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Purpose: Women with locally advanced cervical cancer (LACC) undergoing primary platinum-based chemoradiotherapy and brachytherapy often experience toxicities. Normal-tissue complication probability (NTCP) models quantify toxicity risk and aid in optimizing radiation therapy to minimize side effects. However, it is unclear which predictors to include in an NTCP model. The aim of this systematic review was to provide an overview of the identified predictors contributing to gastrointestinal (GI), genitourinary (GU), and vaginal toxicities and insufficiency fractures for LACC., Methods and Materials: A systematic search was performed and articles evaluating the relationship between predictors and toxicities in women with LACC treated with primary chemoradiation were included. The Quality In Prognosis Studies tool was used to assess risk of bias, with high-risk studies being excluded from further analysis. Relationships between dose-volume parameters, patient and treatment characteristics, and toxicity endpoints were analyzed., Results: Seventy-three studies were identified. Twenty-six had a low or moderate risk of bias and were therefore included. Brachytherapy-related dose-volume parameters of the GI tract, including rectum and bowel equivalent dose in 2 Gy fractions (EQD2) D2 cm 3 , were frequently related to toxicities, unlike GU dose-volume parameters. Furthermore, (recto)vaginal point doses predicted toxicities. Few studies evaluated external beam radiation therapy dose-volume parameters and identified rectum EQD2 V30 Gy, V40 Gy, and V55 Gy, bowel and bladder EQD2 V40 Gy as toxicity predictors. Also, total reference air kerma and vaginal reference length were associated with toxicities. Relationships between patient characteristics and GI toxicity were inconsistent. The extent of vaginal involvement at diagnosis, baseline symptoms, and obesity predicted GU or vaginal toxicities. Only 1 study evaluated insufficiency fractures and demonstrated lower pretreatment bone densities to be associated., Conclusions: This review detected multiple candidate predictors of toxicity. Larger studies should consider insufficiency fractures, assess dose levels from external beam radiation therapy, and quantify the relationship between the predictors and treatment-related toxicities in women with LACC to further facilitate NTCP model development for clinical use., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Importance: Packed red blood cell (PRBC) transfusions are used to treat anemia in patients with cervical cancer undergoing radiotherapy (RT) owing to concerns of hypoxia-induced radioresistance. In the absence of high-quality evidence informing transfusion practices for patients receiving external beam RT (EBRT) and brachytherapy, various arbitrary hemoglobin target levels are used worldwide., Objective: To develop consensus statements to guide PRBC transfusion practices in patients with cervical cancer receiving curative-intent RT with EBRT and brachytherapy., Design, Setting, and Participants: This international Delphi consensus study was completed between November 1, 2019, and July 31, 2020. A total of 63 international clinical experts in gynecologic radiation oncology were invited; 39 (62%) accepted and consented to participate. Consensus building was achieved using a 3-round anonymous Delphi consensus method. Participants rated their agreement or disagreement with statements using a 5-point Likert scale. An a priori threshold of 75% or more was required for consensus., Main Outcomes and Measures: The preplanned primary outcome of this study was to assess hemoglobin transfusion thresholds and targets for both EBRT and brachytherapy by expert consensus., Results: Response rates of 100% (39 of 39), 92% (36 of 39), and 97% (35 of 36) were achieved for the first, second, and third rounds of surveys, respectively. Twenty-three experts (59%) practiced in Canada, 11 (28%) in the United States, 3 (8%) in South America, 1 (3%) in Europe, and 1 (3%) in Asia. Consensus was reached for 44 of 103 statements (43%), which were combined to form the final 27-statement consensus guideline. No specific hemoglobin transfusion threshold was agreed on by consensus for EBRT or brachytherapy. By consensus (89% [31 of 35]), a hemoglobin transfusion target for patients who receive a PRBC transfusion should be 9 g/dL or more and less than 12 g/dL., Conclusions and Relevance: This study presents the first international expert consensus guideline informing PRBC transfusion practices for patients with cervical cancer undergoing EBRT and brachytherapy. A minimum hemoglobin transfusion target of 9 g/dL was endorsed to balance tumor radiosensitivity with appropriate use of a scarce resource. Randomized clinical trials are required to evaluate the optimal transfusion threshold and target that maximize clinical benefit in this patient population.

