Events [CTCAE]) and patient-reported (European Organization for Research and Treatment of Cancer [EORTC]) GI symptoms, respectively. CTCAE severe grade (grade [G] ≥3) events were pooled according to the location in the GI tract (anus/rectum, sigmoid, and colon/small bowel). CTCAE G ≥2 and EORTC "very much" and "quite a bit" plus "very much" scores (≥ "quite a bit") were analyzed for individual symptoms with Cox regression. Logistic regression was used for persistent G ≥1 and EORTC ≥ "quite a bit" symptoms, defined if present in at least half of follow-ups., Results: The incidence of G ≥3 events was 2.8%, 1.8%, and 2.3% for G ≥3 anus/rectum, sigmoid, and colon/small bowel events, respectively. Among G ≥2 symptoms, diarrhea and flatulence were the most prevalent (8.5% and 9.9%, respectively). Among patient-related factors, baseline morbidity, increasing age, smoking status, and low body mass index were associated with GI symptoms to varying degrees. Among treatment-related factors, rectum D 2cm3 and the International Commission on Radiation Units and Measurements recto-vaginal reference point (ICRU RV-RP) correlated with G ≥3 anus/rectum events and moderate/persistent diarrhea, proctitis, bleeding, abdominal cramps, and difficulty in bowel control. Bowel D 2cm3 correlated with G ≥3 sigmoid and colon/small bowel events and moderate/persistent diarrhea and flatulence. For external beam radiation therapy (EBRT), prescription dose correlated with G ≥3 anus/rectum, diarrhea, and difficulty in bowel control. Patients with large lymph-node boost (V57Gy) were at higher risk for G ≥3 sigmoid events, moderate/persistent diarrhea, proctitis, and cramps., Conclusions: The analysis showed that both EBRT and image guided adaptive brachytherapy contribute to GI symptoms after locally advanced cervical cancer treatment. Rectum D 2cm3 , ICRU RV-RP , and bowel D 2cm3 are risk factors for GI morbidity. The risk for various symptoms was lower with an EBRT prescription of 45 Gy than 50 Gy and increased with larger V57Gy., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: A prospective phase 2 study was conducted to evaluate the feasibility and safety of single-application multifractionated (SA-MF), high-dose-rate (HDR), image guided adaptive brachytherapy (IGABT) for cervical cancer., Methods and Materials: Patients (N = 41) with International Federation of Gynaecology and Obstetrics 2009 stage IIB-IVA disease recruited between 2017 and 2019 underwent SA-MF. After completion of external beam radiation therapy of 50 Gy in 25 fractions, patients received magnetic resonance IGABT. The IGABT protocol consisted of a single brachytherapy (BT) application and treatment with 3 fractions of HDR (9 Gy on day 1; 2 fractions of 7 Gy with a minimum 6-hour gap on day 2) after achieving planning aims of the high-risk clinical target volume (HRCTV) receiving >84 Gy EQD2 and 2 cm 3 of the bladder and rectum/sigmoid receiving ≤85 Gy and <71 Gy, respectively. Interfraction variation was addressed by performing computed tomography planning and coregistration using a mutual information-based coordinate system on day 2 before the second fraction. Organ at risk contouring was done on computed tomography, and doses were re-evaluated and reoptimized if required., Results: Thirty-eight patients were treated as per the protocol. All patients underwent Intracavitary + Interstitial BT with needles (median, 4; range, 3-11). The mean ± standard deviation HRCTV volume was 41 ± 21 cm 3 and HRCTV D90 dose was 87.2 ± 3.6Gy. The 0.1 cm 3 and 2 cm 3 to bladder, rectum, and sigmoid were -103.2 ± 10.6 Gy and -84.6 ± 6.8 Gy, 82.2 ± 9.5 Gy and -68.3 ± 5.7 Gy, and 83.5 ± 9.8 Gy and -69.5 ± 5.9 Gy, respectively. Six patients required reoptimization before the second fraction to meet planning aims. Mean overall treatment time was 47 ± 6 days. With a median follow up of 22 months (range, 2-37), 2-year local control and disease-free and overall survival were 90.1%, 85%, and 94.5%, respectively. So far 1 patient with grade II and 2 patients with grade III rectal toxicities have been reported., Conclusion: Magnetic resonance IGABT with SA-MF BT was feasible in 95% of patients. The dosimetric parameters and clinical results