Abstract Purpose Image guided brachytherapy (IGBT) for locally advanced cervical cancer allows dose escalation to the high-risk clinical target volume (HRCTV) while sparing organs at risk (OAR). This ...is the first comprehensive report on clinical outcome in a large multi-institutional cohort. Patients and methods From twelve centres 731 patients, treated with definitive EBRT ± concurrent chemotherapy followed by IGBT, were analysed. Kaplan–Meier estimates at 3/5 years were calculated for local control (LC, primary endpoint), pelvic control (PC), overall survival (OS), cancer specific survival (CSS). In 610 patients, G3–4 late toxicity (CTCAEv3.0) was reported. Results Median follow up was 43 months, percent of patients per FIGO stage IA/IB/IIA 22.8%, IIB 50.4%, IIIA–IVB 26.8%. 84.8% had squamous cell carcinomas; 40.5% lymph node involvement. Mean EBRT dose was 46 ± 2.5 Gy; 77.4% received concurrent chemotherapy. Mean D90 HRCTV was 87 ± 15 Gy (EQD210 ), mean D2cc was: bladder 81 ± 22 Gy, rectum 64 ± 9 Gy, sigmoid 66 ± 10 Gy and bowel 64 ± 9 Gy (all EQD23 ). The 3/5-year actuarial LC, PC, CSS, OS were 91%/89%, 87%/84%, 79%/73%, 74%/65%. Actuarial LC at 3/5 years for IB, IIB, IIIB was 98%/98%, 93%/91%, 79%/75%. Actuarial PC at 3/5 years for IB, IIB, IIIB was 96%/96%, 89%/87%, 73%/67%. Actuarial 5-year G3–G5 morbidity was 5%, 7%, 5% for bladder, gastrointestinal tract, vagina. Conclusion IGBT combined with radio-chemotherapy leads to excellent LC (91%), PC (87%), OS (74%), CSS (79%) with limited severe morbidity.
Abstract Background and purpose Currently, there is no consensus on dose prescription in image guided adaptive brachytherapy (IGABT) in locally advanced cervical cancer. The purpose of this study was ...to provide evidence based recommendations for tumor dose prescription based on results from a multi-center patient series (retroEMBRACE). Materials and methods This study analyzed 488 locally advanced cervical cancer patients treated with external beam radiotherapy ± chemotherapy combined with IGABT. Brachytherapy contouring and reporting was according to ICRU/GEC-ESTRO recommendations. The Cox Proportional Hazards model was applied to analyze the effect on local control of dose-volume metrics as well as overall treatment time (OTT), dose rate, chemotherapy, and tumor histology. Results With a median follow up of 46 months, 43 local failures were observed. Dose (D90) to the High Risk Clinical Target Volume (CTVHR ) ( p = 0.022, HR = 0.967 per Gy) was significant for local control, whereas increasing CTVHR volume ( p = 0.004, HR = 1.017 per cm3 ), and longer OTT ( p = 0.004, HR = 1.023 per day) were associated with worse local control. Histology ( p = 0.084), chemotherapy ( p = 0.49) and dose rate ( p = 1.00) did not have significant impact on local control. Separate analyses according to stage of disease showed that dose to CTVHR , residual gross tumor volume (GTVres ), and Intermediate Risk CTV (CTVIR ) has significant impact on local control. Conclusion CTVHR dose of ⩾85 Gy (D90) delivered in 7 weeks provides 3-year local control rates of >94% in limited size CTVHR (20 cm3 ), >93% in intermediate size (30 cm3 ) and >86% in large size (70 cm3 ) CTVHR . CTVIR and GTVres dose of ⩾60 Gy and ⩾95 Gy (D98) leads to similar local control. A dose of 5 Gy (CTVHR ) is required to compensate an increase of OTT by one week. Increased CTVHR volume by 10 cm3 requires additional 5 Gy for equivalent local control.
