Dose–effect relationship and risk factors for vaginal stenosis after definitive radio(chemo)therapy with image-guided brachytherapy for locally advanced cervical cancer in the EMBRACE study

doi:10.1016/j.radonc.2015.12.025

Radiotherapy and Oncology

Volume 118, Issue 1, January 2016, Pages 160-166

https://doi.org/10.1016/j.radonc.2015.12.025 Get rights and content

Abstract

Background/purpose

To identify risk factors for vaginal stenosis and to establish a dose–effect relationship for image-guided brachytherapy in locally advanced cervical cancer.

Materials/Methods

Patients from the ongoing EMBRACE study with prospectively assessed morbidity (CTCAEv3.0) at baseline and at least one follow-up were selected. Patient-, disease- and treatment characteristics were tested as risk factors for vaginal stenosis G ⩾ 2 in univariate and multivariable analyses (Cox proportional hazards model) and a dose–effect curve was deduced from the estimates. The ICRU rectum point was used to derive the recto-vaginal reference point dose.

Results

In 630 patients included (median follow-up 24 months), 2-year actuarial estimate for vaginal stenosis G ⩾ 2 was 21%. Recto-vaginal reference point dose (HR = 1.025, p = 0.029), external beam radiotherapy (EBRT) dose >45 Gy/25 fractions (HR = 1.770, p = 0.056) and tumor extension in the vagina (HR = 2.259, p ⩽ 0.001) were risk factors for vaginal stenosis, adjusted for center reporting effects. Based on the model curve, the risk was 20% at 65 Gy, 27% at 75 Gy and 34% at 85 Gy (recto-vaginal reference point dose).

Conclusion

Keeping the EBRT dose at 45 Gy/25 fractions and decreasing the dose contribution of brachytherapy to the vagina decrease the risk of stenosis. A planning aim of ⩽65 Gy EQD2 (EBRT + brachytherapy dose) to the recto-vaginal reference point is therefore proposed.

Section snippets

Patients

The EMBRACE study opened in July 2008 and comprises 24 centers worldwide (www.embracestudy.dk). Eligible patients have previously untreated, biopsy proven squamous-, adeno- or adenosquamous carcinoma of the uterine cervix, FIGO stage IB-IVA (and stage IVB with para-aortic metastatic nodes below L1-L2 only), treated with curative intent with definitive radio(chemo)therapy. The study was approved in all participating centers by the relevant local Research Ethics Committee. For the present

Results

For this analysis, the EMBRACE database was extracted in February 2015. Of the 1238 registered patients, 921 patients had complete data available of which 630 patients were treated in centers that registered more than 50 patients in the study and therefore were included in the analysis.

Median follow-up time was 24 months (IQR 12–36 months). Patients completed in median 6 prospective follow-up assessments (IQR 4–8); 5% of the cohort had only one follow-up assessment. Patient, disease and treatment

Discussion

In this prospective analysis, tumor extension in the vagina, EBRT dose and total recto-vaginal reference point dose (EBRT plus brachytherapy) are risk factors for vaginal stenosis G ⩾ 2. With increasing dose to the recto-vaginal reference point, the probability of developing such vaginal morbidity increased significantly.

Few retrospective studies using the historic standard loading patterns prescribed to point A, have tried to establish a maximum tolerance dose of the vaginal mucosa, but these

Conflict of interest

There are no conflicts of interests to declare.

Acknowledgments

This study was sponsored by the Medical University of Vienna. Uncommitted research funding was provided by Nucletron, an Elekta company and Varian Medical Systems.

Financial support by the Austrian Federal Ministry of Economy, Family, and Youth and the Austrian Foundation for Research, Technology, and Development and Danish Cancer Society and CIRRO – The Lundbeck Foundation Center for Investigational Research in Radiation Oncology is gratefully acknowledged.

