Quality assurance of HDR prostate plans: Program implementation at a community hospital

Adenocarcinoma of the prostate is currently the most commonly diagnosed cancer in men in the United States, and the second leading cause of cancer mortality. The utilization of radiation therapy is regarded as the definitive local therapy of choice for intermediate- and high-risk disease, in which there is increased risk for extracapsular extension, seminal vesicle invasion, or regional node involvement. High-dose-rate (HDR) brachytherapy is a logical treatment modality to deliver the boost dose to an external beam radiation therapy (EBRT) treatment to increase local control rates. From a treatment perspective, the utilization of a complicated treatment delivery system, the compressed time frame in which the procedure is performed, and the small number of large dose fractions make the implementation of a comprehensive quality assurance (QA) program imperative. One aspect of this program is the QA of the HDR treatment plan. Review of regulatory and medical physics professional publications shows that substantial general guidance is available. We provide some insight to the implementation of an HDR prostate plan program at a community hospital. One aspect addressed is the utilization of the low-dose-rate (LDR) planning system and the use of existing ultrasound image sets to familiarize the radiation therapy team with respect to acceptable HDR implant geometries. Additionally, the use of the LDR treatment planning system provided a means to prospectively determine the relationship between the treated isodose volume and the product of activity and time for the department’s planning protocol prior to the first HDR implant. For the first 12 HDR prostate implants, the root-mean-square (RMS) deviation was 3.05% between the predicted product of activity and time vs. the actual plan values. Retrospective re-evaluation of the actual implant data reduced the RMS deviation to 2.36%.     

Quality assurance of HDR prostate plans: Program implementation at a community hospital

Adenocarcinoma of the prostate is currently the most commonly diagnosed cancer in men in the United States, and the second leading cause of cancer mortality. The utilization of radiation therapy is regarded as the definitive local therapy of choice for intermediate- and high-risk disease, in which there is increased risk for extracapsular extension, seminal vesicle invasion, or regional node involvement. High-dose-rate (HDR) brachytherapy is a logical treatment modality to deliver the boost dose to an external beam radiation therapy (EBRT) treatment to increase local control rates. From a treatment perspective, the utilization of a complicated treatment delivery system, the compressed time frame in which the procedure is performed, and the small number of large dose fractions make the implementation of a comprehensive quality assurance (QA) program imperative. One aspect of this program is the QA of the HDR treatment plan. Review of regulatory and medical physics professional publications shows that substantial general guidance is available. We provide some insight to the implementation of an HDR prostate plan program at a community hospital. One aspect addressed is the utilization of the low-dose-rate (LDR) planning system and the use of existing ultrasound image sets to familiarize the radiation therapy team with respect to acceptable HDR implant geometries. Additionally, the use of the LDR treatment planning system provided a means to prospectively determine the relationship between the treated isodose volume and the product of activity and time for the department’s planning protocol prior to the first HDR implant. For the first 12 HDR prostate implants, the root-mean-square (RMS) deviation was 3.05% between the predicted product of activity and time vs. the actual plan values. Retrospective re-evaluation of the actual implant data reduced the RMS deviation to 2.36%.     

Concurrent chemoradiation for cervical cancer: Comparison of LDR and HDR brachytherapy