Purpose: Accurate target definition is critical for the appropriate application of radiation therapy. In 2008, the Radiation Therapy Oncology Group (RTOG) published an international collaborative atlas to define the clinical target volume (CTV) for intensity modulated pelvic radiation therapy in the postoperative treatment of endometrial and cervical cancer. The current project is an updated consensus of CTV definitions, with removal of all references to bony landmarks and inclusion of the para-aortic and inferior obturator nodal regions., Methods and Materials: An international consensus guideline working group discussed modifications of the current atlas and areas of controversy. A document was prepared to assist in contouring definitions. A sample case abdominopelvic computed tomographic image was made available, on which experts contoured targets. Targets were analyzed for consistency of delineation using an expectation-maximization algorithm for simultaneous truth and performance level estimation with kappa statistics as a measure of agreement between observers., Results: Sixteen participants provided 13 sets of contours. Participants were asked to provide separate contours of the following areas: vaginal cuff, obturator, internal iliac, external iliac, presacral, common iliac, and para-aortic regions. There was substantial agreement for the common iliac region (sensitivity 0.71, specificity 0.981, kappa 0.64), moderate agreement in the external iliac, para-aortic, internal iliac and vaginal cuff regions (sensitivity 0.66, 0.74, 0.62, 0.59; specificity 0.989, 0.966, 0.986, 0.976; kappa 0.60, 0.58, 0.52, 0.47, respectively), and fair agreement in the presacral and obturator regions (sensitivity 0.55, 0.35; specificity 0.986, 0.988; kappa 0.36, 0.21, respectively). A 95% agreement contour was smoothed and a final contour atlas was produced according to consensus., Conclusions: Agreement among the participants was most consistent in the common iliac region and least in the presacral and obturator nodal regions. The consensus volumes formed the basis of the updated NRG/RTOG Oncology postoperative atlas. Continued patterns of recurrence research are encouraged to refine these volumes., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to assess the impact of the evolving role of the addition of chemotherapy to postoperative radiotherapy on oncological outcomes and toxicity in patients with early-stage cervical cancer after radical hysterectomy., Methods: Retrospective cohort study of patients with stage IB1-IIB FIGO 2009 cervical cancer treated from November 1999 to May 2015 by primary surgery and radiotherapy (46-50.4 Gy in 1.8-2.0 Gy fractions) with or without concurrent cisplatin (40 mg/m 2 , 5-6 weekly cycles) with or without a brachytherapy boost. Chemotherapy was allocated depending on the risk factors for recurrence. Incidences of all outcomes were calculated using Kaplan-Meier's methodology and compared by log-rank tests. Risk factors for recurrence and survival were identified using Cox's proportional hazards models., Results: A total of 154 patients were included, median follow-up was 9.6 years (IQR: 6.1-12.8). Five-year pelvic recurrence-free survival was 75.3%; 74.7% in patients with high-risk factors treated with radiotherapy; and 77.3% in those treated with chemoradiation (P=0.43). Distant metastasis-free survival at 5 years was 63.4%; 63.6% in high-risk patients after radiotherapy; and 57.1% after chemoradiation (P=0.36). Five-year overall survival was 63.9%: 66.8% and 51.6% after radiotherapy and after chemoradiation in patients with high-risk factors (P=0.37), respectively. Large tumor size was a risk factor for vaginal and pelvic recurrence, ≥2 involved lymph nodes was a significant risk factor for para-aortic recurrence and death. Mild treatment-related late toxicity was observed in 53.9% of the patients. Five-year severe (grade 3-5) late rectal, bladder, bowel, and vaginal toxicities were, respectively, 1.3%, 0%, 3.4%, and 