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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.
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.
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 cm³, 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.
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.
Definitive radiation for advanced cervix cancer is not associated with vaginal shortening—a prospective vaginal length and dose correlation
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Prospectively measure change in vaginal length after definitive chemoradiation (C-EBRT) with Intracavitary Brachytherapy (ICBT) for locally advanced cervix cancer (LACC) and correlate with vaginal dose (VD).
Twenty one female patients with LACC receiving C-EBRT and ICBT underwent serial vaginal length (VL) measurements. An initial measurement was made at the time of the first ICBT procedure and subsequently at 3 month intervals up to 1 year post radiation. The vagina was contoured as a 3-dimensional structure for each brachytherapy plan. The difference in VL before and at least 6 months after the last fraction of brachytherapy was considered as an indicator of toxicity.
The mean initial VL was 8.7 cm (6.5–12) with median value of 8.5 cm. The mean VL after 6 months was 8.6 cm (6.5–12) and VL change was not found to be statistically significant. The median values (interquartile ranges) for vaginal D0.1cc, D1cc, and D2cc were 129.2 Gy (99.6–252.2), 96.9 Gy (84.2–114.9), and 89.6 Gy (82.4–102.2), respectively. No significant correlation was found between vaginal length change and the dosimetric parameters calculated for all patients.
Definitive C-EBRT and ICBT did not significantly impact VL in this prospective cohort probably related to acceptable doses per ICRU constraints. Estimate of vaginal stenosis and sexual function was not performed in this cohort which is a limitation of this study and which we hope to study prospectively going forward.
Comparing long-term sexual dysfunction across different uterine cancer treatment modalities
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The objective of this study was to assess differences in long-term sexual and menopausal side effects after uterine cancer treatment among treatment modalities.
This is a cross-sectional study that examined women treated for uterine cancer from 2006–2018. Eligible women included those who underwent a hysterectomy/bilateral salpino-oophorectemy alone (HS), with brachytherapy (BT), or with external beam radiation therapy (EBRT). A noncancer cohort of women who underwent a hysterectomy/BSO for benign indications were also identified (non-CA). To compare outcomes, we utilized a shortened form of the female sexual function index (FSFI) and the menopause survey, which consists of 3 subscales: hot flashes, vaginal symptoms, and urinary symptoms. Demographic, comorbidity, and other treatment variables were collected. Survey totals were compared across cohorts using ANOVA tests and logistic regression.
A total of 284 women completed the Menopause Survey (Non-CA 64, HS 60, BT 69, EBRT 91); 116 women reported sexual activity in the last 4 weeks and completed the FSFI (NC 32, HS 21, BT 31, EBRT 32). The mean FSFI score for the entire cohort was 11.4 (SD 4.16), which indicates poor sexual function. There was no significant difference between any cohort in the overall FSFI score (p = 0.708) or in any of the FSFI subscales (all p > 0.05). On univariate analysis, BT was associated with fewer menopausal hot flashes and vaginal symptoms compared to the non-CA cohort (p < 0.05), which did not persist on multivariable analysis.
There was no significant difference in sexual dysfunction or menopausal symptoms in those treated for uterine cancer with or without adjuvant radiation. Most patients reported poor sexual function.
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Contouring of emerging organs-at-risk (OARS) of the female pelvis and interobserver variability: A study by the Italian association of radiotherapy and clinical oncology (AIRO)
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To provide straightforward instructions for daily practice in delineating emerging organs-at-risk (OARs) of the female pelvis and to discuss the interobserver variability in a two-step multicenter study.
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).
Fifteen radiation oncologists from different Institutions joined the study. The participants had a high agreement degree for pelvic bones sub-structures delineation according to DICE (IBM: 0.9 ± 0.02; LPBM: 0.91 ± 0.01). A moderate degree according to DICE was showed for ovaries (Right: 0.61 ± 0.16, Left: 0.72 ± 0.05), vagina (0.575 ± 0.13), bladder sub-structures (0.515 ± 0.08) and EAS (0.605 ± 0.05), whereas a low degree for the other sub-structures of the anal-rectal sphincter complex (LAM: 0.345 ± 0.07, PRM: 0.41 ± 0.10, and IAS: 0.4 ± 0.07).
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.
EviGUIDE - a tool for evidence-based decision making in image-guided adaptive brachytherapy for cervical cancer
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To develop a novel decision-support system for radiation oncology that incorporates clinical, treatment and outcome data, as well as outcome models from a large clinical trial on magnetic resonance image-guided adaptive brachytherapy (MR-IGABT) for locally advanced cervical cancer (LACC).
A system, called EviGUIDE, was developed that combines dosimetric information from the treatment planning system, patient and treatment characteristics, and established tumor control probability (TCP), and normal tissue complication probability (NTCP) models, to predict clinical outcome of radiotherapy treatment of LACC. Six Cox Proportional Hazards models based on data from 1341 patients of the EMBRACE-I study have been integrated. One TCP model for local tumor control, and five NTCP models for OAR morbidities.
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BrachytherapyDose–effect relationship and risk factors for vaginal stenosis after definitive radio(chemo)therapy with image-guided brachytherapy for locally advanced cervical cancer in the EMBRACE study

Abstract

Background/purpose

Materials/Methods

Results

Conclusion

Section snippets

Patients

Results

Discussion

Conflict of interest

Acknowledgments

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Radiother Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Radiother Oncol

Radiother Oncol

Radiother Oncol

Radiother Oncol

Radiother Oncol

Radiother Oncol

Brachytherapy
Dose–effect relationship and risk factors for vaginal stenosis after definitive radio(chemo)therapy with image-guided brachytherapy for locally advanced cervical cancer in the EMBRACE study