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Background: The role of artificial intelligence and radiomics in prediction model development in cancer has been increasing every passing day. Cervical cancer is the 4th most common cancer in women worldwide, contributing to 6.5% of all cancer types. The treatment outcome of cervical cancer patients varies and individualized prediction of disease outcome is of paramount importance. Purpose: The purpose of this study is to develop and validate the digital signature for 5-year overall survival prediction in cervical cancer using robust CT radiomic and clinical features. Materials and Methods: Pretreatment clinical features and CT radiomic features of 68 patients, who were treated with chemoradiation therapy in our hospital, were used in this study. Radiomic features were extracted using an in-house developed python script and pyradiomic package. Clinical features were selected by the recursive feature elimination technique. Whereas radiomic feature selection was performed using a multi-step process i.e., step-1: only robust radiomic features were selected based on our previous study, step-2: a hierarchical clustering was performed to eliminate feature redundancy, and step-3: recursive feature elimination was performed to select the best features for prediction model development. Four machine algorithms i.e., Logistic regression (LR), Random Forest (RF), Support vector classifier (SVC), and Gradient boosting classifier (GBC), were used to develop 24 models (six models using each algorithm) using clinical, radiomic and combined features. Models were compared based on the prediction score in the internal validation. Results: The average prediction accuracy was found to be 0.65 (95% CI: 0.60– 0.70), 0.72 (95% CI: 0.63–0.81), and 0.77 (95% CI: 0.72–0.82) for clinical, radiomic, and combined models developed using four prediction algorithms respectively. The average prediction accuracy was found to be 0.69 (95% CI: 0.62–0.76), 0.79 (95% CI: 0.72–0.86), 0.71 (95% CI: 0.62–0.80), and 0.72 (95% CI: 0.66–0.78) for LR, RF, SVC and GBC models developed on three datasets respectively. Conclusion: Our study shows the promising predictive performance of a robust radiomic signature to predict 5-year overall survival in cervical cancer patients. [ABSTRACT FROM AUTHOR]

Background: There is paucity of outcome data of patients with cervical cancer presenting with malignant obstructive uropathy. The present retrospective study describes outcomes of patients with cervical cancer who presented with obstructive uropathy at the time of diagnosis and underwent urinary diversion with percutaneous nephrostomy (PCN) before/during treatment.Methods: Patients who underwent PCN from January 2010 to June 2015 were included. Intent of treatment (radical or palliative) was decided within multidisciplinary team depending on disease stage, Karnofsky performance status (KPS), and degree of renal derangement. Treatment and outcome details were retrieved from electronic records. Time to normalization of creatinine, feasibility of delivering planned treatment, and overall survival (OS) were determined. Impact of various prognostic factors on outcomes was determined using univariate or multivariate analysis.Results: After PCN and double-J stenting, 50% were eligible for (chemo) radiation. All radically treated patients (26/52) received brachytherapy. The median EQD2 to point A was 78 Gy (72-84 Gy). The median OS was 10 (0.5-60) months. Patients who completed chemoradiation had median OS of 31 months. Those receiving radical radiation and palliative radiation had median OS of 11 and 6 months, respectively. On univariate analysis, smaller tumor size (p = 0.03), high KPS (P = 0.04), and radical intent of treatment (P = 0.05) predicted for OS.Conclusion: Patients presenting with obstructive uropathy have median OS less than a year despite urinary diversion. Select cohort with good performance status, small tumor size, and serum creatinine of ≤3 mg/dL may be selected for diversion procedures and potential radical treatment. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study is to compare the quality of life (QOL) between adjuvant three-dimensional conformal radiotherapy (3DCRT) or intensity-modulated radiotherapy (IMRT) for cervical cancer.Materials and Methods: QOL assessment was done at the baseline and then longitudinally after completing (chemo) radiation. All patients completed EORTC QLQ-C30 and EORTC QLQ Cx-24 modules. Independent-sample t-test was used to compare the mean scores between the two groups. Analysis of variance was used to compare differences in QOL measures over the six time points (baseline, post-RT, 3, 6, 9, and 12 months after treatment) and between treatment groups (3DCRT vs. IMRT). Linear mixed model was also performed to account for attrition.Results: Overall, 64 patients (image-guided IMRT, n = 40 and 3DCRT, n = 24) completed QOL assessment. The median age and follow-up period were 48 years and 15.5 months, respectively. General QOL domains such as emotional (at 12 months, P = 0.04) and social (at 3 months, P = 0.02 and 12 months, P = 0.03) were better with IMRT. Pain (12 months, P = 0.03); fatigue (12 months, P = 0.05); nausea and vomiting (12 months, P = 0.03); insomnia (post-RT, P = 0.05 and 12 months, P = 0.03); appetite loss (post-RT and 12 months, P = 0.04); and diarrhea (6 months, P = 0.02 and 12 months, P = 0.003) scores were significantly better with IMRT. On linear mixed model analysis, there was a significant interaction between treatment cohort and assessment intervals for physical, emotional, and social functioning, appetite loss, diarrhea, lymphedema, and menopausal symptom scores were significantly better with IMRT.Conclusions: Treatment technique (IMRT vs. 3DCRT) impacts early QOL in undergoing adjuvant radiation for cervical cancer. [ABSTRACT FROM AUTHOR]

