Manifestation Pattern of Early-Late Vaginal Morbidity After Definitive Radiation (Chemo)Therapy and Image-Guided Adaptive Brachytherapy for Locally Advanced Cervical Cancer: An Analysis From the EMBRACE Study

doi:10.1016/j.ijrobp.2014.01.032

International Journal of Radiation OncologyBiologyPhysics

Volume 89, Issue 1, 1 May 2014, Pages 88-95

https://doi.org/10.1016/j.ijrobp.2014.01.032 Get rights and content

Background and Purpose

Brachytherapy in the treatment of locally advanced cervical cancer has changed substantially because of the introduction of combined intracavitary/interstitial applicators and an adaptive target concept, which is the focus of the prospective, multi-institutional EMBRACE study (www.embracestudy.dk) on image-guided adaptive brachytherapy (IGABT). So far, little has been reported about the development of early to late vaginal morbidity in the frame of IGABT. Therefore, the aim of the present EMBRACE analysis was to evaluate the manifestation pattern of vaginal morbidity during the first 2 years of follow-up.

Methods and Materials

In total, 588 patients with a median follow-up time of 15 months and information on vaginal morbidity were included. Morbidity was prospectively assessed at baseline, every 3 months during the first year, and every 6 months in the second year according to the Common Terminology Criteria for Adverse Events, version 3, regarding vaginal stenosis, dryness, mucositis, bleeding, fistula, and other symptoms. Crude incidence rates, actuarial probabilities, and prevalence rates were analyzed.

Results

At 2 years, the actuarial probability of severe vaginal morbidity (grade ≥3) was 3.6%. However, mild and moderate vaginal symptoms were still pronounced (grade ≥1, 89%; grade ≥2, 29%), of which the majority developed within 6 months. Stenosis was most frequently observed, followed by vaginal dryness. Vaginal bleeding and mucositis were mainly mild and infrequently reported.

Conclusion

Severe vaginal morbidity within the first 2 years after definitive radiation (chemo)therapy including IGABT with intracavitary/interstitial techniques for locally advanced cervical cancer is limited and is significantly less than has been reported from earlier studies. Thus, the new adaptive target concept seems to be a safe treatment with regard to the vagina being an organ at risk. However, mild to moderate vaginal morbidity is still pronounced with currently applied IGABT, and it needs further attention.

Introduction

The state-of-the-art treatment for patients with locally advanced cervical cancer is definitive radiation (chemo)therapy, with brachytherapy being an essential component (1). In the past 2 decades, with the introduction of image-guided adaptive brachytherapy (IGABT) based on repeated volumetric imaging (computed tomography [CT], magnetic resonance imaging [MRI]), local control has substantially improved. This implies the detailed delineation of target volumes and organs at risk (OAR) and dose adaptation according to pre-established dose aims and constraints, without prescribing the dose to the traditional point A but rather to a precisely specified target volume 2, 3. The overall incidence of (late) side effects shows also a decreasing trend in comparison with the 2-dimensional (2D) era 4, 5, 6, 7, 8. This new target concept, however, also has a significant impact on the dose to some OAR (9), including the vagina, where the dose can vary substantially, with some patients receiving much less dose to the vagina and some receiving considerably more (10). Large doses are most notably present in patients with large tumors treated with combined intracavitary/transvaginal interstitial brachytherapy. However, information about the clinical consequences of these doses in the vagina as OAR and their impact on the patient's quality of life is very limited (11).

Owing to the improvements in treatment outcome, a progressively increasing number of long-term survivors of cervical cancer is expected in the future. Severe treatment-related side effects are rare, but mild to moderate morbidity can have a significant impact on the patients' well-being and health-related quality of life (12). With regard to vaginal morbidity, changes related to feminine self-perception and sexual functioning are a particularly important source of symptom-related distress in the years after treatment (13).

To characterize vaginal morbidity associated with current treatment strategies for locally advanced cervical cancer, the present analysis of the prospective multi-institutional EMBRACE study (www.embracestudy.dk) was initiated.