To compare the contours and dose-volume histograms (DVH) of the tumor and organs at risk (OAR) with computed tomography (CT) vs. magnetic resonance imaging (MRI) in cervical cancer brachytherapy.
Ten ...patients underwent both MRI and CT after applicator insertion. The dose received by at least 90% of the volume (D(90)), the minimal target dose (D(100)), the volume treated to the prescription dose or greater for tumor for the high-risk (HR) and intermediate-risk (IR) clinical target volume (CTV) and the dose to 0.1 cm3, 1 cm3, and 2 cm3 for the OARs were evaluated. A standardized approach to contouring on CT (CT(Std)) was developed, implemented (HR- and IR-CTV(CTStd)), and compared with the MRI contours.
Tumor height, thickness, and total volume measurements, as determined by either CT or CT(Std) were not significantly different compared with the MRI volumes. In contrast, the width measurements differed in HR-CTV(CTStd) (p = 0.05) and IR-CTV(CTStd) (p = 0.01). For the HR-CTV(CTStd), this resulted in statistically significant differences in the volume treated to the prescription dose or greater (MRI, 96% vs. CT(Std), 86%, p = 0.01), D(100) (MRI, 5.4 vs. CT(Std), 3.4, p <0.01), and D(90) (MRI, 8.7 vs. CT(Std), 6.7, p <0.01). Correspondingly, the IR-CTV DVH values on MRI vs. CT(Std), differed in the D(100) (MRI, 3.0 vs. CT(Std), 2.2, p = 0.01) and D(90) (MRI, 5.6 vs. CT(Std), 4.6, p = 0.02). The MRI and CT DVH values of the dose to 0.1 cm3, 1 cm3, and 2 cm3 for the OARs were similar.
Computed tomography-based or MRI-based scans at brachytherapy are adequate for OAR DVH analysis. However, CT tumor contours can significantly overestimate the tumor width, resulting in significant differences in the D(90), D(100), and volume treated to the prescription dose or greater for the HR-CTV compared with that using MRI. MRI remains the standard for CTV definition.
To establish dose-response relationships for late side effects of the rectum and bladder in cervix cancer patients after magnetic resonance image-guided adaptive brachytherapy (IGABT).
A cohort of ...141 patients was treated with 45 to 50.4 Gy with or without cisplatin plus 4 fractions of 7 Gy IGABT. Doses for the most exposed 2, 1, and 0.1-cm(3) (D(2 cc), D(1 cc), D(0.1 cc)) volumes of the rectum and bladder were converted into the equivalent dose in 2 Gy fractions (EQD2), using a linear quadratic model (α/β = 3 Gy). Late side effects were prospectively assessed (using late effects in normal tissues subjective, objective, management and analytic LENT SOMA) scales. Dose-response relationships were determined by logit analyses.
Eleven patients developed rectal side effects, and 23 patients had urinary side effects. A significant dose effect was found for all rectal dose-volume histogram (DVH) parameters for patients with side effect grades of 1 to 4 but was only significant for D(2 cc) and D(1 cc) for grades ≥ 2. The ED10 values for D(2 cc) were 73 Gy for grades 1 to 4 and 78 Gy for grades 2 to 4 rectal morbidity. For bladder side effects, a significant dose effect was shown for all DVH parameters for complication grades ≥ 2; the respective ED10 was 101 Gy.
Well-defined dose-response curves could be established for D(2 cc) in the rectum and the urinary bladder.
To evaluate the predictive value of dose-volume histogram (DVH) parameters for late side effects of the rectum, sigmoid colon, and bladder in image-guided brachytherapy for cervix cancer patients.