Supplemental digital content is available in the text. Objectives: A global unmet medical need exists for effective treatments for persistent, recurrent, or metastatic cervical cancer, as patients have a short life expectancy. Recently, immunotherapies have shown promising survival benefits for patients with advanced forms of cancer. Axalimogene filolisbac (ADXS11-001), a Listeria monocytogenes immunotherapy with a broad effect on the immune system, is under investigation for treatment of human papillomavirus–associated cancers including cervical cancer. Methods: This phase 2 study evaluated the safety and efficacy of ADXS11-001, administered with or without cisplatin, in patients with recurrent/refractory cervical cancer following prior chemotherapy and/or radiotherapy. A total of 109 patients were treated, and 69 were evaluable for tumor response at equal to or more than 3 months postbaseline. Results: Median overall survival (OS) was comparable between treatment groups (ADXS11-001: 8.28 months; 95% confidence interval [CI], 5.85–10.5 months; ADXS11-001 + cisplatin: 8.78 months; 95% CI, 7.4–13.3 months). The 12- and 18-month milestone OS rates were 30.9% versus 38.9%, and 23.6% versus 25.9% for each group, respectively (34.9% and 24.8% combined). Median progression-free survival (6.10 vs 6.08 months) and the overall response rate (17.1% vs 14.7%) were similar for both groups. ADXS11-001 was generally well tolerated; adverse events were predominantly mild to moderate in severity and not related to treatment. More adverse events were reported in the combination group (429 vs 275). Conclusions: These promising safety and efficacy results, including the encouraging 12-month 34.9% combined OS rate, warrant further investigation of ADXS11-001 for treatment of recurrent/refractory cervical cancer. [ABSTRACT FROM AUTHOR]

Background: Cervical cancer is the second most common cancer among Indian women. This present retrospective study was conducted to report patient outcomes with locally advanced cervical cancer treated in the year 2010.Materials and Methods: Case records of cervical cancer patients registered from January 1, 2010, to December 31, 2010 were retrieved. A total of 1200 patients were registered, of which 583 received either definitive or adjuvant radiotherapy (RT). Of these, 345 patients who received complete treatment at our hospital were included for outcome analysis. Descriptive statistics were used to summarize patient- and treatment-related variables, and Kaplan-Meier analysis was performed for survival analysis.Results: The median age was 56 years (range: 33-90). Squamous carcinoma was the most common histology (91.4%) and the majority were FIGO Stage III (45.4%). Median follow-up of the cohort was 44 months (1-85 months). The 5-year disease-free survival (DFS) across stages was 50%. Most important predictor of DFS was FIGO staging (Stage II vs. Stage III: 62% vs. 45%) and use of concurrent chemoradiotherapy (CTRT) l (RT vs. CTRT: 32% vs. 57%, respectively). Patients aged >70 years had a significantly poor DFS at 5 years; however, did not have any effect on survival. Grade 3 or more late toxicity was seen in only 5% of the patients.Conclusion: Five-year DFS of 62% and 45% of Stage II and III patients treated under routine care represents comparable stage-matched results to the rest of the world, respectively. [ABSTRACT FROM AUTHOR]