0.9%. Any late severe toxicity was observed in 5.5% of patients treated with radiotherapy and in 15.3% of those treated with chemoradiation (P=0.07)., Conclusion: Postoperative (chemo)radiation for early-stage cervical cancer patients with risk factors for recurrence yields adequate pelvic tumor control, but overall survival is limited due to distant metastasis., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: The aim of this survey was to acquire an overview of the current management of cervical cancer with an emphasis on the early disease stages., Materials and Methods: A hyperlink to the survey was sent to the European Society of Gynaecological Oncology Office database. The survey contained 6 groups of questions regarding the characteristics of respondents, pretreatment workup, management of the early stages of cervical cancer, adjuvant treatment, fertility-sparing treatment, and surveillance., Results: In total, 566 responses were collected. The most frequent imaging method used in the workup was magnetic resonance imaging (74%), followed by computed tomography (54%) and positron emission tomography/computed tomography (25%). Conization or simple hysterectomy was a preferred procedure in stage T1a1 lymphovascular space invasion (LVSI)-positive for 79% of respondents, in stage T1a2 LVSI-negative for 58%, and in stage T1a2 LVSI-positive for 28%. Sentinel lymph node biopsy alone was reported in stage T1a1 by 17% and in stage T1b1 less than 2 cm by 9%, whereas systematic lymphadenectomy by 29% and 90% of respondents. Macrometastases, micrometastases, and isolated tumor cells in lymph nodes were considered indications for adjuvant treatment by 96%, 93%, and 68% of respondents, respectively. Neoadjuvant chemotherapy was reported by 28% and 19% of respondents in fertility-sparing and nonsparing management in stage T1b1. Over 60% of respondents recommend primary surgery for their patients with T1b2 N0 disease and 81% of them use a combination of adverse prognostic factors as indication for adjuvant radiotherapy in pN0 disease., Conclusions: The results of this survey indicate considerable differences in the workup and treatment of cervical cancer in current clinical practice.

Objective: Sexual problems among cervical cancer survivors may in part be caused by reduced vaginal blood flow due to damaged hypogastric nerves during radical hysterectomy with pelvic lymphadenectomy and/or by radiation-induced vaginal changes after pelvic radiotherapy. A nerve-sparing modification of radical hysterectomy (NSRH) may preserve vaginal blood flow. Vaginal blood flow during sexual arousal was compared between different treatment modalities., Methods: We investigated premenopausal women treated for early-stage cervical cancer with radical hysterectomy (n = 29), NSRH (n = 28), NSRH with radiotherapy (n = 14), and controls (n = 31). Genital arousal and subjective sexual arousal in response to sexual stimuli were measured using vaginal photoplethysmography and a questionnaire. Results were compared by using a between-study (treatment groups) by within-study (stimulus) design., Results: Participants were aged 29 to 51 years (mean, 42 years) and at 1 to 14 years (mean, 5 years) after treatment. Measured vaginal blood flow in women treated with NSRH was similar to controls. Women treated with radical hysterectomy had a significantly lower vaginal blood flow compared with controls overall and lower compared with the NSRH group during sexual stimulation. Women treated with radiotherapy had a vaginal blood flow intermediate between the other groups without significant differences. The erotic films were equally effective in enhancing subjective sexual arousal among treatment groups., Conclusions: Cervical cancer treatment with radical hysterectomy disrupts the vaginal blood flow response, and this may be prevented by conducting an NSRH. Treatment with radiotherapy did not significantly impact vaginal blood flow, but further investigation is needed with a larger sample.