PurposeTo compare clinical outcomes between low-dose-rate (LDR) brachytherapy and high-dose-rate (HDR) brachytherapy for cervical cancer patients.Methods and MaterialsAll consecutive newly diagnosed cervical cancer patients undergoing pretreatment 18-fluorodeoxyglucose positron emission tomography imaging and treated with curative-intent definitive chemoradiation from 1997 to 2016 at a U.S. academic center were included. Brachytherapy boost was LDR or HDR 2D treatment planning from 1997 to 2005 and HDR with MR-based 3D planning from 2005 to 2016. Local control (LC), cancer-specific survival (CSS), and late bowel/bladder complications were evaluated.ResultsTumor stages were International Federation of Gynecology and Obstetrics IB1-IIB (n = 457; 75%) and III-IVA (n = 152; 25%). Brachytherapy was LDR for 104 patients and HDR for 505 patients. Concurrent weekly cisplatin was administered to 536 patients (88%). With median followup of 9.4 years, there was no difference in LC (p = 0.24) or CSS (p = 0.50) between LDR and HDR brachytherapy. Cox multivariable regression showed that only International Federation of Gynecology and Obstetrics stage III-IVA (HR=2.4, p = 0.004) was associated with worse LC. A propensity-matched cohort (90 LDR vs. 90 HDR) was created, and the 5-year LC rates were 88% LDR and 82% HDR, p = 0.26; 5-year CSS rates were 66% LDR and 58% HDR, p = 0.19; 5-year grade ≥3 bowel/bladder toxicities were 23% LDR and 16% HDR, p = 0.44. For all patients, the 5-year late toxicity in stage III-IVA patients was higher with LDR 47% vs. HDR 15%, p = 0.03, with no difference in LC, 86% and 75%, respectively (p = 0.09).ConclusionsThere was no difference in LC with either LDR or HDR brachytherapy. The late complication rate was reduced with HDR and 3D-planned brachytherapy compared to LDR and 2D-planned brachytherapy.     

Computed tomography versus magnetic resonance imaging in high-dose-rate prostate brachytherapy planning: The impact on patient-reported health-related quality of life

PurposeHigh-dose-rate (HDR) prostate brachytherapy uses volumetric imaging for treatment planning. Our institution transitioned from computed tomography (CT)-based planning to MRI-based planning with the hypothesis that improved visualization could reduce treatment-related toxicity. This study aimed to compare the patient-reported health-related quality of life (hrQOL) and physician-graded toxicity outcomes of CT-based and MRI-based HDR prostate brachytherapy.MethodsFrom 2016 to 2019, 122 patients with low- or intermediate-risk prostate cancer were treated with HDR brachytherapy as monotherapy. Patients underwent CT only or CT and MRI imaging for treatment planning and were grouped per treatment planning imaging modality. Patient-reported hrQOL in the genitourinary (GU), gastrointestinal (GI), and sexual domains was assessed using International Prostate Symptom Score and Expanded Prostate Cancer Index Composite Short Form-26 questionnaires. Baseline characteristics, changes in hrQOL scores, and physician-graded toxicities were compared between groups.ResultsThe median follow-up was 18 months. Patient-reported GU, GI, and sexual scores worsened after treatment but returned toward baseline over time. The CT cohort had a lower baseline mean International Prostate Symptom Score (5.8 vs. 7.8, p = 0.03). The other patient-reported GU and GI scores did not differ between groups. Overall, sexual scores were similar between the CT and MRI cohorts (p = 0.08) but favored the MRI cohort at later follow-up with a smaller decrease in Expanded Prostate Cancer Index Composite Short Form-26 sexual score from baseline at 18 months (4.9 vs. 19.8, p = 0.05). Maximum physician-graded GU, GI, and sexual toxicity rates of grade ≥2 were 68%, 3%, and 53%, respectively, with no difference between the cohorts (p = 0.31).ConclusionOur study shows that CT- and MRI-based HDR brachytherapy results in similar rates of GU and GI toxicity. MRI-based planning may result in improved erectile function recovery compared with CT-based planning.     