Purpose: Recent guidelines recommend magnetic resonance imaging–based brachytherapy (MRBT) for locally advanced cervical cancer. However, its implementation is challenging within the developing world. This article reports the outcomes of patients with locally advanced cervical cancer treated with chemoradiation and point A–based brachytherapy (BT) using x-ray– or computed tomography–based planning. Methods: Patients treated between January 2014 and December 2015 were included. Patients underwent x-ray– or computed tomography–based BT planning with an aim to deliver equivalent doses in 2 Gy (EQD2) > 84 Gy10 to point A while minimizing maximum dose received by rectum or bladder to a point or 2 cc volume to < 75 Gy EQD2 and < 90 Gy EQD2, respectively. The impact of known prognostic factors was evaluated. Results: A total of 339 patients were evaluated. Median age was 52 (32 to 81) years; 52% of patients had stage IB2 to IIB and 48% had stage III to IVA disease. There was 85% compliance with chemoradiation, and 87% of patients received four or more cycles. Median point A dose was 84 (64.8 to 89.7) Gy. The median rectal and bladder doses were 73.5 (69.6 to 78.4) Gy3 and 83 (73.2 to 90.0) Gy3, respectively. At a median follow-up of 28 (4 to 45) months, the 3-year local, disease-free, and overall survival for stage IB to IIB disease was 94.1%, 83.3%, and 82.7%, respectively. The corresponding rates for stage III to IVA were 85.1%, 60.7%, and 69.6%. Grade III to IV proctitis and cystitis were observed in 4.7% and 0% of patients, respectively. Conclusion: This audit demonstrates good 3-year outcomes that are comparable to published MRBT series. Conventional BT with selective use of interstitial needles and MRBT should continue as standard procedures until level-I evidence for MRBT becomes available. [ABSTRACT FROM AUTHOR]

Abstract: Neuroendocrine carcinomas of the cervix are uncommon, characterized by a histomorphological spectrum and, mostly, an aggressive clinical course. There are only few substantial studies on such cases documented from our country, where cervical cancer is the second most common cancer affecting women. Herein, we present a spectrum of 50 cervical neuroendocrine carcinomas, including histopathologic features, terminology, immunohistochemical (IHC) profile, and clinical outcomes, wherever available. Fifty tumors occurred in women, with their age ranging from 23 to 69 years (mean, 48.6 years; median, 46.5 years). Stagewise, among 25 cases, most cases (6, or 24%) presented with stage IB. Average tumor size was 4.7 cm. On histopathologic review, 26 tumors (52%) were classified as small cell carcinoma (SMCA); 14 (28%), as large cell neuroendocrine carcinomas (LCNECs); 4 (8%), as SMCA+LCNECs; and 6, as mixed carcinomas, including 3 tumors (6%) with SMCA and squamous cell carcinoma (SCC), 2 tumors (4%) with LCNEC and adenocarcinoma, and a single tumor (2%) with LCNEC and squamous cell carcinoma. On IHC performed in 41 tumors (82%), 36 tumors (87.8%) were positive for at least a single neuroendocrine marker, and 22 (53.6%) expressed 2 neuroendocrine markers. Synaptophysin was positive in 22 (59.4%) of 37 tumors; chromogranin, in 27 (72.9%) of 37; CD56, in 8 (100%) of 8; and neuron-specific enolase in 7 (87.5%) of 8 tumors. Treatment wise, among 30 patients (60%), 6 (20%) underwent surgery, including Wertheim hysterectomy (5) and simple hysterectomy (1); 8 (26.6%) underwent surgery with adjuvant treatment, and 10 patients (33.3%) were offered chemotherapy and/or radiotherapy. On follow-up (27 patients, or 54%) over 1 to 144 months, 16 patients (59.2%) were alive with disease over median duration of 9 months, and 7 (25.9%) were free of disease over median duration of 26.5 months. There were 5 recorded deaths. Thirteen tumors (48.1%) metastasized, most commonly to liver. In cases with early stage disease and adjuvant treatment, including radiotherapy, LCNEC histology fared well. This study forms the largest documented series on cervical neuroendocrine carcinomas from our country, testifying the current histopathologic classification system. Although SMCAs can be recognized on morphology, LCNECs need to be correctly identified because these can be misdiagnosed in the absence of neuroendocrine markers. Synaptophysin, chromogranin, and CD56 are optimal IHC markers. Small cell carcinomas, pure or mixed, are relatively more aggressive. All these tumors are best treated with multimodal therapy. Early stage disease treated with radical surgery and adjuvant treatment seems to increase survival. Despite aggressive treatment, prognosis is dismal. [Copyright &y& Elsevier]

Background: Cervical cancer is one of the most common cancers seen in developing countries, especially in India. Recent years have seen many new developments in various modalities used in the management of cervical cancer. Although it is important to remain abreast with these advancements, the availability of resources and challenges in practices across the country cannot be ignored. Materials and Methods: This is a conference update aiming at reviewing all major advancements with their due merit, which can influence the evidence in daily practice of treatment for cervical cancer in the developing nations. Pre-formulated guidelines questions developed by the scientific committee were discussed and voted by national and international faculty as well as delegates in the light of current evidence and available resources in developing countries for practice. Results: The results of these discussions and voting were compiled and are presented as guidelines for practice. Conclusion: These recommendations are aimed to help centers in developing countries to deliver and improve best care with available recourses to cervical cancer patients. [ABSTRACT FROM AUTHOR]