The primary objective of this report is to evaluate early to late vaginal morbidity during the first 2 years of follow-up. This is the first prospective study in the frame of IGABT focusing on detailed evaluation of individual vaginal symptoms with regard to their contribution to overall vaginal morbidity and to the manifestation pattern of symptoms over time in a large, multi-institutional patient cohort.

Section snippets

Methods and Materials

The EMBRACE study is a prospective observational study with 24 participating centers worldwide. It was approved in all participating centers by the respective National Ethics Committees. Since July 2008, the study has included more than 1000 patients and is about to finish accrual. For this report, patients with data from at least 1 completed follow-up visit regarding morbidity and tumor control were included in the analysis.

Results

At the date of closure of the database for this analysis in January 2013, 767 patients from 19 centers were included in the EMBRACE study. Follow-up data regarding morbidity and tumor control were available in 588 patients, who were thus included in this analysis. The median follow-up time was 15 months (range, 1-49 months), with 162 patients (28%) having at least 24 months of follow-up. The patient, disease, and treatment characteristics are reported in Table 1.

Discussion

The ongoing EMBRACE study represents a large cohort of patients with locally advanced cervical cancer treated with definitive radiation (chemo)therapy and IGABT who were prospectively followed up. The aim of this analysis was to describe vaginal morbidity within the first 24 months after the end of treatment.

Two years after treatment, there was a low incidence of any serious vaginal side effects (grade3 and grade4, 2%), but a high actuarial probability that a patient would have any grade1 or

Conclusion

Severe grade 3/4 vaginal morbidity after definitive radiation (chemo)therapy including IGABT for locally advanced cervical cancer within 2 years is limited and significantly less than in previous studies with radiographic treatment planning. Thus, the new adaptive target concept including the use of intracavitary/interstitial techniques seems to be a safe treatment with regard to major morbidity in the vagina being an OAR. However, mild to moderate morbidity occurs in the majority of patients