Assessment of a source position checking tool for the quality assurance of transfer tubes used in HDR 192Ir brachytherapy treatments

PurposeThe determination of source positions before treatment is an essential part of the quality assurance (QA) associated with high dose rate brachytherapy treatments. The purpose of this study was to design and commission a tool to allow the quantification of source positions across multiple transfer tube types.Methods and MaterialsA bespoke flexi-adapter jig, three transfer tube adapters, and a film piercing pointer were designed and built for source position QA across three transfer tube types—the standard, 6 French, and gynae transfer tubes. The jig was calibrated against a manufacturer source position check tool, and intratube and intertube source position variations investigated across a total of 40 transfer tubes, using strips of Gafchromic film irradiated at multiple positions 20 mm apart with a microSelectron V3 afterloader (Elekta, Holland). The performance of the jig in localizing the nominal dwell positions relative to the manufacturer check tool was assessed. Associated expanded uncertainties were quantified in line with the International Organization for Standardization Guidelines.ResultsThe mean expanded uncertainty associated with the use of the jig was 0.4 ± 0.0 mm (k = 1). The performance of the jig was 0.3 ± 0.0 mm, while the intratube and intertube source positional variations were observed to be within ±1.0 mm across most transfer tubes.ConclusionsA bespoke flexi-adapter jig capable of allowing source position measurements to be carried out on various transfer tube types has been designed. Measurement results highlight the need for routine QA of all transfer tubes in clinical use.     

The effect of catheter displacement and anatomical variations on the dose distribution in MRI-guided focal HDR brachytherapy for prostate cancer

PurposeThe aim of this study was to analyze the effect of catheter displacement and anatomical variations of prostate and organs at risk on dose distribution in MRI-guided 19 Gy single fraction focal high-dose-rate brachytherapy (HDR-BT) of the prostate.Methods and MaterialsSeventeen patients with localized prostate cancer were enrolled in a prospective trial investigating focal HDR-BT in a 1.5 T MRI-HDR-BT facility. The diagnostic MRI delineations were registered with intraoperative MR scan, and a single fraction of 19 Gy was applied to the visible tumor. Self-anchoring umbrella catheters were used for HDR-BT delivery. A 1.5 T MRI was performed directly after ultrasound (US)-guided catheter placement for treatment planning. After treatment and before removal of catheters, a posttreatment 1.5 T MRI was performed. Regions of interest were also delineated on the posttreatment MR images and the catheters of 17 patients were reconstructed. The dose plan was constructed for the posttreatment MRI scan to assess the influence of catheter migration and anatomical variation on the dose delivered to the target and the organs at risk. Also on the posttreatment MRI, the complete catheter reconstruction was reassessed, to correct for, for example, bending of the catheters. The displacement of catheters between the MRI scans was determined by comparing the catheter tip positions on the treatment planning and posttreatment 1.5 T MRI scans.ResultsThe displacements of 241 catheters were investigated. Average (range) displacements of the umbrella catheters are 0.6 (0–2.9) mm in the x-direction, 0.5 (0–2.1) mm in the y-direction, and 0.9 (0–5.5) mm in the z-direction. In 3 patients, the displacement was >4 mm and up to 5.5 mm. This occurred in respectively 1/13, 1/16, and 1/18 catheters in these patients. The dosimetric differences between the intraoperative treatment and the posttreatment plans were in most patients less than 1.5 Gy. In 4 patients, a dose difference in clinical target volume D95 of >2 Gy up to 5.8 Gy was reported. No discrimination can be made between dose differences due to catheter displacement and/or organ movement/anatomy changes.ConclusionsIn general, catheter displacements were in the order of a mm and differences in dose to the clinical target volume and the organs at risk between the treatment and posttreatment plans smaller than 1.5 Gy. In some patients, dose differences up to 5.8 Gy were determined, due to either individual larger catheter displacement and/or anatomy changes. A longer followup is necessary to assess the clinical implications of individual large dose differences.     