Purpose: To investigate diffusion-weighted imaging (DWI) as a response biomarker in patients undergoing chemoradiation for postoperative recurrences of cervical cancer. Materials and Methods: From October 2008 to March 2011, 20 patients were included. All underwent T2-weighted (T2W) and DWI before and after chemoradiation. Gross tumor volume (GTV), lateral extent, apparent diffusion coefficient (ADC), and presence of regions of focally restricted diffusion were determined at baseline. Response to chemoradiation was categorized as either partial or complete. Receiver operator characteristics (ROC) curve identified thresholds of GTV and ADC that best predict for partial response. Univariate and multivariate analysis were performed on SPSS version 15. Results: The median GTV was 24.5 cc (4.1-110 cc). Central and lateral disease was present in 8 and 12 patients, respectively. The median ADC was 1 ? 10-3 mm2/s (0.8-1.3 x 10-3 mm2/s) and 12/20 (60%) patients had focal restricted diffusion. Overall 10/20 patients had partial response. ROC analysis identified volume of 25 cc or higher [sensitivity = 80%, specificity = 80%, area under curve (AUC) = 0.76, P = 0.04] and ADC more than 1 x 10-3 mm2/s (sensitivity = 70%, specificity = 50%, AUC = 0.62; P = 0.34) to best predict for partial response. On univariate analysis bulky disease (77.7% vs. 27%; P = 0.03), lateral disease (66.6% vs. 25%; P = 0.08), and focal regions of restricted diffusion (66.6% vs. 25%; P = 0.06) predicted for partial response to chemoradiation. All factors continued to be significant on multivariate analysis. On restricting analysis to bulky tumors ADC greater than 0.95 x 10-3 mm>2/s predicted partial response with high sensitivity (85.7%) and specificity (100%) (AUC 0.96; P = 0.05). On univariate analysis lateral disease (P = 0.04), high baseline ADC (P = 0.07) predicted for partial response. Conclusions: Baseline ADC and focal regions of ADC restriction predict for partial response with moderate sensitivity and specificity in patients with postoperative recurrences of cervical cancer and need to be validated in larger cohort. [ABSTRACT FROM AUTHOR]

To evaluate clinical outcomes of CT-based adaptive intracavitary and interstitial brachytherapy (IC followed by IC-ISBT) in locally advanced cervical cancer (LACC) in resource-constrained settings. LACC patients treated with adaptive brachytherapy techniques were analyzed to evaluate treatment characteristics and clinical outcomes. The Kaplan-Meier method was used for survival analysis, and the log-rank test for univariate analysis. Out of 141 eligible patients with LACC, 87 (61.7%) patients received external beam radiotherapy (EBRT) in referral hospitals, while 54 (38.3%) were treated at our center. We divided our cohort into two groups: poor EBRT responder group (n = 70 [49.6%]) where IC-ISBT was adapted to achieve optimum tumor doses and OAR optimization group 71 (50.4%) where IC-ISBT was performed to reduce OAR doses. Median HRCTV-D90 dose was 88 Gy (range 70–109 Gy) with median HRCTV volume 33cc (range 15–96). Median D2cc doses to OARs were 90 Gy (range 70–107), 71 Gy (range 55–105) and 70 Gy (range 47–90) to bladder, rectum and sigmoid, respectively. At median follow-up of 32 months, 3-year local control (LC), locoregional control (LRC), disease-free survival (DFS) and overall survival (OS) were 83%, 75%, 64% and 72%, respectively. Subgroup analysis revealed significantly better outcomes for OAR optimization compared to poor EBRT responders, with 3-year LC (95% vs. 70.1%, p < 0.001), LRC (87.3% vs. 62.7%, p < 0.001), DFS (79.2% vs. 49.4%, p < 0.001), and OS (86.2% vs. 57.4%, p < 0.001) In resource-constrained settings, implementation of Adaptive IC-ISBT is a viable alternative for optimizing OAR doses in LACC. However proactive approach employing IC-ISBT for tumor dose-escalation from first fraction of BT is warranted for improving LC in poor EBRT responders. [ABSTRACT FROM AUTHOR]

