Image-guided Brachytherapy For Cervical Cancer Research Articles

Outcome and toxicity of chemoradiation using volumetric modulated arc therapy followed by 3D image-guided brachytherapy for cervical cancer: Vietnam National Cancer Hospital experience.

Volumetric modulated arc therapy (VMAT) and 3D image-guided brachytherapy (3D-IGBT) have recently been introduced in Vietnam for the treatment of locally advanced cervical cancer. This study aims to assess the outcomes and toxicities of chemoradiation using VMAT followed by 3D-IGBT in Vietnamese cervical cancer patients. A prospective interventional study on 72 patients with 2018 International Federation of Gynecology and Obstetrics (FIGO) stage IB3-IIIC2 disease who underwent concurrent chemoradiation using VMAT, followed by 3D-IGBT according to EMBRACE-II protocol. Primary endpoints were locoregional control; secondary endpoints were systemic control and toxicity. Median body volume received 43 Gy was 1589.1 cm3 (range 1214.8-2574.8). Median high-risk clinical target volume (CTV-HR) was 18.8 cm3 (range 8.6-61.2) with a median dose to 90% (D90) of CTV-HR of 90.6 Gy (range 86.8-99.6). Mean doses to 2cc (D2cc) of bladder, rectum, and sigmoid were 75.8, 55.2, and 62.1 Gy, respectively. At median 19-month follow-up (range 12-25), locoregional control and systemic control were 95.8% and 81.9%, respectively. Systemic control was the lowest in N2 disease (54.5%). Grade ≥ 3 acute toxicities were less than 10%, except neutropenia (31.9%). Extended-field radiation increased significantly nausea, fatigue, and thrombocytopenia. No grade ≥ 3 proctitis or cystitis; 8.3% had grade 3 vaginal stenosis. VMAT-based chemoradiation therapy followed by 3D-IGBT achieved high locoregional control with manageable toxicities in locally advanced cervical cancer. Systemic control correlated with disease stage.

Saturday, June 18, 20229:30 AM - 10:30 AM GPP06 Presentation Time: 9:30 AM: Image-Guided Cervical Cancer Brachytherapy: Summary of Consensus Recommendations from the Society for Abdominal Radiology and American Brachytherapy Society

<h3>Purpose</h3> To summarize recommendations regarding imaging guidance for cervical cancer brachytherapy implant placement from the Society of Abdominal Radiology (SAR) and American Brachytherapy Society (ABS). <h3>Materials and Methods</h3> A comprehensive literature search was conducted on PubMed for image-guided cervical cancer brachytherapy (BT) using radiography, ultrasound (US), computed tomography (CT), and magnetic resonance imaging (MRI). Original research studies were included for evaluation if they included sensitivity and specificity of tumor detection, complication rates, or additional quantitative imaging results directly related to brachytherapy, such as geometric distortion measurements. The literature review was evaluated by an expert panel of members from the Society for Abdominal Radiology (SAR) and American Brachytherapy Society (ABS). These data were analyzed to determine an overall level of evidence for each recommendation and the subsequent strength of each claim. <h3>Results</h3> Three-dimensional (3D) imaging is recommended for treatment planning whenever feasible due to the rate of toxicities ≥ Grade 3 decreasing from between 0-13.5% with 2D planning to 0-5.8% with 3D planning. US guidance is highly recommended for tandem selection and insertion to reduce uterine perforation rates from 2.3-34%/insertion without US-guidance to 0-1.4%/insertion with US. US-guided interstitial needle placement is feasible when post-implant 3D imaging is available for treatment planning. Post-implant CT is recommended over orthogonal radiography to reduce genitourinary and gastrointestinal complications and evaluate proper applicator positioning. Tumor visualization is optimal on T2-weighted (T2w) MRI, which also provides improved specificity for assessment of parametrial invasion. CT-based treatment planning should refer to prior MRI for high risk-clinical target volume (HR-CTV) contouring, when available. Treatment planning on MRI is highly recommended for HR-CTV delineation, and post-applicator imaging should include at minimum both a 2D sagittal T2w and 3D axial T2w fast spin echo-based sequence. <h3>Conclusions</h3> Imaging-guidance for cervical brachytherapy implant placement is now standard-of-care. 3D imaging with MRI is highly recommended for treatment planning purposes, although CT-based planning also results in fewer complications as compared to 2D planning techniques. Ultrasound is useful for applicator placement, but application to treatment planning is limited.