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A contouring atlas with anatomical boundaries for each emerging OAR was realized by radiation oncologists and radiologists who are experts in pelvic imaging, as per their knowledge and clinical practice. These contours were identified as quality benchmarks for the analysis subsequently carried out. Radiation oncologists not involved in setting the custom-built contouring atlas and interested in the treatment of gynecological cancer were invited to participate in this 2-step trial. In the first step all participants were supplied with a selected clinical case of locally advanced cervical cancer and had to identify emerging OARs (Levator ani muscle; Puborectalis muscle; Internal anal sphincter; External anal sphincter; Bladder base and trigone; Bladder neck; Iliac Bone Marrow; Lower Pelvis Bone Marrow; Lumbosacral Bone Marrow) based on their own personal knowledge of pelvic anatomy and experience. The suggested OARs and the contouring process were then presented at a subsequent webinar meeting with a contouring laboratory. Finally, in the second step, after the webinar meeting, each participant who had joined the study but was not involved in setting the benchmark received the custom-built contouring atlas with anatomical boundaries and was requested to delineate again the OARs using the tool provided. The Dice Similarity Coefficient (DSC) and the Jaccard Similarity Coefficient (JSC) were used to evaluate the spatial overlap accuracy of the different volume delineations and compared with the benchmark; the Hausdorff distance (HD) and the mean distance to agreement (MDA) to explore the distance between contours. All the results were reported as sample mean and standard deviation (SD).
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This study found a moderate to low level of agreement in the delineation of the female pelvis emerging OARs, with a high degree of variability among observers. The development of delineation tools should be encouraged to improve the routine contouring of these OARs and increase the quality and consistency of radiotherapy planning.
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To quantify the association of persistent morbidity with different aspects of quality of life (QOL) in locally advanced cervical cancer (LACC) survivors.
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Persistent symptoms are associated with QOL reductions in LACC survivors. Organ-related symptoms showed smaller differences than general symptoms such as fatigue and pain. In addition to optimizing treatment to minimize organ-related morbidity, effort should be directed towards a more comprehensive and targeted morbidity management.
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The EMBRACE-vaginal morbidity substudy prospectively evaluated physician-assessed vaginal changes and patient-reported-outcomes (PRO) on vaginal and sexual functioning problems and distress in the first 2-years after image-guided radio(chemo)therapy and brachytherapy for locally advanced cervical cancer.
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113 eligible patients were included. Mostly mild (grade 1) vaginal changes were reported over time in about 20% (range 11–37%). At 2-years, 47% was not sexually active. Approximately 50% of the sexually active women reported any vaginal and sexual functioning problems and distress over time; more substantial vaginal and sexual problems and distress were reported by up to 14%, 20% and 8%, respectively. Physician-assessed vaginal changes and PRO sexual satisfaction differed significantly (p ≤ .05) between baseline and first follow-up, without further significant changes over time. No or only small associations between physician-assessed vaginal changes and PRO vaginal functioning problems and sexual distress were found.
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Citation Excerpt :
At a median follow-up of 15 months, the actuarial probability of vaginal morbidity Grade≥1 at 2 years after treatment was 89%. The probability of Grade≥2 was estimated at 29% and severe Grade≥3 vaginal morbidity was 3.6% (17). Vaginal stenosis (VS) was the most frequently observed vaginal symptom after treatment, with a 2-year actuarial incidence of 75% for Grade≥1, 22% for Grade≥2, and 1.6% for Grade≥3.
There is growing awareness of the importance of sexual health in the quality of life of cancer patients and survivors. Brachytherapy, a vital component for the curative treatment of cervical cancer, leads to both direct and indirect sequelae that result in vaginal and sexual morbidity. The emergence of 3D image-guided adaptive brachytherapy has led to a better understanding of dose-and-effect relationships for critical organs-at-risk and there are new recommendations for vaginal dose reporting in the ongoing EMBRACE II study. An understanding of the vagina as an organ-at-risk and its dose-and-effect relationships can help brachytherapists limit dose to the vagina and improve sexual morbidity. Brachytherapists play a critical role in the primary and secondary prevention of vaginal and sexual sequelae resulting from treatment. Through close surveillance and recognition of common symptoms, brachytherapists can intervene with effective strategies to prevent and treat vaginal and sexual symptoms. This review summarizes the current literature on dosimetric factors that may predict for vaginal morbidity. It will focus on quantitative and qualitative reports of brachytherapy-related vaginal toxicity and sexual dysfunction. Lastly, it will review the available evidence supporting clinical interventions to mitigate the development and progression of vaginal and sexual sequelae to improve functional quality post-treatment.

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: Supported by the Austrian Federal Ministry of Economy, Family, and Youth and the Austrian Foundation for Research, Technology, and Development and CIRRO—the Lundbeck Foundation Center for Investigational Research in Radiation Oncology. Sponsored by the Medical University of Vienna. Research funds have been provided by Nucletron, an Elekta company, and Varian Medical Systems.

: Conflict of interest: none.

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Clinical InvestigationManifestation Pattern of Early-Late Vaginal Morbidity After Definitive Radiation (Chemo)Therapy and Image-Guided Adaptive Brachytherapy for Locally Advanced Cervical Cancer: An Analysis From the EMBRACE Study

Background and Purpose

Methods and Materials

Results

Conclusion

Introduction

Section snippets

Methods and Materials

Results

Discussion

Conclusion

Semin Oncol

Radiother Oncol

Radiother Oncol

Radiother Oncol

Radiother Oncol

Radiother Oncol

Radiother Oncol

Radiother Oncol

Radiother Oncol

Clinical Investigation
Manifestation Pattern of Early-Late Vaginal Morbidity After Definitive Radiation (Chemo)Therapy and Image-Guided Adaptive Brachytherapy for Locally Advanced Cervical Cancer: An Analysis From the EMBRACE Study