Cervical cancer continues to be a major public health concern in India and other low- and middle-income countries. Tata Memorial Centre, India, has been at the forefront in providing treatment, developing best practice guidelines for low-cost efficacious interventions, conducting practice-changing randomized trials and engaging in regional and international collaborations for education and research in cervical cancer. This review summarizes how cervical cancer research and clinical care has evolved over the past two decades at the Tata Memorial Centre, right from testing low-cost public health screening of cervical cancers to the incorporation of the latest technological advancements and providing high-quality evidence for therapeutic management of cervical cancer. The various ongoing strategies for improving survival, toxicity reduction, translational research studies, educational activities and teaching programmes initiated by the Tata Memorial Centre at both national and international levels are discussed. [ABSTRACT FROM AUTHOR]

To report acute hematological toxicity (HT) in patients receiving post-operative bowel sparing intensity-modulated radiotherapy (IMRT) and cisplatin and its dosimetric predictors. Clinical database of Phase III trial (NCT01279135), that randomized patients to post-operative conformal or intensity modulated radiation therapy, was searched to select patient strata that received bowel sparing IMRT (50 Gy/25#/5 wks) and concurrent cisplatin (40 mg m–2). Pelvic bone marrow (BM) was retrospectively delineated in two sets: whole bone (WB), and freehand (FH) inner cavity of bone. Dose volume histograms (DVH) of BM were obtained. Receiver operating characteristic (ROC) curve identified DVH thresholds that predicted for Grade≥ II HT with highest specificity. Univariate and multivariate analysis was performed. Overall 75 patients received concurrent cisplatin. Grades I–V HT was observed in 38.7%, 42.7%, 14.7%, 0%, and 0% patients, respectively. Grade ≥ II leukopenia, neutropenia, anemia, and thrombocytopenia were observed in 26%, 40%, 26.5%, and 1.4% respectively. None of the HT resulted in treatment break. On univariate analysis, whole pelvis+ lumbar FH V30 >55% & V40>35%, whole pelvis WB and FH V40 > 35%, and lower pelvis WB and FH V40 >20% correlated for Grade ≥ II leucopenia and neutropenia. None of the BM dose volume constraints predicted for overall HT or neutropenia on multivariate analysis. The IMRT arm of NCT01279135 (PARCER study) that employed strict bowel constraints had unintentional but desirable BM sparing. None of the BM subvolume DVH parameters could be validated on multivariate analysis. The prospective study reports feasibility of bone marrow sparing with bowel sparing post-operative pelvic IMRT and concurrent chemotherapy for cervical cancer. The present study reports low incidence of hematological and gastrointestinal toxicity during post-operative chemoradiation with IMRT. As both whole bone and freehand pelvis BM contours predicted for HT, hence an easier method of whole bone contouring should continue to be used till further validation of more specific BM subvolumes becomes available. The study results highlight the need for further research into dose volume constraints during post-operative IMRT. [ABSTRACT FROM AUTHOR]

To evaluate clinical outcomes of recurrent gynaecological cancers treated with reirradiation (reRT) using advanced brachytherapy (BT) technique. Seventy-six women who underwent reRT with BT for gynaecological cancers at our institute between January 2000 and December 2019 were analysed to determine patient, disease and treatment characteristics and clinical outcomes. Descriptive analysis was used for demographics, and the Kaplan Meir method was used for survival analysis. Median age at recurrence was 55 years (Range: 35–73). Forty-three patients had recurrent cervical cancer with intact uterus, and 33 had recurrent vault/vaginal cancers post adjuvant RT. Eight patients received EBRT prior to BT (Range: 30–50Gy). Twenty-two patients (28.9%) received salvage chemotherapy before consideration of brachytherapy. Brachytherapy application was done using MUPIT in 38, Vienna applicator in 20, Syed Neblett in 8, central vaginal cylinder in 3, multicatheter intravaginal applicator in 2, tandem-ovoids in 4 and Houdek applicator in 1 patient. Median cumulative EQD2 for all courses of radiation was 108 Gy (IQR 92-123 Gy). At median follow up of 39 months, local control (LC), progression-free survival (PFS) and Overall survival (OS) at 2-years was 60%, 56.3%, and 72.9 respectively. Patients who had recurrences beyond 2 years had significantly better OS compared to early recurrences. Patients who received BT doses >40 Gy had a higher LC and PFS. Grade 3 to 4 late rectal toxicity was seen in 10 (13%), bladder toxicity in 6 (8%) and vaginal fibrosis in 24 (31%) patients. The use of advanced BT approach in reirradiation setting is a feasible and safe option in treatment of post-treatment recurrent cervical, endometrial, and vaginal cancers. [ABSTRACT FROM AUTHOR]