HDR brachytherapy boost using MR-only workflow for intermediate- and high-risk prostate cancer: 8-year results of a pilot study

PurposeTo report 8-year clinical outcome with high-dose-rate brachytherapy (HDRBT) boost using MRI-only workflow for intermediate (IR) and high-risk (HR) prostate cancer (PC) patients.Methods and MaterialsFifty-two patients were treated with 46–60 Gy of 3D conformal radiotherapy preceded and/or followed by a single dose of 8–10 Gy MRI-guided HDRBT. Interventions were performed in a 0.35 T MRI scanner. Trajectory planning, navigation, contouring, catheter reconstruction, and dose calculation were exclusively based on MRI images. Biochemical relapse-free- (BRFS), local relapse-free- (LRFS), distant metastasis-free- (DMFS), cancer-specific-(CCS) and overall survival (OS) were analyzed. Late morbidity was scored using the Common Terminology Criteria for Adverse Events (CTCAE 4.0) combined with RTOG (Radiation Therapy Oncology Group) scale for urinary toxicity and rectal urgency (RU) determined by Yeoh.ResultsMedian follow-up time was 107 (range: 19–143) months. The 8-year actuarial rates of BRFS, LRFS, DMFS, CSS and OS were 85.7%, 97%, 97.6%, and 77.6%, respectively. There were no Gr.3 GI side effects. The 8-year actuarial rate of Gr.2 proctitis was 4%. The 8-year cumulative incidence of Gr.3 GU side effects was 8%, including two urinary stenoses (5%) and one cystitis (3%). EPIC urinary and bowel scores did not change significantly over time.ConclusionsMRI-only HDR-BT boost with moderate dose escalation provides excellent 8-year disease control with a favorable toxicity profile for IRPC and HRPC patients. Our results support the clinical importance of MRI across the BT workflow.     

Comparison of dose-escalated,image-guided radiotherapy vs. dose-escalated,high-dose-rate brachytherapy boost in a modern cohort of intermediate-risk prostate cancer patients

PurposeWe compared outcomes in intermediate-risk prostate cancer patients treated with dose-escalated adaptive image-guided radiation therapy (IGRT) or dose-escalated high-dose-rate brachytherapy boost (HDR-B).Methods and MaterialsPatients with intermediate-risk prostate cancer by National Comprehensive Cancer Network criteria were treated with either CT-based off-line adaptive IGRT (n = 734) or HDR-B (n = 282). IGRT was delivered with 3D-conformal or intensity-modulated radiation therapy with a median dose of 77.4 Gy. For HDR-B, the whole pelvis received a median 46 Gy, and the prostate 2 implants of 9.5 Gy (n = 71), 10.5 Gy (n = 155), or 11.5 Gy (n = 56).ResultsMedian followup was 3.7 years for IGRT and 8.0 years for HDR-B (p < 0.001). Eight-year biochemical control was 86% for IGRT and 91% for HDR-B (p = 0.22), disease-free survival 67% for IGRT and 79% for HDR-B (p = 0.006), and overall survival 75% for IGRT and 86% for HDR-B (p = 0.009). Cause-specific survival (8-year, 100% vs. 99%), freedom from distant metastases (98% vs. 97%), and freedom from local recurrence (98% vs. 98%) did not differ (p > 0.50 each). A worse prognosis group was defined by percent positive prostate biopsy cores >50%, perineural invasion, or stage T2b–c, encompassing 260 (35%) IGRT and 171 (61%) HDR-B patients. These patients evidenced a 5-year biochemical control of 96% for HDR-B and 87% for IGRT (p = 0.002).ConclusionsDose-escalated IGRT and HDR-B both yield excellent clinical outcomes for patients with intermediate-risk prostate cancer. Improved biochemical control with HDR-B for patients with worse pretreatment characteristics suggests that a subgroup of intermediate-risk prostate cancer patients may benefit from dual-modality treatment.     