A ...total of 141 patients received external-beam radiotherapy and image-guided brachytherapy with or without chemotherapy. The DVH parameters for the most exposed 2, 1, and 0.1 cm(3) (D(2cc), D(1cc), and D(0.1cc)) of the rectum, sigmoid, and bladder, as well as International Commission on Radiation Units and Measurements point doses (D(ICRU)) were computed. Total doses were converted to equivalent doses in 2 Gy by applying the linear-quadratic model (α/β = 3 Gy). Late side effects were prospectively assessed using the Late Effects in Normal Tissues-Subjective, Objective, Management and Analytic score. The following patient groups were defined: Group 1: no side effects (Grade 0); Group 2: side effects (Grade 1-4); Group 3: minor side effects (Grade 0-1); and Group 4: major side effects (Grade 2-4).
The median follow-up was 51 months. The overall 5-year actuarial side effect rates were 12% for rectum, 3% for sigmoid, and 23% for bladder. The mean total D(2cc) were 65 ± 12 Gy for rectum, 62 ± 12 Gy for sigmoid, and 95 ± 22 Gy for bladder. For rectum, statistically significant differences were observed between Groups 1 and 2 in all DVH parameters and D(ICRU). Between Groups 3 and 4, no difference was observed for D(0.1cc). For sigmoid, significant differences were observed for D(2cc) and D(1cc), but not for D(0.1cc) in all groups. For bladder, significant differences were observed for all DVH parameters only comparing Groups 3 and 4. No differences were observed for D(ICRU).
The parameters D(2cc) and D(1cc) have a good predictive value for rectal toxicity. For sigmoid, no prediction could be postulated because of limited data. In bladder, DVH parameters were predictive only for major toxicity.
To investigate the value of dose-volume histogram (DVH) parameters for predicting local control in magnetic resonance (MR) image-guided brachytherapy (IGBT) for patients with cervical cancer.
Our ...study population consists of 141 patients with cervical cancer (Stages IB-IVA) treated with 45-50 Gy external beam radiotherapy plus four times 7 Gy IGBT with or without cisplatin. Gross tumor volume (GTV), high-risk clinical target volume (HRCTV), and intermediate-risk clinical target volume (IRCTV) were contoured, and DVH parameters (minimum dose delivered to 90% of the volume of interest D90 and D100) were assessed. Doses were converted to the equivalent dose in 2 Gy (EQD2) by applying the linear quadratic model (alpha/beta = 10 Gy). Groups were defined for patients with or without local recurrence (LR) in the true pelvis for tumor size at diagnosis (GTV at diagnosis GTVD of 2-5 cm (Group 1) or greater than 5 cm (Group 2) and for tumor size response at IGBT (HRCTV) of 2-5 cm (Group 2a) or greater than 5 cm (Group 2b).
Eighteen LRs were observed. The most important DVH parameters correlated with LR were the D90 and D100 for HRCTV. Mean D90 and D100 values for HRCTV were 86 +/- 16 and 65 +/- 10 Gy, respectively. The D90 for HRCTV greater than 87 Gy resulted in an LR incidence of 4% (3 of 68) compared with 20% (15 of 73) for D90 less than 87 Gy. The effect was most pronounced in the tumor group (Group 2b).
We showed an increase in local control in IGBT in patients with cervical cancer with the dose delivered, which can be expressed by the D90 and D100 for HRCTV. Local control rates greater than 95% can be achieved if the D90 (EQD2) for HRCTV is 87 Gy or greater.
•Rigid registration on applicator good for contour mapping and applicator reconstruction.•Current DIR algorithms are not yet robust enough to handle complexities.•Wide range of uncertainties when ...using deformable dose accumulation.•Direct addition of doses provides reasonable estimate for target, bladder and rectum.•Substantial uncertainties if EBRT dose gradients in the region of the BT boost.