In this dosimetric comparison study it was shown that IMPT with robust planning reduces dose to surrounding organs in cervical and endometrial cancer treatment compared with IMRT. Especially for the para-aortic region, clinically relevant dose reductions were obtained for kidneys, spinal cord and bowel, justifying the use of proton therapy for this indication., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Chemoradiation (RT-CT) is standard treatment for locally advanced cervical cancer (LACC). This study tried to establish if radiotherapy combined with hyperthermia (RT-HT) should be preferred in bulky and/or FIGO-stage ⩾III., Methods: In this open-label, multicenter randomized trial, patients with LACC were randomly assigned by a computer-generated, biased coin minimization technique to RT-CT or RT-HT. Central randomization was done with stratification by FIGO-stage, tumour diameter and nodal status. Primary endpoint was event free survival (EFS). Secondary endpoints were pelvic recurrence free survival (PRFS), overall survival (OS) and treatment related toxicity. Analysis was done by intention to treat., Results: The trial was closed prematurely (87 of 376 planned patients enrolled: 43 RT-CT; 44 RT-HT). Median follow-up time was 7.1 years. The cumulative incidence of an event was 33% in the RT-CT group and 35% in the RT-HT group. The corresponding hazard rate (HR) for EFS was 1.15 (CI: 0.56-2.36, p=0.7). Also the hazards for PRFS (0.94; CI 0.36-2.44) and OS (1.04; CI 0.48-2.23) at 5 years were comparable between both treatment arms as was grade ⩾3 radiation related late toxicity (6 RT-CT and 5 RT-HT patients)., Conclusion: After 25% of intended accrual, data suggest comparable outcome for RT-CT and RT-HT., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Purpose: The purpose of this study was to assess variability in contouring the gross tumor volume (GTV) and clinical target volume (CTV) of 3 clinical cervix cancer cases by a cohort of international experts in the field in preparation for the development of an online teaching atlas., Methods and Materials: Twelve international experts participated. Three clinical scenarios: node positivity (PLN), retroverted uterus (RV), and parametrial invasion (PI) were used. Sagittal and axial magnetic resonance images of the clinical cases were downloaded to participants' treatment planning systems for contouring. The GTV/cervix/uterus/parametria/vagina and nodal CTV were contoured. Contour consensus was assessed for sensitivity/specificity using an expectation maximization algorithm called Simultaneous Truth and Performance Level Estimation and experts' overall agreement was summarized by kappa statistics., Results: Agreement for GTV in the 3 clinical cases was high (Simultaneous Truth and Performance Level Estimation sensitivity, 0.54-0.92; specificity, 0.97-0.98; and kappa measure for PLN, RV, and PI was 0.86, 0.76, and 0.42; P < .0001). Moderate to substantial agreement was seen for nodal CTV (kappa statistics for PLN, RV, and PI was 0.65, 0.58, and 0.62; P < .0001), uterus (kappa for PLN, RV, and PI was 0.45, 0.74, and 0.77; P < .0001), and parametria (kappa for PLN, RV, and PI was 0.49, 0.62, and 0.50; P < .0001). Contouring heterogeneity was greatest for the cervix (kappa measure for PLN, RV, and PI was 0.15, 0.4, and 0.24; P < .0001) and vagina (kappa for PLN, RV, and PI was 0.47, 0.36 and 0.46; P < .0001), reflecting difficulties in determining the interface between GTV and these tissues., Conclusion: Kappa statistics of the different CTV components generally demonstrated moderate to substantial agreement among international experts in the field of gynecological radiation therapy. Further planning target volume margins accounting for organ motion and setup errors are a necessary addition to the CTV., (Copyright © 2015. Published by Elsevier Inc.)