Preliminary Analysis Of Early And Late Radiation Responses In 3D Image-Guided Brachytherapy For Cervical Cancer

Rationale – The use of 3D image-guided brachytherapy (3D-IGBT) allows adequately optimizing the dose distribution to bring a target therapeutic dose to clinical target volume (CTV), thereby minimizing an impact on critical organs, while ensuring a decrease in the incidence and severity of radiation-caused complications. Use of 3D-IGBT also allows improving the quality of life in patients with cervical cancer. Objective – To conduct a preliminary analysis of the incidence of early and late radiation responses in 3D-IGBT of locally advanced cervical cancer (LACC). Materials and Methods – The objects of our study were female patients with stages IIB and IIIB of cervical squamous cell carcinoma, without confirmed metastases, preceding chemotherapy (CHT) and/or radiation therapy (RT), and surgical interventions in this localization, who underwent combined chemoradiotherapy during the study. Results – Statistically significant results were obtained when analyzing the incidence of late radiation responses. It is important to point out that when assessing early toxicity in the main group with 3D-IGBT, grade 3 responses were not diagnosed, while in the control group, they were observed in 4 (9.1%) women. For instance, the manifestation of grade 3 delayed radiation injuries in the rectum was diagnosed in 3 (6.8%) women in the control group, while in the main group, they were not detected. Grade 2 cystitis was observed in a smaller number of women in the group with 3D-IGBT, compared with the control group (9.1% vs. 13.6%, p&lt;0.05). Grade 3 delayed radiation responses in the bladder were diagnosed in 4 (9.1%) women in the control group, whereas among the patients of the main group with 3D-IGBT, they were not recorded at all (p &lt;0.05). Grade II reactions in the vaginal mucosa and cervix were diagnosed more often in the control group (16.7% vs. 13.6%, p&lt;0.05). Conclusion – Hence, the method we have used to optimize the treatment of LACC by means of 3D planning in accordance with toxicity criteria exhibited a definite advantage, compared with RT with 2D planning. Based on the results of our research, we concluded that optimization of RT for LACC using 3D-IGBT created clinically favorable conditions for effective therapy: it reduced the risk of displacement of the applicators and decreased an impact on the patient via reducing the total radiation doses and incidence of severe early and late toxic effects, providing good outcomes of local control regardless of tumor size and clinical stage.

Contemporary image-guided cervical cancer brachytherapy: Consensus imaging recommendations from the Society of Abdominal Radiology and the American Brachytherapy Society

To present recommendations for the use of imaging for evaluation and procedural guidance of brachytherapy for cervical cancer patients. An expert panel comprised of members of the Society of Abdominal Radiology Uterine and Ovarian Cancer Disease Focused Panel and the American Brachytherapy Society jointly assessed the existing literature and provide data-driven guidance on imaging protocol development, interpretation, and reporting. Image-guidance during applicator implantation reduces rates of uterine perforation by the tandem. Postimplant images may be acquired with radiography, computed tomography (CT), or magnetic resonance imaging (MRI), and CT or MRI are preferred due to a decrease in severe complications. Pre-brachytherapy T2-weighted MRI may be used as a reference for contouring the high-risk clinical target volume (HR-CTV) when CT is used for treatment planning. Reference CT and MRI protocols are provided for reference. Image-guided brachytherapy in locally advanced cervical cancer is essential for optimal patient management. Various imaging modalities, including orthogonal radiographs, ultrasound, computed tomography, and magnetic resonance imaging, remain integral to the successful execution of image-guided brachytherapy.

Usefulness of Metal Artifact-reduced Reconstruction for Image-guided Brachytherapy for Cervical Cancer

To evaluate the usefulness of single-energy metal artifact reduction (SEMAR) for target delineation in brachytherapy for cervical cancer patients with metal hip implants. A series of four definitive brachytherapy sessions in the same patient was analyzed. At each brachytherapy session, the identical set of computed tomography images was subjected with or without SEMAR treatment. For both SEMAR-treated and -untreated sets, five radiation oncologists delineated the high-risk clinical target volume (HR-CTV), bladder, and rectum, for which the volume, Dice coefficient, and the dose volume parameters were compared between SEMAR-treated and -untreated datasets. The bladder volume was significantly greater in the SEMAR-treated datasets compared with the SEMAR-untreated datasets. Importantly, for the bladder, Dice coefficient among five radiation oncologists was significantly higher for the SEMAR-treated datasets compared with the SEMAR-untreated datasets. These effects of SEMAR treatment were not evident for HR-CTV and the rectum. These data indicate that SEMAR treatment contributes to improve delineation of the bladder in brachytherapy for cervical cancer patients with metal hip implants.