achieved so far look promising., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: In 2018, the International Federation of Gynecology and Obstetrics (FIGO) proposed a new staging for cervical cancer. The present study was designed to reclassify patients with locally advanced cervix cancer and perform a comparative evaluation with FIGO 2009., Methods and Materials: Patients with locally advanced cervical cancer (stage IB2-IVA) who had baseline cross-sectional imaging and received (chemo-) radiation and brachytherapy were included. Survival outcomes were analyzed according to FIGO 2009. Patients were then reclassified according to FIGO 2018, and TNM classification outcomes were analyzed. FIGO stage and known prognostic factors were included in univariate analysis, and multivariate analysis was performed to investigate the prognostic value of clinical stage., Results: Six hundred thirty-two patients were included. Overall, 185 (29.3%) patients had pelvic adenopathy, and 51 (8.2%) had positive paraortic nodes. At a median follow-up of 33 months, 116 (18.3%) patients had recurrence. Three-year disease-free survival (DFS) according to FIGO 2009 for stage IB, IIA, IIB, IIIA, IIIB, and IVA was 86%, 91%, 76%, 57%, 65%, and 61%, respectively. The 3-year DFS after restaging according to FIGO 2018 for stage IB, IIA, IIB, IIIA, IIIB, IIIC1, IIIC2, and IVA was 100%, 93%, 84%, 53%, 77%, 74%, 61%, and 61%, respectively. Patients with clinically significant lymphadenopathy had inferior outcomes compared with node-negative patients (62.9% vs 77.8%; P = .002). Patients with ≥3 paraortic nodes had poorer DFS than patients with <3 paraortic lymphadenopathy (13.6% vs 56.3%; P = .001). Furthermore, patients with primary tumor volume >30 cm 3 had worse 3-year DFS than those with primary tumor volume ≤30 cm 3 (67.4% vs 78.5%; P = .002)., Conclusions: FIGO 2018 modification is associated with heterogenous outcomes in node-positive patients that are affected by primary tumor and nodal volume. We propose a modification to the existing TNM staging system to allow more robust classification of outcomes., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: This phase II study evaluated the utility of magnetic resonance imaging (MRI) and positron emission tomography for planning radiation and brachytherapy in patients with postsurgical recurrence of cervical cancer., Methods and Materials: The study (NCT01391065) recruited patients with residual or recurrent disease after hysterectomy. Patients underwent baseline T2 weighted (T2W) MRI, 18 F-flouro-deoxyglucose ( 18 F-FDG), 18 F-flouro thymidine ( 18 F-FLT) and 18 F-flouromisonidazole ( 18 F-F Miso) positron emission tomography (PET) and received external radiation (50 Gy/25 fractions for 5 weeks) and weekly cisplatin (40 mg/m 2 ). MRI was performed at brachytherapy and used for delineation of clinical target volume (CTV). Patients with parametrial disease at baseline received interstitial brachytherapy (16-20 Gy/4-5 fractions) and those with vaginal disease received intracavitary brachytherapy (12-14 Gy/2-4 fractions). Kaplan-Meier analysis was performed to evaluate locoregional relapse, disease free survival, and overall survival. Common Toxicity Criteria for adverse event reporting (CTCAE) v4.1 was used for toxicity scoring and European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questtionaire Core 30 (QLQC-30) and Cx 24 for quality-of-life reporting., Results: Between January 2011 and February 2016, 60 patients were included, of which 50 received study treatment. The mean gross tumor volume on T2 W MR was 20 (IQR 3.6-90) cc. The metabolic tumor volume was 15 (interquartile range [IQR] 2.1-56.1) cc. The median FLT volume was 10 (IQR 0-48) cc. A total of 8 patients had 18- F F Miso uptake. The median CTV at brachytherapy was 38 (12-85) cc. The median CTVD90 and D 98 was 71 (53-74) and 74 (53-74) Gy. At a median follow-up of 60 (5-93) months, the 5-year local control, disease free survival, and overall survival were 84%, 73%, and 74.5%, respectively. Grade III and IV proctitis and cystitis were observed in 4% and 2% of patients. On multivariate analysis baseline tumor volume, on T2 W MR impacted disease free (91% vs 