This review provides an overview of the current status of image registration for image guided gynaecological brachytherapy including combination with external beam radiotherapy. Contour propagation between individual fractions and dose accumulation can be useful for cervix cancer radiotherapy. Contour mapping and applicator reconstruction with rigid registration based on the applicator geometry provide good accuracy. However, deformable image registration is particularly challenging in the pelvic region, due to the large and complex deformations caused by tumor shrinkage, bladder and rectum filling, insertion of a brachytherapy applicator and presence of packing material. This causes substantial limitations and uncertainties when using it in the clinical workflow so that the current generation of deformable image registration algorithms is not yet robust enough to handle complexities involving the dose accumulation of external beam and brachytherapy. The direct addition of doses provides a reasonable estimate of the total absorbed dose. However, in case of significant dose gradients from external beam boosts or midline-shielding adding dose contributions from the different radiotherapy modalities and fractions remains subject to large uncertainties.
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•Image guided adaptive brachytherapy (IGABT) is changing clinical practice.•The EMBRACE studies benchmark IGABT in cervix cancer.•A multi-parametric dose prescription protocol is ...being validated in EMBRACE II.•EMBRACE II is hypothesised to improve outcome: disease, morbidity, quality of life.
The publication of the GEC-ESTRO recommendations one decade ago was a significant step forward for reaching international consensus on adaptive target definition and dose reporting in image guided adaptive brachytherapy (IGABT) in locally advanced cervical cancer. Since then, IGABT has been spreading, particularly in Europe, North America and Asia, and the guidelines have proved their broad acceptance and applicability in clinical practice. However, a unified approach to volume contouring and reporting does not imply a unified administration of treatment, and currently both external beam radiotherapy (EBRT) and IGABT are delivered using a large variety of techniques and prescription/fractionation schedules.
With IGABT, local control is excellent in limited and well-responding tumours. The major challenges are currently loco-regional control in advanced tumours, treatment-related morbidity, and distant metastatic disease. Emerging evidence from the RetroEMBRACE and EMBRACE I studies has demonstrated that clinical outcome is related to dose prescription and technique. The next logical step is to demonstrate excellent clinical outcome with the most advanced EBRT and brachytherapy techniques based on an evidence-based prospective dose and volume prescription protocol.
The EMBRACE II study is an interventional and observational multicentre study which aims to benchmark a high level of local, nodal and systemic control while limiting morbidity, using state of the art treatment including an advanced target volume selection and contouring protocol for EBRT and brachytherapy, a multi-parametric brachytherapy dose prescription protocol (clinical validation of dose constraints), and use of advanced EBRT (IMRT and IGRT) and brachytherapy (IC/IS) techniques (clinical validation). The study also incorporates translational research including imaging and tissue biomarkers.
Image guided adaptive brachytherapy (IGABT) for cervical cancer improves pelvic control and survival across all stages. Improvement in pelvic control is larger in advanced stages, but improvement in ...survival is similar across stages. This paper analyzes the patterns of failure in the RetroEMBRACE cohort to investigate this discrepancy.
731 patients from 12 institutions treated with chemoradiation therapy and magnetic resonance imaging or computed tomography-based IGABT were evaluated. The pattern of failure at time of first relapse was analyzed.
Three hundred twenty-five failures (single and synchronous) occurred in 222 of 731 patients (30%). Among the 325 failures, 9% were local and 6% regional. Pelvic (local or regional) failures made up 13%, paraaortic node (PAN) 9%, systemic 21%, and distant (systemic + PAN) 24%. Of the 222 patients with treatment failure, 21% had pelvic failure alone, 57% had distant failure alone, and 23% had both pelvic and distant failure. Of all failures that occurred, 40% to 50% occurred in the first year, with a further 20% to 30% occurring in the second year. Although local, regional, and PAN failure tended to plateau after year 3, systemic failure continued to occur up to year 10.
Implementation of IGABT has changed the patterns of relapse after chemoradiation therapy for cervical cancer. The predominant failure after IGABT is systemic, whereas the predominant failure with conventional brachytherapy is pelvic. Effective treatments to eradicate micrometastases in PAN and distant organs are needed in addition to IGABT and chemoradiation therapy to maximize local, regional, PAN, and systemic control and improve survival.
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