Morbidity following image-guided brachytherapy for cervical cancer: Patient and treatment related factors

PurposeThis retrospective study aims to assess factors associated with the occurrence of toxicity after brachytherapy (BT), as boost after external beam radiotherapy (EBRT) for treatment of invasive cervix carcinoma. METHODS AND MATERIALSAll consecutive patients diagnosed with cervical carcinoma, and treated with concurrent radiochemotherapy from August 2017 to January 2020 were retrospectively included. An isodose conformation index (ICI) was developed to assess the percentage of the prescription isodose contained within the intermediate risk clinical target volume (IR-CTV). ResultsEighty-one patients with invasive cervix carcinoma from stage IB to stage IVa were included. Thirty-two (40%) and 49 (60%) patients were treated with Pulsed Dose Rate (PDR) and High Dose Rate (HDR) BT, respectively. Median follow-up was 19.6 months (5.6–41.2). The main factors associated with development of gastrointestinal toxicity were: the median volume of the prescription isodose (67.9cm[3] [37.6–92.9] vs. 49.1cm[3] [34.5–53.5], p = 0.05), the value of ICI (59% [51%-83%] vs. 86% [65%-96%], p = 0.01), the median equivalent dose delivered to the sigmoid (D2cc= 58.4 GyEQD2 [53.9–61.1] vs. 55.2 GyEQD2 [52.8–57.5], p = 0.06) and the median equivalent dose delivered to the IR-CTV (D90= 63.9 GyEQD2 [60.6–66.4] vs. 61.2 GyEQD2 [59.4–64.5], p = 0.03). The proportion of patients who received EBRT lymph node boost was higher in patients who developed urinary toxicity than in patients who did not (57.1% vs. 28.6%, p = 0.08). Anticoagulant (p = 0.02) and antiaggregant therapy (p = 0.01) were associated with occurrence of both urinary and gastrointestinal toxicity. ConclusionSOur study confirms the predictive value of irradiated volume in the occurrence of gastrointestinal toxicity, as well as the need for a better conformation to the target volume. Precautions should be considered in patients with vascular comorbidities.

Dose rate in the highest irradiation area of the rectum correlates with late rectal complications in patients treated with high-dose-rate computed tomography-based image-guided brachytherapy for cervical cancer.

The purpose of this study was to evaluate the effect of dose rate to the rectum on late rectal complications in patients treated with computed tomography (CT)-based image-guided brachytherapy (IGBT) for cervical cancer. The subjects were 142 patients with cervical cancer who underwent Ir-192 high-dose-rate (HDR)-IGBT between March 2012 and January 2018. The dose rate to the rectum was calculated using in-house software. The minimum, mean and maximum effective dose rate (EDR) was calculated for voxels of the rectal volume covered by cumulative doses >D0.1cc, >D2cc, and > D5cc. The average EDR of three to four brachytherapy sessions was calculated (EDR for patients; EDRp). The total dose of the rectum was calculated as the biologically equivalent dose in 2-Gy fractions (EQD2). The associations between EDRp for D0.1cc, D2cc, and D5cc and the respective rectal EQD2 values with late rectal complications were then analyzed. The median follow-up period was 40 months. Patients with rectal complications of ≥Grade 1 received a significantly higher mean EDRp for D0.1cc–5cc and had a greater EQD2 for D0.1cc–5cc. Multivariate analysis was performed using the mean EDRp for D2cc, EQD2 for D2cc, heavy smoking and BMI. Of these four variables, mean EDRp for D2cc (HR = 3.38, p = 0.004) and EQD2 for D2cc (HR = 2.59, p = 0.045) emerged as independent predictors for late rectal complications. In conclusion, mean EDRp and EQD2 were associated with late rectal complications in patients treated with HDR CT-based IGBT for cervical cancer.