65%, P = .03) and overall survival (96% vs 77%, P = .06)., Conclusions: Image-guided assisted radiation and brachytherapy are associated with good to excellent local control and survival in patients with vaginal recurrences of cervical cancer., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: Although cancer stem cells (CSCs) have been reported across solid tumors, there is a dearth of data regarding CSC and its impact on outcomes of cervical cancer., Methods and Materials: From October 2013 to December 2015, patients with squamous cancer of the cervix (stage IB2-IVA) were included. Pretreatment and posttreatment biopsy was obtained and immunohistochemistry was performed for SOX-2, OCT-4, Nanog, CD44, and Podoplanin. All patients received concurrent radiation and brachytherapy to an equivalent dose of 80 to 84 Gy to point A with concurrent weekly cisplatin. Correlation of CSC expression was performed with known prognostic factors. The effect of stem cell expression on disease outcomes was tested within multivariate analysis., Results: One hundred fifty patients were included. The median dose to point A was 83 Gy (46-89 Gy) and a median of 4 cycles (range, 0-6 cycles) of chemotherapy was administered. At baseline, moderate to strong immunohistochemical expression of SOX-2, OCT-4, Nanog, CD44, and Podoplanin was observed in 12.8%, 4.8%, 24.4%, 15.5%, and 1.3% of patients, respectively. At median follow-up of 30 months (range, 3-51 months), locoregional and distant relapse was observed in 12.2% and 23.1% of patients, of whom 4.7% had both local and distant relapse. The 3-year disease-free survival rate was 87%. On multivariate analysis, moderate to high CSC expression and CD44 low status (hazard ratio [HR] = 8.8; 95% confidence interval [CI], 1.0-77.2; P < .04) independently predicted for locoregional relapse-free survival. International Federation of Gynecology and Obstetrics stage (HR = 2.6; 95% CI, 1.3-5.4; P = .004) and presence of residual tumor after external radiation (HR = 3.5; 95% CI, 1.8-6.5; P = .0001) predicted for a detriment in disease-free survival., Conclusions: The presence of stem cell proteins and loss of CD44 independently predicts for reduced locoregional control in locally advanced cervical cancer. Further investigation into the interaction of stem cell and CD44 biology is warranted., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: Although magnetic resonance imaging (MRI) represents the gold standard for image guided adaptive brachytherapy (IGABT) for cervical cancer, the majority of brachytherapy (BT) continues to be guided by computed tomography (CT). However, CT seems to overestimate the target-volume definition, and the potential of transrectal ultrasonography (TRUS) needs further evaluation. This prospective, comparative study aimed to evaluate CT-based target contouring with the incorporation of TRUS during BT., Methods and Materials: Patients with locally advanced cervical cancer undergoing magnetic resonance IGABT between January 2013 and March 2014 were included. During the BT procedure, TRUS imaging with central tandem in situ was acquired at 3 representative levels. Reference points/dimensions (D1-D4) of the hypoechoic region on TRUS images with respect to the central tandem were recorded. CT and magnetic resonance BT planning imaging was performed after BT application. The high-risk clinical target volume (HR-CTV) was contoured on CT scans with incorporation of clinical and TRUS imaging findings and was compared with the gold standard MRI-based target approach., Results: The image sets of 25 patients (International Federation of Gynecology and Obstetrics clinical stage IIB [11; 44%] and IIIB [14; 56%]) were evaluable. The mean (±standard deviation) volumes of HR-CTV on CT and MRI imaging were 39.1 (±20) cm³ and 39 (±19) cm³, respectively (r = 0.92; P < .001) . A significant correlation was found between the HR-CTV dimensions (width and thickness) of CT and MRI scans at various levels (r = 0.70-0.80; P < .001) . In addition, the absolute differences in target dimensions between CT and MRI were <0.5 cm. A strong correlation was seen between CT and MRI for patients with medial and lateral parametrial invasion (P < .05) compared with no parametrial disease at BT. Furthermore, the mean differences in HR-CTV width between CT and MRI contours at various levels, irrespective of parametrial involvement, was only 0.1 to 0.4 cm., Conclusions: This study suggests that a CT-based target and organ-at-risk delineation using MRI at diagnosis and real-time TRUS information during BT seems comparable with the gold standard MRI-based approach in IGABT for cervical cancer., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: To determine the clinical impact of magnetic resonance image guided adaptive brachytherapy (IGABT) for locally advanced cervical cancer (LACC) (stages II and III) in a tertiary care cancer hospital in a low and middle income countries setting., Methods and Materials: Ninety-four LACC patients enrolled in a prospective EMBRACE (An International Study on MRI-Guided Brachytherapy in Locally Advanced Cervical Cancer) protocol treated with external radiation therapy (45 Gy in 25 fractions) with or without weekly cisplatin, followed by magnetic resonance IGABT (4 fractions of 7 Gy), were analyzed in detail for dosimetric and clinical outcomes including late toxicities., Results: The mean (± standard deviation) high-risk clinical target volume (HR-CTV) at the first session of brachytherapy and at the second session of brachytherapy for the current study cohort was 46.94 ± 24.6 cm 3 and 42.7 ± 22.5 cm 3 , respectively, with mean minimum dose received by 90% volume (D 90 ) of 88.3 ± 4.4 equivalent 2-Gy fractionation (Gy EQD2 ). At median follow-up (39 months), the local control rate (LCR) and overall progression-free survival rate were 90.1% ± 3.4% and 72.1% ± 4.8%, respectively, with grade 3 bladder toxicity in 3% of patients and rectum toxicity in 9%. The LCR at 39 months was significantly better in patients with stage IIB and IVA disease versus stage IIIB disease (100% vs 85%, P=.013). Local failures were limited to stage IIIB only and were associated with significantly larger HR-CTVs at brachytherapy (70 ± 25.7 cm 3 vs 44.3 ± 21.9 cm 3 , P=.01) but not with HR-CTV D 90 doses (which were similar for patients who had local failures vs those who did not: 86.3 ± 3.9 α/β equal to 10 Gy (Gy 10 ) vs 88.5 ± 5 α/β equal to 10 Gy, P=.987)., Conclusions: IGABT leads to a significant improvement in LCR and overall progression-free survival in LACC and should be considered for wider implementation in developing countries to improve outcomes., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: The present study investigates relationship between dose-volume parameters and severe bowel toxicity after postoperative radiation treatment (PORT) for cervical cancer., Methods and Materials: From June 2010 to December 2012, a total of 71 patients undergoing PORT were included. Small bowel (SB) and large bowel (LB) loops were contoured 2 cm above the target volume. The volume of SB and LB that received 15 Gy, 30 Gy, and 40 Gy was calculated (V15 SB, V15 LB, V30 SB, V30 LB, V40 SB, V 40 LB). On follow-up, bowel toxicity was scored using Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. A reciever operating characteristic (ROC) curve identified volume thresholds that predicted for grade 3 or higher toxicity with highest specificity. All data was dichotomized across these identified cut-off values. Univariate and multivariate analysis was performed using SPSS, version 15., Results: The median patient age was 47 years (range, 35-65 years). Of the 71 patients, 46 received image-guided intensity modulated radiation therapy, and 25 received conformal radiation (50 Gy in 25 fractions for 5 weeks). Overall, 63 of 71 patients received concurrent chemotherapy. On a median follow-up of 18 months (range, 8-29 months), grade 2 or higher bowel toxicity was seen in 22 of 71 patients (30.9%) and grade 3 or higher bowel toxicity was seen in 9 patients (12.6%). On univariate analysis, V15 SB <275 cc (P=.01), V30 SB <190 cc (P=.02), V40 SB <150 cc (P=.01), and V15 LB <250 cc (P=.03), and V40 LB <90 cc (P=.04) predicted for absence of grade 3 or higher toxicity. No other patient- or treatment-related factors were statistically significant. On multivariate analysis, only V15 SB (P=.002) and V15 LB (P=.03) were