Brachytherapy (BT) for cervix cancer was listed as a level I priority and reduced number of implants and multiple fractions were recommended during COVID-19 pandemic. We present early clinical outcome of this approach. Patients treated with (chemo)radiotherapy and BT with single implant and multiple fractions BT were included. Treatment protocol included 3−5 fractions of 5−8.5 Gy with an aim to achieve point A dose of 70 Gy EQD2 10Gy (or HRCTV dose of >80 Gy EQD2 10Gy) in those undergoing intracavitary (IC) and HRCTV dose >85 Gy EQD2 10Gy in patients undergoing Intracavitary-Interstitial (IC/IS) whereas maintaining bladder (B2cc), rectum (R2cc), sigmoid (S 2cc) doses of 90, 75, and 75 Gy EQD2 3Gy. Time to event analysis was used to report oncological endpoints. Toxicity was reported using crude proportions. From April 2020 to March, 2021, 64 patients with stage IB2-IV received single implant and multi-fraction BT after external radiation of 45 Gy/25 fractions/5 weeks. Only 76.7% (n = 49) received concurrent chemotherapy. Median overall treatment time (OTT) was 56 days (38−131 days). Overall, 62.5% (n = 40) patients received IC and 37.5% (n = 24) received IC+IS. The median HRCTV was 34.7 cc (IQR 25−41). Median (IQR) point A dose, HRCTV D90, B2cc, R2cc, and S2cc for those undergoing IC was 74 Gy (71−78), 80 Gy (73−84), 86 Gy (82−89), 70 Gy (65−74), 65 Gy (59−73) respectively. For the IC+IS cohort, HRCTV D90, B2cc, R2cc, and S2cc was 84 Gy (78−89 Gy), 89 Gy (86−92), 70 Gy (67−74), 68 Gy (59−76). At a median follow-up of 16 months (5−27) the 2-year local control, pelvic control, cause specific and overall survival was 88%, 85.3%, 92.2%, and 81.3% respectively. Late gastrointestinal and genitourinary grade ≥III toxicities were 14% and 1.5% each. Abbreviated BT outcomes are encouraging for oncological outcomes despite delays in overall treatment time and omission of chemotherapy. Further mature follow up is needed. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 cm3 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 cm3 and HRCTV D90 dose was 87.2 ± 3.6Gy. The 0.1 cm3 and 2 cm3 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. [ABSTRACT FROM AUTHOR]

Background & objectives: There is limited information available on the temporal course of late stage radiotherapy adverse effects. The present study reports on the temporal course of late toxicities after chemoradiation and brachytherapy. Methods: Women with cervical cancer who presented with late toxicity after (chemo) radiation were included in the study. Grade of toxicity (Clinical Toxicity Criteria for Adverse Events version 4.03) and type of intervention were recorded at three-monthly interval for the first year and then six monthly until 24 months. Direct cost for the management of toxicity was calculated. Univariate analysis was performed to understand the impact of various factors on persistence of toxicity. Results: Ninety two patients were included in this study. Grades I, II, III and IV toxicities were observed in 50 (54%), 33 (36%), 7 (8%) and 2 (2%) patients, respectively, at first reporting. Patients spent a median of 12 (3-27) months with toxicity. At 12 months, 48/92 (52.2%) patients had a complete resolution of toxicity, whereas 27/92 (29.3%) patients had low grade (I-II) persistent toxicity. Only 6/92 (6.5%) patients who had grade III−IV toxicity had resolution to a lower grade. Four (4.3%) patients died due to toxicity. At 24 months, 9 (10%) patients continued to have grade ≥ III toxicity. On an average, 7 (2-24) interventions were required for the clinical management of late toxicity and median direct cost incurred was ₹ 50,625 (1,125-303,750). Interpretation & conclusions: In this study late radiation toxicity resolved within 12 months in more than half of patients. However, others are likely to have had persistent lower grade toxicity or progression to higher grade. Structured strategies are hence needed for the effective management of late toxicities. [ABSTRACT FROM AUTHOR]

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 cm3 had worse 3-year DFS than those with primary tumor volume ≤30 cm3 (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. [ABSTRACT FROM AUTHOR]