Preliminary survey of 3D image-guided brachytherapy for cervical cancer at representative hospitals in Asian countries

3D image-guided brachytherapy (3D-IGBT) has become a standard therapy for cervical cancer. However, the use of 3D-IGBT is limited in East and Southeast Asia. This study aimed to clarify the current usage patterns of 3D-IGBT for cervical cancer in East and Southeast Asia. A questionnaire-based survey was performed in 11 countries within the framework of the Forum for Nuclear Cooperation in Asia. The questionnaire collected the treatment information of patients with cervical cancer who underwent 3D-IGBT. The cumulative external beam radiotherapy and 3D-IGBT doses were summarized and normalized to a biological equivalent dose of 2 Gy per fraction (EQD2) using a linear-quadratic model. Of the 11 institutions representing the participating countries, six (55%) responded to the questionnaire. Overall, data of 36 patients were collected from the six institutions. Twenty-one patients underwent whole-pelvic irradiation and 15 underwent whole-pelvic irradiation with central shielding. Patients received a median of four treatment sessions of 3D-IGBT (range, 2–6). All 3D-IGBT sessions were computed tomography (CT)-based and not magnetic resonance image-based. The median doses to the high-risk clinical target volume D90, bladder D2cc, rectum D2cc and sigmoid colon D2cc were 80.9 Gy EQD2 (range, 58.9–105.9), 77.7 Gy EQD2 (range, 56.9–99.1), 68.0 Gy EQD2 (range, 48.6–90.7) and 62.0 Gy EQD2 (range, 39.6–83.7), respectively. This study elucidated the current patterns of 3D-IGBT for the treatment of cervical cancer in East and Southeast Asia. The results indicate the feasibility of observational studies of CT-based 3D-IGBT for cervical cancer in these countries.

A 3-year follow-up study of radiotherapy using computed tomography–based image-guided brachytherapy for cervical cancer

Outcomes for patients with Stage IB1–IVA cervical cancer treated with computed tomography (CT)-based image-guided brachytherapy (IGBT) were examined in this study. A total of 84 patients were analyzed between March 2012 and June 2015. Whole-pelvic radiotherapy with a central shield was performed for each patient, and the total pelvic sidewall dose was 50 Gy. IGBT was delivered in 2–4 fractions. The initial prescription dose (6.8 Gy) was delivered at Point A, and the dose distribution was modified manually by graphical optimization. The total dose was calculated as the biologically equivalent dose in 2 Gy fractions (EQD2). Concurrent chemotherapy was administered to 64 patients (76%). The median follow-up period was 36 months (range 2–62 months). The 3-year overall survival, local control, and progression-free survival rates were 94%, 89% and 81%, respectively. The mean EQD2 for HR-CTV D90 was 73.4 Gy, and the EQD2 for HR-CTV D90 was not significantly associated with the local control rate. In multivariate analysis, adenocarcinoma (P = 0.03) and tumor size ≥45 mm (P = 0.06) were risk factors for local control. The patients were divided into four groups based on histology (squamous cell carcinoma vs adenocarcinoma) and tumor size (<45 vs ≥45 mm). Those with large adenocarcinomas had significantly worse outcomes. In conclusion, CT-based IGBT achieved favorable local control, but different treatment strategies may be necessary for large adenocarcinomas.

Rectal Dose-Volume Parameters and a Source Strength of Ir-192 are Significant Independent Predictors of Late Rectal Morbidity in Patients with Computed Tomography-Based Image-Guided Brachytherapy for Cervical Cancer

Rectal Dose-Volume Parameters and a Source Strength of Ir-192 are Significant Independent Predictors of Late Rectal Morbidity in Patients with Computed Tomography-Based Image-Guided Brachytherapy for Cervical Cancer

Computed tomography-based image-guided brachytherapy for cervical cancer: correlations between dose-volume parameters and clinical outcomes.