Background and Purpose: We investigated the effects of socio-demographic, treatment- and tumor-specific determinants on the risk of developing a second malignancy among patients treated for cervical cancer., Material and Methods: We included patients with a first cervical cancer (N=12,048) from the Netherlands Cancer Registry (NCR), 1989-2008. Standardized incidence ratios (SIR) and absolute excess risks (AER) per 10,000 person-years were calculated to estimate the burden of second cancers in cervical cancer survivors. Incidence rate ratios (IRR) were computed to identify predictors for second cancers among cervical cancer survivors., Results: During the study period, 676 (5.6%) patients were diagnosed with a second cancer. Smoking-related cancers contributed the most to the overall burden of second cancers (AER=21) and risks remained elevated after 10 years of follow-up (SIR=1.8, 95% CI: 1.4-2.2), yet it decreased markedly in the younger birth cohorts. Cervical cancer survivors who underwent radiotherapy were at higher risk for a second tumor when compared to those without radiotherapy, especially at smoking-related sites (IRR=1.6 (1.2-2.3))., Conclusion: Patients with cervical cancer had a significantly increased risk for a second cancer compared to the general population, especially for smoking- and irradiation-related tumors. Long-term follow-up suggested the importance of smoking cessation and the benefits of counseling cervical cancer patients accordingly, particularly those who received radiotherapy., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objective: Conventional radical hysterectomy with pelvic lymphadenectomy (RHL) for early-stage cervical cancer is associated with significant bladder, anorectal, and sexual dysfunction. Nerve-sparing modification of RHL (NS-RHL) has been developed with the aim to reduce surgical treatment-related morbidity. Postoperative radiation therapy (RT) is offered to patients with unfavorable prognostic features to improve local control. The aim of the study was to assess self-reported morbidity of various types of treatment in cervical cancer patients., Methods: Self-reported symptoms were prospectively assessed before and 1 and 2 years after treatment by the Dutch Gynaecologic Leiden Questionnaire., Results: Included were 229 women (123 NS-RHL and 106 conventional RHL). Ninety-four (41%) received RT. Up to 2 years (response rate, 81%), women reported significantly more bowel, bladder, and sexual symptoms compared with the pretreatment situation. No significant difference was found between the conventional RHL and NS-RHL with the exception of the unexpected finding that a smaller percentage in the NS-RHL group (34% vs 68%) complained about numbness of the labia and/ or thigh. Radiation therapy had a negative impact on diarrhea, urine incontinence, lymphedema, and sexual symptoms (especially a narrow/short vagina)., Conclusions: In the current longitudinal cohort study, treatment for early-stage cervical cancer was associated with worse subjective bladder, anorectal, and sexual functioning, irrespective of the surgical procedure used. Postoperative RT resulted in a significant deterioration of these functions. The results have to be interpreted with caution in view of the study design and method used.

Purpose: To determine current practice patterns with regard to gynecologic high-dose-rate (HDR) brachytherapy among international members of the Gynecologic Cancer Intergroup (GCIG) in Japan/Korea (Asia), Australia/New Zealand (ANZ), Europe (E), and North America (NAm)., Methods and Materials: A 32-item survey was developed requesting information on brachytherapy practice patterns and standard management for Stage IB-IVA cervical cancer. The chair of each GCIG member cooperative group selected radiation oncology members to receive the survey., Results: A total of 72 responses were analyzed; 61 respondents (85%) used HDR. The three most common HDR brachytherapy fractionation regimens for Stage IB-IIA patients were 6 Gy for five fractions (18%), 6 Gy for four fractions (15%), and 7 Gy for three fractions (11%); for Stage IIB-IVA patients they were 6 Gy for five fractions (19%), 7 Gy for four fractions (8%), and 7 Gy for three fractions (8%). Overall, the mean combined external-beam and brachytherapy equivalent dose (EQD2) was 81.1 (standard deviation [SD] 10.16). The mean EQD2 recommended for Stage IB-IIA patients was 78.9 Gy (SD 10.7) and for Stage IIB-IVA was 83.3 Gy (SD 11.2) (p = 0.02). By region, the mean combined EQD2 was as follows: Asia, 71.2 Gy (SD 12.65); ANZ, 81.18 (SD 4.96); E, 83.24 (SD 10.75); and NAm, 81.66 (SD, 6.05; p = 0.02 for Asia vs. other regions).The ratio of brachytherapy to total prescribed dose was significantly higher for Japan (p = 0.0002)., Conclusion: Although fractionation patterns may vary, the overall mean doses administered for cervical cancer are similar in Australia/New Zealand, Europe, and North America, with practitioners in Japan administering a significantly lower external-beam dose but higher brachytherapy dose to the