Objective(s): The objective of this study was to evaluate the clinical outcomes and prognostic factors affecting survival of cervical cancer patients presenting with lower third vaginal involvement. Materials/Methods: The patients with histologically proven invasive cervical cancer with clinical FIGO-2009 stage IIIA and IIIB with lower one-third vaginal involvement, treated with radio (chemo) therapy between 2010 and 2016 at our institution were retrospectively analyzed. Results: There were 118 cervical cancer patients with lower third vaginal involvement with median age of 56.5 years (Range: 33–77 years). Forty-five patients were of FIGO stage IIIA, 73 patients staged as stage IIIB at diagnosis with predominant squamous histology. At a median follow up of 30 months, 12 patients (10.1%) developed local vaginal recurrences and 4 patients (3.3%) had developed loco regional recurrences, 27 patients (23%) developed distant and 2 patients developed loco-regional and distant relapses. The 3- year DFS and OS rates were 61.5% and 69.8% respectively. The 3-year DFS and OS of patients with IIIA was significantly better than IIIB patients (71% vs 56%, p: 0.02 and 76% vs 66%, p: 0.01 respectively) on univariate analysis. Concurrent chemotherapy and absence of persistent disease emerged as independent predictors of survival on multi-variate analysis. Conclusion: The outcome of patients with FIGO IIIA is better than IIIB with lower vaginal involvement. Elderly patients, patients not receiving concomitant chemotherapy and presence of residual disease at BT are associated with poorer outcomes. • The 3-year DFS and OS rates of cervical cancer patients with lower vaginal involvement are 61.5% and 69.8% respectively. • The outcome of patients with FIGO IIIA is better than IIIB with lower vaginal involvement. • Elderly patients, no concomitant chemotherapy and presence of residual disease are associated with poorer survival. • Adaptive approach during brachytherapy yields better outcome in cervical cancer patients with lower vaginal involvement. [ABSTRACT FROM AUTHOR]

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. The study (NCT 01391065) recruited patients with residual or recurrent disease after hysterectomy. Patients underwent baseline T2 weighted (T2W) MRI, 18F-flouro-deoxyglucose (18F-FDG), 18F-flouro thymidine (18F-FLT) and 18F-flouromisonidazole (18F-F Miso) positron emission tomography (PET) and received external radiation (50 Gy/25 fractions for 5 weeks) and weekly cisplatin (40 mg/m2). 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. 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). Image-guided assisted radiation and brachytherapy are associated with good to excellent local control and survival in patients with vaginal recurrences of cervical cancer. [ABSTRACT FROM AUTHOR]

Objective: Extended-field radiotherapy (EFRT) with concurrent chemotherapy represents standard treatment in cervical cancer patients with para-aortic lymph nodal (PALN) metastasis. While EFRT with Intensity Modulated RT (IMRT) has been demonstrated to reduce toxicities, the dose thresholds for minimizing acute toxicity is not clear. The present study was undertaken to report the early toxicity with extended-field intensity-modulated radiotherapy (EF-IMRT) for carcinoma of the cervix in our cohort of patients and determine dose-volume parameters that predict =grade II haematological toxicity and diarrhoea. Methodology: This was a retrospective study of consecutive cervical cancer patients with PALN metastasis treated with EF-IMRT. Patients received rotational IMRT +/- neoadjuvant chemotherapy (NACT) and/or concurrent chemotherapy (45-50 Gy/25#/5 weeks) followed by high-dose rate brachytherapy. Acute haematological and gastrointestinal toxicity (diarrhoea and vomiting) was correlated with doses received by bowel and marrow. Receiver operator characteristics curves were used for deriving thresholds that predict for increased toxicity and tested on univariate and multivariate analysis. Finally, disease free and overall survival (DFS and OS) was calculated. Results: A total of 43 patients were included. One-fourth of the patients (11/43) received NACT and 88% received concurrent chemotherapy. Within the upfront EF-IMRT cohort, 22.6% and 9.7% patients developed grade =III haematological (HT) and gastrointestinal (GI) toxicity respectively, with an increase in HT (= grade III HT =67%) in patients receiving NACT (p = 0.007). In the entire cohort bone marrow Volume receiving 10 Gy (V10>) 90% correlated with an increase in = grade III HT (p = 0.05). No dose volume thresholds could be validated for GI toxicity. The OS and DFS at 2 years was 56% and 54%, respectively. Conclusion: EF-IMRT is a feasible option for cervical cancer patients with PALN involvement and is associated with acceptable grade III toxicity. Future studies need to focus on minimizing HT toxicity. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective With an aim to investigate the impact of Human Papilloma Virus (HPV) 16/18 infection on clinical outcomes in locally advanced cervical cancers treated with radical radio (chemo) therapy, we undertook this prospective study. Methods Between May 2010 and April 2012, 150 histologically proven cervical cancer patients treated with radio (chemo) therapy were accrued. Cervical biopsies/brushings were collected at pre-treatment, end of treatment and at 3 monthly intervals up to 24 months. Quantitative estimation of HPV 16/18 was done using real-time polymerase chain reaction (RT-PCR) and correlated with various clinical end-points. Results Out of 150 patients accrued, 135 patients were considered for final analysis. Pre-treatment HPV16/18 DNA was detected in 126 (93%) patients, with HPV-16 present in 91%. The mean log (± SD) HPV-16 and HPV-18 viral load at pre-treatment was 4.76 (± 2.5) and 0.14 (± 2.1) copies/10 ng of DNA, respectively. Though significant decline in viral load was observed on follow-ups ( p < 0.0001); by 9-month follow-up, 89 (66%) patients had persistence of HPV infection. Patients with persistent HPV 16/18 infection had a significantly higher overall and loco-regional relapses [44/89 (49%) and 29/89 (32%)] as compared to HPV clearance by 9 months [12/43 (28%) and 5/43 (11%)] with p = 0.024 and p = 0.02, respectively. Also, persistent HPV infection by 24-month showed a significant impact on loco-regional control (LRC) and recurrence-free survival (RFS). Conclusion In locally advanced cervical cancers treated with radical radio (chemo) therapy, persistent HPV 16/18 infection is significantly high in immediate post-treatment period and correlated with higher loco-regional, overall relapses and was also associated with early relapses. [ABSTRACT FROM AUTHOR]