This study evaluated the oncologic outcomes and complications of cervical cancer patients in terms of CT-based image-guided brachytherapy (IGBT) parameters. Of 68 cervical cancer patients treated with definitive radiotherapy/concurrent chemoradiotherapy, most received whole-pelvis external beam RT (EBRT) of 40 Gy in 20 fractions, pelvic EBRT with central shield of 10 Gy in 5 fractions, and CT-based IGBT of 18 Gy in 3 fractions prescribed to point A. Cumulative EBRT and IGBT doses were calculated as the total equivalent dose in 2 Gy fractions (EQD2). The median follow-up was 31 (3–52) months. The 2-year overall survival, local control, pelvic control, and disease-free survival rates of the 68 patients were 92%, 83%, 82% and 73%, respectively. The HR-CTV D90, length from the tandem axis to left/right margin of the HR-CTV (T-LR), and HR-CTV volume were significant IGBT parameters for predicting local/pelvic control. Patients who received an HR-CTV D90 of >60 Gy, compared with ≤60 Gy, had significantly better local/pelvic control. Furthermore, 70 Gy was a marginally significant HR-CTV D90 cut-off affecting local control. T-LR was an independent IGBT parameter predicting local/pelvic control on multivariate analysis. Three patients developed Grade 3 or higher treatment-related complications. The D2cm3 of organs at risk were not significant predictors of complications. Future challenges for further improving outcomes include additional interstitial needles for irregularly shaped HR-CTVs, and moderate dose escalation, especially for patients with poor tumor responses.

Use of Radial-Transducer Intracavitary Ultrasonography in 3d Image-Guided Brachytherapy for Cervical Cancer: Phantom Experiment

Use of Radial-Transducer Intracavitary Ultrasonography in 3d Image-Guided Brachytherapy for Cervical Cancer: Phantom Experiment

Clinical preliminary observation on image-guided brachytherapy for cervical cancer

Clinical preliminary observation on image-guided brachytherapy for cervical cancer

Vaginal dose assessment in image-guided brachytherapy for cervical cancer: Can we really rely on dose-point evaluation?

PurposeAlthough dose–volume parameters in image-guided brachytherapy have become a standard, the use of posterior–inferior border of the pubic symphysis (PIBS) points has been recently proposed in the reporting of vaginal doses. The aim was to evaluate their pertinence. Methods and MaterialsNineteen patients who received image-guided brachytherapy after concurrent radiochemotherapy were included. Per treatment, CT scans were performed at Days 2 and 3, with reporting of the initial dwell positions and times. Doses delivered to the PIBS points were evaluated on each plan, considering that they were representative of one-third of the treatment. The movements of the applicator according to the PIBS point were analysed. ResultsMean prescribed doses at PIBS −2, PIBS, PIBS +2 were, respectively, 2.23 ± 1.4, 6.39 ± 6.6, and 31.85 ± 36.06 Gy. Significant differences were observed between the 5 patients with vaginal involvement and the remaining 14 at the level of PIBS +2 and PIBS: +47.60 Gy and +7.46 Gy, respectively (p = 0.023 and 0.03). The variations between delivered and prescribed doses at PIBS points were not significant. However, at International commission on radiation units and measurements rectovaginal point, the delivered dose was decreased by 1.43 ± 2.49 Gy from the planned dose (p = 0.019). The delivered doses at the four points were strongly correlated with the prescribed doses with R2 ranging from 0.93 to 0.95. The movements of the applicator in regard of the PIBS point assessed with the Digital Imaging and Communications in Medicine coordinates were insignificant. ConclusionThe doses evaluated at PIBS points are not impacted by intrafractional movements. PIBS and PIBS +2 dose points allow distinguishing the plans of patients with vaginal infiltration. Further studies are needed to correlate these parameters with vaginal morbidity.

The changing landscape of brachytherapy for cervical cancer: a Canadian practice survey.

We documented changes in practice from 2009 to 2012 for cervical cancer brachytherapy in Canada. Centres with gynecologic brachytherapy services were sent an e-mail questionnaire querying their 2012 practice. Responses are reported and compared with practice patterns identified in a similar survey for 2009. The response rate was 77% (24 of 31 centres). Almost all use high-dose-rate brachytherapy (92%); low-dose-rate brachytherapy has been completely phased out. Most continue to move patients from the site of applicator insertion to the radiation treatment simulation suite (75%) or to a diagnostic imaging department (29%), or both. In 2012, the imaging modalities used for dose specification were computed tomography [ct (75%)], magnetic resonance imaging [mri (38%)], plain radiography (21%), and cone-beam ct (8%). The number of institutions using mri guidance has markedly increased during the period of interest (9 vs. 1). Most respondents (58% vs. 14%) prescribed using guidelines from the Groupe Européen de Curiethérapie and the European Society for Therapeutic Radiology and Oncology, but they also used point A as a reference. Commonly used high-dose radiation regimens included 30 Gy in 5 fractions and 24 Gy in 3 fractions. In Canada, image-guided brachytherapy for cervical cancer continues to evolve. Although ct-based imaging remains the most commonly used modality, many centres have adopted mri for at least 1 brachytherapy treatment. More centres are using fewer fractions and a slightly lower biologically effective dose, but are still achieving EQD2 (2-Gy equivalent) doses of 80-90 Gy in combination with external-beam radiation therapy.