cervix. Given common goals, standardization should be possible in future clinical trials., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: Accurate target definition is vitally important for definitive treatment of cervix cancer with intensity-modulated radiotherapy (IMRT), yet a definition of clinical target volume (CTV) remains variable within the literature. The aim of this study was to develop a consensus CTV definition in preparation for a Phase 2 clinical trial being planned by the Radiation Therapy Oncology Group., Methods and Materials: A guidelines consensus working group meeting was convened in June 2008 for the purposes of developing target definition guidelines for IMRT for the intact cervix. A draft document of recommendations for CTV definition was created and used to aid in contouring a clinical case. The clinical case was then analyzed for consistency and clarity of target delineation using an expectation maximization algorithm for simultaneous truth and performance level estimation (STAPLE), with kappa statistics as a measure of agreement between participants., Results: Nineteen experts in gynecological radiation oncology generated contours on axial magnetic resonance images of the pelvis. Substantial STAPLE agreement sensitivity and specificity values were seen for gross tumor volume (GTV) delineation (0.84 and 0.96, respectively) with a kappa statistic of 0.68 (p < 0.0001). Agreement for delineation of cervix, uterus, vagina, and parametria was moderate., Conclusions: This report provides guidelines for CTV definition in the definitive cervix cancer setting for the purposes of IMRT, building on previously published guidelines for IMRT in the postoperative setting., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: To report response rate, pelvic tumor control, survival, and late toxicity after treatment with combined radiotherapy and hyperthermia (RHT) for patients with locally advanced cervical carcinoma (LACC) and compare the results with other published series., Methods and Materials: From 1996 to 2005, a total of 378 patients with LACC (International Federation of Gynecology and Obstetrics Stage IB2-IVA) were treated with RHT. External beam radiotherapy (RT) was applied to 46-50.4 Gy and combined with brachytherapy. The hyperthermia (HT) was prescribed once weekly. Primary end points were complete response (CR) and local control. Secondary end points were overall survival, disease-specific survival, and late toxicity. Patient, tumor, and treatment characteristics predictive for the end points were identified in univariate and multivariate analyses., Results: Overall, a CR was achieved in 77% of patients. At 5 years, local control, disease-specific survival, and incidence of late toxicity Common Terminology Criteria for Adverse Events Grade 3 or higher were 53%, 47%, and 12%, respectively. In multivariate analysis, number of HT treatments emerged as a predictor of outcome in addition to commonly identified prognostic factors., Conclusions: The CR, local control, and survival rates are similar to previously observed results of RHT in the randomized Dutch Deep Hyperthermia Trial. Reported treatment results for currently applied combined treatment modalities (i.e., RT with chemotherapy and/or HT) do not permit definite conclusions about which combination is superior. The present results confirm previously shown beneficial effects from adding HT to RT and justify the application of RHT as first-line treatment in patients with LACC as an alternative to chemoradiation.

Purpose: To develop an atlas of the clinical target volume (CTV) definitions for postoperative radiotherapy of endometrial and cervical cancer to be used for planning pelvic intensity-modulated radiotherapy., Methods and Materials: The Radiation Therapy Oncology Group led an international collaboration of cooperative groups in the development of the atlas. The groups included the Radiation Therapy Oncology Group, Gynecologic Oncology Group, National Cancer Institute of Canada, European Society of Therapeutic Radiology and Oncology, and American College of Radiology Imaging Network. The members of the group were asked by questionnaire to define the areas that were to be included in the CTV and to outline theses areas on individual computed tomography images. The initial formulation of the group began in late 2004 and culminated with a formal consensus conference in June 2005., Results: The committee achieved a consensus CTV definition for postoperative therapy for endometrial and cervical cancer. The CTV should include the common, external, and internal iliac lymph node regions. The upper 3.0 cm of the vagina and paravaginal soft tissue lateral to the vagina should also be included. For patients with cervical cancer, or endometrial cancer with cervical stromal invasion, it is also recommended that the CTV include the presacral lymph node region., Conclusion: This report serves as an international template for the definition of the CTV for postoperative intensity-modulated radiotherapy for endometrial and cervical cancer.