statistically significant., Conclusions: V 15 Gy SB and LB are independent predictors of late grade 3 or higher toxicity. Restricting V15 SB and V15 LB to <275 cc and <250 cc can reduce grade 3 or higher toxicity to less than 5%., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: To evaluate three-dimensional needle displacements during multifractionated interstitial brachytherapy (BT) for cervical cancers., Methods and Materials: Patients scheduled to undergo pelvic interstitial BT for postoperative and or postradiation vault recurrences were included from November 2009 to December 2010. All procedures were performed under spinal anesthesia. Postprocedure BT planning CT scans were obtained with patients in supine position with arms on the chest (interslice thickness of 3 mm). Thereafter, verification CT was repeated at every alternate fraction. Needle displacements were measured in reference to a relocatable bony point. The mean cranial, caudal, anteroposterior, and mediolateral displacements were recorded. Statistical significance of mean interfraction displacements was evaluated with Wilcoxon Test., Results: Twenty patients were included. Seventeen received boost BT (20 Gy/5 fractions/3 days) after external radiation, three received radical BT alone (36 Gy/9 fractions/5-8 days). An average of three scans (range, 2-3) were available per patient, and 357 needle displacements were analyzed. For the entire study cohort, the average of mean needle displacement was 2.5 mm (range, 0-7.4), 17.4 mm (range, 0-27.9), 1.7 mm (range, 0-6.7), 2.1 mm (range, 0-9.5), 1.7 mm (range, 0-9.3), and 0.6 mm (range, 0-7.8) in cranial, caudal, anterior, posterior, right, and left directions, respectively. The mean displacement in the caudal direction was higher between Days 1 and 2 than that between Days 2 and 3 (13.4 mm vs. 3.8 mm; p = 0.01). The average caudal displacements were no different between reirradiation and boost cohort (15.2 vs. 17.8 mm)., Conclusions: Clinically significant caudal displacements occur during multifractionated pelvic brachytherapy. Optimal margins need to be incorporated while preplanning brachytherapy to account for interfraction displacements., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: Rational design of targeted radiotherapy (RT) in prostate cancer (Pca) hinges on a better understanding of spatial patterns of recurrence. We sought to identify pathological factors predictive for site of local recurrence (LR) after external beam RT., Methods and Materials: Prospective databases were reviewed to identify men with LR after RT from 1997 through 2009. Patients with biochemical failure and biopsy-confirmed Pca more than 2 years after RT were evaluated. Prediction for site of recurrence based on the following pretreatment factors was determined on independent and cluster-sextant basis: presence of malignancy, dominant vs. nondominant percentage core length (PCL) involvement, PCL ≥ or <40%, and Gleason score. Sites of dominant PCL were defined as sextants with peak PCL involvement minus 10%, and >5% for each patient., Results: Forty-one patients with low-intermediate risk Pca constituted the study cohort. Median time to biopsy after RT was 51 months (range, 24-145). Of 246 sextants, 74 were involved with tumor at baseline. When sextants are treated as independent observations the presence of malignancy (77% vs. 22%, p = 0.0001), dominant PCL (90% vs. 46%, p = 0.0001), and PCL ≥40% (89% vs. 68 %, p = 0.04) were found to be significant predictors for LR, although PCL ≥40% did not retain statistical significance if sextants were considered correlated. The vast majority of patients (95%) recurred at the original site of dominant PCL or PCL ≥40%, and 44% also recurred in regions of nondominant PCL <40% (n = 8) and/or benign sampling (n = 14) at baseline., Conclusions: LR after RT predominantly occurs in regions bearing higher histological tumor burden but are not isolated to these sites. Our data highlights the value of spatially resolved baseline pathological sampling and may assist in the design of clinical trials tailoring RT dose prescriptions to subregions of the prostate gland., (Copyright © 2012 Elsevier Inc. All rights reserved.)