A questionnaire-based survey on 3D image-guided brachytherapy for cervical cancer in Japan: advances and obstacles.

The purpose of this study is to survey the current patterns of practice, and barriers to implementation, of 3D image-guided brachytherapy (3D-IGBT) for cervical cancer in Japan. A 30-item questionnaire was sent to 171 Japanese facilities where high-dose-rate brachytherapy devices were available in 2012. In total, 135 responses were returned for analysis. Fifty-one facilities had acquired some sort of 3D imaging modality with applicator insertion, and computed tomography (CT) and magnetic resonance imaging (MRI) were used in 51 and 3 of the facilities, respectively. For actual treatment planning, X-ray films, CT and MRI were used in 113, 20 and 2 facilities, respectively. Among 43 facilities where X-ray films and CT or MRI were acquired with an applicator, 29 still used X-ray films for actual treatment planning, mainly because of limited time and/or staffing. In a follow-up survey 2.5 years later, respondents included 38 facilities that originally used X-ray films alone but had indicated plans to adopt 3D-IGBT. Of these, 21 had indeed adopted CT imaging with applicator insertion. In conclusion, 3D-IGBT (mainly CT) was implemented in 22 facilities (16%) and will be installed in 72 (53%) facilities in the future. Limited time and staffing were major impediments.

Reply to the comment of S. VanDyk and K. Narayan on the editorial "IMRT, IGRT and other high technology become standard in external beam radiotherapy: But is image-guided brachytherapy for cervical cancer too expensive?" J Med Phys 2015;40:1-4.

Reply to the comment of S. VanDyk and K. Narayan on the editorial "IMRT, IGRT and other high technology become standard in external beam radiotherapy: But is image-guided brachytherapy for cervical cancer too expensive?" J Med Phys 2015;40:1-4.

The using of megavoltage computed tomography in image-guided brachytherapy for cervical cancer: a case report.

We present a case of cervical cancer treated by concurrent chemoradiation. In radiation therapy part, the combination of the whole pelvic helical tomotherapy plus image-guided brachytherapy with megavoltage computed tomography of helical tomotherapy was performed. We propose this therapeutic approach could be considered in a curative setting in some problematic situation as our institution.

Improved visualisation of cervix applicators for magnetic resonance-only-guided brachytherapy planning

AbstractObjectivesCurrent guidelines for image-guided cervical cancer brachytherapy planning recommend both computed tomography (CT) and magnetic resonance imaging (MRI) for adequate visualisation of the applicator and soft tissues, respectively. MRI-only planning would be ideal as it would save time within the patient pathway and avoid the concomitant CT exposures. However, applicator visualisation on MRI is usually achieved using fluid-filled fiducial marker tubes, which can be awkward to use and suffer from unwanted air bubble artefacts. Therefore, a new fiducial-free imaging technique was developed.MethodsA dual echo time (TE) turbo spin echo sequence was used, at 1·5 T, to provide both T2-weighted images (100 ms TE) for tissue visualisation and strongly proton density-weighted images (17 ms TE) for improved applicator visualisation. In-house software was used to automatically segment the applicator in the short TE images (using Otsu's method) and transfer the information to the long TE images to provide a single fused dataset.ResultsThe method was evaluated successfully using titanium applicators in three patient cases and using a plastic applicator in a tissue-equivalent gel phantom.ConclusionsThe dual-echo technique provides a simple and efficient method for improving the visualisation of brachytherapy applicators in cervical cancer MRI images without the need for marker tubes.

EP-1910: Predictive factors for high D2cc of the organs at risk in image-guided brachytherapy for cervical cancer

EP-1910: Predictive factors for high D2cc of the organs at risk in image-guided brachytherapy for cervical cancer