A phase IB clinical trial of 15 Gy HDR brachytherapy followed by hypofractionated/SBRT in the management of intermediate-risk prostate cancer

PurposeHigh dose-rate (HDR) brachytherapy is commonly administered as a boost to external beam radiation therapy (EBRT). Our purpose was to compare toxicity with increasingly hypofractionated EBRT in combination with a single 15 Gy HDR boost for men with intermediate-risk prostate cancer.Methods and MaterialsForty-two men were enrolled on this phase IB clinical trial to one of three EBRT dose cohorts: 10 fractions, seven fractions, or five fractions. Patients were followed prospectively for safety, efficacy, and health-related quality of life (Expanded Prostate Index Composite). Efficacy was assessed biochemically using the Phoenix definition.ResultsWith a median follow up of 36 months, the biochemical disease-free survival was 95.5%. One man developed metastatic disease at 5 years. There was no significant minimally important difference in EPIC PRO for either urinary, bowel, or sexual domains. There was one acute Grade 3 GI and GU toxicity, but no late Grade 3 GU or GI toxicities.ConclusionFifteen gray HDR brachytherapy followed by a five fraction SBRT approach results in high disease control rates and low toxicity similar to previously reported HDR protocols with significant improvement in patient convenience and resource savings. While mature results with longer follow up are awaited, this treatment approach may be considered a safe and effective option for men with intermediate-risk disease.     

Patient-reported health-related quality of life for men treated with low-dose-rate prostate brachytherapy as monotherapy with 125-iodine, 103-palladium,or 131-cesium: Results of a prospective phase II study

PurposeTo compare quality of life (QoL) after brachytherapy with one of the three approved radioactive isotopes.Methods and MaterialsPatients with mostly favorable intermediate-risk prostate cancer were treated on this prospective phase II trial with brachytherapy as monotherapy, without hormonal therapy. QoL was recorded at baseline and each follow-up by using the Expanded Prostate Cancer Index Composite instrument. The minimal clinically important difference was defined as half the standard deviation of the baseline score for each domain. Mixed effect models were used to compare the different isotopes, and time-driven activity-based costing was used to compute costs.ResultsFrom 2006 to 2013, 300 patients were treated with iodine-125 (I-125, n = 98, prescribed dose [PD] = 145 Gy), palladium-103 (Pd-103, n = 102, PD = 125 Gy), or cesium-131 (Cs-131, n = 100, PD = 115 Gy). Median age was 64.9 years. Median follow-up time was 5.1 years for the entire cohort, and 7.1, 4.8 and 3.3 years for I-125, Pd-103, and Cs-131 groups, respectively. All three isotope groups showed an initial drop in QoL at first follow-up, which gradually improved over the first 2 years for urinary and bowel domains. QoL profiles were similar between I-125 and Pd-103, whereas Cs-131 showed a statistically significant decrease in QoL regarding bowel and sexual function at 12 months compared with Pd-103. However, these differences did not reach the minimal clinically important difference. Compared with I-125, the use of Pd-103 or Cs-131 resulted in cost increases of 18% and 34% respectively.ConclusionsThe three different isotopes produced a similar QoL profile. Statistically significant differences favored Pd-103/I-125 over Cs-131 for bowel and sexual QoL, but this did not reach clinical significance.     

Incidence and dosimetric predictive factors of late rectal toxicity after low-dose-rate brachytherapy combined with volumetric modulated arc therapy in high-risk prostate cancer at a single institution: Retrospective study