Purpose To investigate dose-response relationship between vaginal doses and long-term morbidity. Methods and Materials Patients receiving adjuvant pelvic (chemo) radiation and brachytherapy for cervical cancer from January 2011 to December 2014 were included. Baseline vaginal length was determined clinically and from imaging at BT planning. Dose points were defined along mucosa and at 5 mm depth at 12, 3, 6, and 9 ‘o’ clock positions at every 2 cm from apex to introitus. Cumulative equivalent doses in 2 Gy were calculated. Vaginal stenosis was reported in reference to baseline length according to CTCAE version 3.0. Receiver operator characteristics curve was used to identify dose thresholds for univariate and multivariate analysis. Results Overall, 78 women with median age of 49 (32–71) years were included. The median dose at vaginal apex mucosa and 5 mm depth was 118 Gy 3 (78–198) and 81 Gy 3 (70–149) respectively. At median follow-up of 36 (18–60) months, vaginal stenosis ≥25%, and grade ≥ II telangiectasia was observed in 33.3% and 45.7%, respectively. On receiver operator characteristics analysis, apical mucosal dose >142 Gy 3 and recto-vaginal point dose >86 Gy 3 predicted for stenosis on univariate ( p = 0.02, p = 0.06) and multivariate analysis ( p = 0.04). The probability of stenosis increased from 32% at 70 Gy 3 , 38% at 80 Gy 3 , and 45% at 90 Gy 3 rectovaginal point dose. No correlation was observed between vaginal doses and telangiectasia and vaginal stenosis and sexual quality of life. Conclusion Vaginal apex mucosal dose >142 Gy 3 independently predicts for vaginal stenosis. [ABSTRACT FROM AUTHOR]

Cervical cancer is one of the most common cancers in women with an incidence of around 6.5 % of all the cancer in women worldwide. Early detection and adequate treatment according to staging improve the patient's life expectancy. Outcome prediction models might aid treatment decisions, but a systematic review on prediction models for cervical cancer patients is not available. We performed a systematic review for prediction models in cervical cancer following PRISMA guidelines. Key features that were used for model training and validation, the endpoints were extracted from the article and data were analyzed. Selected articles were grouped based on prediction endpoints i.e. Group1: Overall survival, Group2: progression-free survival; Group3: recurrence or distant metastasis; Group4: treatment response; Group5: toxicity or quality of life. We developed a scoring system to evaluate the manuscript. As per our criteria, studies were divided into four groups based on scores obtained in our scoring system, the Most significant study (Score > 60 %); Significant study (60 % > Score > 50 %); Moderately Significant study (50 % > Score > 40 %); least significant study (score < 40 %). A meta-analysis was performed for all the groups separately. The first line of search selected 1358 articles and finally 39 articles were selected as eligible for inclusion in the review. As per our assessment criteria, 16, 13 and 10 studies were found to be the most significant, significant and moderately significant respectively. The intra-group pooled correlation coefficient for Group1, Group2, Group3, Group4, and Group5 were 0.76 [0.72, 0.79], 0.80 [0.73, 0.86], 0.87 [0.83, 0.90], 0.85 [0.77, 0.90], 0.88 [0.85, 0.90] respectively. All the models were found to be good (prediction accuracy [c-index/AUC/R2] >0.7) in endpoint prediction. Prediction models of cervical cancer toxicity, local or distant recurrence and survival prediction show promising results with reasonable prediction accuracy [c-index/AUC/R2 > 0.7]. These models should also be validated on external data and evaluated in prospective clinical studies. [ABSTRACT FROM AUTHOR]