PurposeThe purpose of this study is to investigate the incidence of rectal toxicity and to identify the associated dosimetric predictive parameters after I-125 seed low-dose-rate brachytherapy (LDR-BT) combined with volumetric modulated arc therapy (VMAT) and dose constraints.Methods and MaterialsIn total, 110 patients with high-risk prostate cancer received 110 Gy LDR-BT, followed by 45 Gy VMAT. Rectal toxicity was recorded according to Common Terminology Criteria for Adverse Events v.4.03. The dosimetric factors associated with LDR-BT and VMAT were analyzed to determine their relationship with rectal toxicity. Receiver operating characteristic (ROC) curve analysis was performed for ≥ grade 2 (G2) rectal toxicity prediction.ResultsThe follow-up duration was 10.1–115.2 months (median 60.5 months). Seven patients had G2 rectal hemorrhage, and none of the patients had grade 3 rectal hemorrhage. In the univariate analysis, the rectal volume receiving 100% of the prescribed dose (rV₁₀₀) (p < 0.001), the dose covering 2 cc of the rectum (rD_2cc) during LDR-BT (p = 0.002), and the combined rD_2cc during LDR-BT and VMAT (p = 0.001) were identified as predictors of G2 rectal hemorrhage. In the ROC curve analysis, the cutoff value was 0.46 cc for rV₁₀₀, 74.0 Gy for rD_2cc, and 86.8 GyEQD₂ for combined rD_2cc.ConclusionPredictors of late ≥ G2 rectal hemorrhage are rV₁₀₀, rD_2cc, and combined rD_2cc. The incidence of rectal toxicity is low and acceptable in this setting and is highly dependent on the rectal dose of LDR-BT. The use of higher-quality LDR-BT and VMAT dose constraints may further reduce the rate of rectal hemorrhage.     

Racial differences in the PSA bounce in predicting prostate cancer outcomes after brachytherapy: Evidence from the Department of Veterans Affairs

PurposeAfrican American men have historically had poorer prostate cancer biochemical and survival outcomes than Caucasians. However, emerging data suggest nononcologic factors drive much of this disparity. Prior evidence has suggested an association between a transient prostate specific antigen (PSA) bounce and improved biochemical control. However, racial differences in this relationship have remained relatively unexplored.Methods and MaterialsWe identified 4477 men treated for low- or intermediate-risk prostate cancer within the U.S. Department of Veterans Affairs (VA) from 2000 to 2010 with brachytherapy alone or in combination with external beam radiotherapy without androgen deprivation. Longitudinal PSA data were used to define to biochemical failure and PSA bounce. Cox proportional hazard models were used explore racial differences in the relationship between the PSA bounce and time to biochemical failure.ResultsThirty-one percent of our sample experienced a PSA bounce, with African Americans more likely to experience a bounce (42%) compared with Caucasians (29%); p < 0.001. Despite this, African Americans had a higher likelihood of biochemical failure (hazard ratio [HR] 1.4; p = 0.006). However, African American men experiencing a PSA bounce were less likely to experience a biochemical failure (HR = 0.64; p = 0.046), whereas this relationship was not statistically significant for Caucasians (HR = 0.78; p = 0.092). On multivariate analysis, African Americans receiving brachytherapy alone were most sensitive to the protective benefit of the PSA bounce (HR = 0.64).ConclusionsA PSA bounce was associated with improved biochemical control among patients receiving brachytherapy as part of their treatment for low- or intermediate-risk prostate cancer at the VA. African American men treated with brachytherapy had a particularly pronounced biochemical control benefit of a PSA bounce.     

The use of supplemental external beam radiotherapy in men with low-risk prostate cancer undergoing brachytherapy before and after the 1999 American Brachytherapy Society Guideline statement

PurposeIn 1999, the American Brachytherapy Society (ABS) recommended brachy-monotherapy for men with low-risk prostate cancer because of the potential for increased toxicity with combined external beam radiotherapy (EBRT) and brachytherapy without the proof of increased efficacy. We investigated the patterns of care in the community in this patient population before and after the reporting of the ABS guideline.Methods and MaterialsThe study cohort consisted of 4943 men (median age, 69.0 years) with low-risk prostate cancer treated with brachytherapy with or without supplemental EBRT from 1991 to 2007 across 21 community radiation oncology centers. Multivariable logistic regression analysis was performed to determine if there was a significant association between the year of brachytherapy, prostate-specific antigen level, clinical tumor (T) category, patient's age, and the use of supplemental EBRT.ResultsSupplemental EBRT was used in 647 men (13%). The EBRT use initially increased until 2001 and then decreased yielding a significant association (adjusted odds ratio [AOR], 0.92; p < 0.001) between the EBRT use and the year of brachytherapy using a quadratic formulation. Specifically, EBRT use peaked at 24.6% in 2001 and subsequently declined to 3.3% by 2007. Men with clinical category T2a as compared with T1c disease (AOR, 1.43; p < 0.001) were more likely to receive combined modality therapy.ConclusionsThe use of supplemental EBRT in men with low-risk prostate cancer treated with brachytherapy has decreased since 2001. This change in practice patterns suggests gradual adoption of the 1999 ABS practice guidelines.     

Predictive performance of an OVH-based treatment planning quality assurance model for prostate VMAT: Assessing dependence on training cohort size and composition

Radiotherapy treatment planning quality assurance models are used to assess overall plan quality in terms of dose-volume characteristics, by predicting an optimal dosimetry based on a dataset of prior cases (the training cohort). In this study, a treatment planning quality assurance model for prostate cancer patients treated with volumetric modulated arc therapy was developed using the concept of the overlap volume histogram for geometric comparison to the training cohort. The model was developed on the publically available Erasmus iCycle dataset in order to remove the effect of plan quality/inter-planner variability on the model's predictive capabilities. The model was used to predict anus, rectum, and bladder dose volume histograms. Two versions were developed: the n = 114 case (leave-one-out method) which made predictions using the complete Erasmus dataset, and the similarity index (SI)-based model which used a smaller training cohort allocated in order of geometric similarity determined using an overlap volume histogram-derived SI. The difference in mean dose (predicted-achieved) of the SI model at cohort sizes of 10, 20, 30, 40, 50, 75, and 100 was compared to the leave-one-out method for 5 patients, in an attempt to determine the "optimum" cohort size for the SI-based model in this dataset. Performance of the optimized SI model was compared to the leave-one-out method for all patients using the following metrics: difference in mean and median dose, difference in V65Gy and V75Gy (rectum only), similarity of predicted and achieved mean dose, and mean dose volume histograms residual. The "optimum" cohort size for the SI-based model was determined to be 45. The SI-based model implementing this cohort size yielded slightly better outcomes in all performance metrics for the rectum and anus, but worse for the bladder. SI-based training cohort allocation can lead to better predictive efficacy, but the cohort size should be optimized for each individual organ.     

Initiatives for education,training, and dissemination of morbidity assessment and reporting in a multiinstitutional international context: Insights from the EMBRACE studies on cervical cancer

In 2008, the GEC ESTRO Gyn network launched the first multiinstitutional, observational, and prospective international study on MRI-guided brachytherapy in locally advanced cervical cancer patients (EMBRACE-I). EMBRACE-I was followed by EMBRACE-II from 2016 and ongoing. Among the aims of the EMBRACE studies are to benchmark morbidity outcomes and develop dose-volume effects and predictive models for morbidity. The EMBRACE studies collect both physician (CTCAE v.3) and patient (EORTC QLQ-C30/CX24) reported outcomes, including baseline information, in a regular follow-up schedule. The EMBRACE studies feature high numbers of patients (EMBRACE-I N = 1416, EMBRACE-II N = 1500 expected) enrolled from many institutions worldwide (EMBRACE-I n = 23, EMBRACE-II n = 45). This large-scale multiinstitutional approach offers a unique opportunity to investigate and develop new strategies for improving the quality of assessment and reporting of morbidity.This report presents an overview of the challenges and pitfalls regarding the assessment and reporting of morbidity encountered during more than a decade of development and research activities within the EMBRACE consortium.This includes the recognition and evaluation of inconsistencies in the morbidity assessment, and consequently, the provision of assistance and training in the scoring procedure to reduce systematic assessment bias.In parallel, a variety of methodological approaches were tested to comprehensively summarize morbidity outcomes, and a novel approach was developed to refine dose-effect models and risk factor analyses.The purpose of this report is to present an overview of these findings, describe the learning process, and the strategies that have consequently been implemented regarding educational activities, training, and dissemination.