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.
Despite significant advances in the screening, detection, and treatment of preinvasive cervical lesions, invasive cervical cancer is the fifth most common cancer in European women. There are large ...disparities in Europe and worldwide in the incidence, management, and mortality of cervical cancer.
The European Society of Gynaecological Oncology (ESGO), the European Society for Radiotherapy and Oncology (ESTRO), and the European Society of Pathology (ESP) jointly develop clinically relevant and evidence-based guidelines in order to improve the quality of care for women with cervical cancer across Europe and worldwide.
The ESGO/ESTRO/ESP nominated an international multidisciplinary development group consisting of practicing clinicians and researchers who have demonstrated leadership and expertise in the care and research of cervical cancer (23 experts across Europe). To ensure that the guidelines are evidence based, the current literature identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the development group. The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 159 international reviewers, selected through ESGO/ESTRO/ESP and including patient representatives.
The guidelines cover comprehensively staging, management, and follow-up for patients with cervical cancer. Management includes fertility sparing treatment; stage T1a, T1b1/T2a1, clinically occult cervical cancer diagnosed after simple hysterectomy; early and locally advanced cervical cancer; primary distant metastatic disease; cervical cancer in pregnancy; and recurrent disease. Principles of radiotherapy and pathological evaluation are defined.
Abstract
Background. The first Nordic protocol for three-dimensional (3D) planned radiotherapy in locally advanced cervical cancer was the prospective NOCECA study (1994-2000). NOCECA consisted of ...computed tomography (CT)-based 3D conformal external beam radiotherapy (EBRT) with a simultaneous integrated boost (SIB) to the primary tumour combined with brachytherapy (BT) based on x-ray imaging. In NOCECA the planning aim was to achieve 80 Gy at point A from EBRT and BT combined. However, the balance of dose between EBRT and BT was determined by tumour size at diagnosis with more EBRT dose given to point A and less by BT in more advanced stages. In 2005 image-guided adaptive brachytherapy (IGABT) based on magnetic resonance imaging (MRI) and optimisation of the BT dose distribution to the remaining tumour and cervix at time of BT (HR CTV) was introduced in Aarhus. EBRT remained like in NOCECA until 2008 when the SIB to the primary tumour was abandoned and IMRT was introduced as routine technique. In this study, we report outcome of our first five-year experience with IGABT using our NOCECA cohort as reference. Material and methods. The NOCECA cohort comprising 99 patients was compared with 140 consecutive patients treated by IGABT. Patients with para-aortic nodes were excluded in NOCECA but were present in 9% of the patients treated with IGABT. No patient in NOCECA received chemotherapy whereas concomitant cisplatin was given to 79% of the IGABT patients. Results. With IGABT actuarial local control was 91% at three years. When comparing NOCECA with IGABT overall survival was significantly improved from 63% to 79% (p = 0.005). In parallel, both moderate and severe late morbidity were reduced by about 50% (p = 0.02). Conclusion. Introduction of IGABT reduced morbidity and generated a very high rate of local control, which likely has improved survival by at least as much as concomitant chemotherapy.
Background:
Despite significant advances in the screening, detection, and treatment of preinvasive cervical lesions, invasive cervical cancer is the fifth most common cancer in European women. There ...are large disparities in Europe and worldwide in the incidence, management, and mortality of cervical cancer.
Objective:
The European Society of Gynecological Oncology (ESGO), the European Society for Radiotherapy and Oncology (ESTRO), and the European Society of Pathology (ESP) jointly develop clinically relevant and evidence-based guidelines in order to improve the quality of care for women with cervical cancer across Europe and worldwide.
Methods:
The ESGO/ESTRO/ESP nominated an international multidisciplinary development group consisting of practicing clinicians and researchers who have demonstrated leadership and expertise in the care and research of cervical cancer (23 experts across Europe). To ensure that the guidelines are evidence based, the current literature identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the development group. The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 159 international reviewers, selected through ESGO/ESTRO/ESP and including patient representatives.
Results:
The guidelines cover comprehensively staging, management, and follow-up for patients with cervical cancer. Management includes fertility sparing treatment; stage T1a, T1b1/T2a1, clinically occult cervical cancer diagnosed after simple hysterectomy; early and locally advanced cervical cancer; primary distant metastatic disease; cervical cancer in pregnancy; and recurrent disease. Principles of radiotherapy and pathological evaluation are defined.
For cervical cancer (CC), circulating cell‐free HPV DNA (ccfHPV) may establish disease severity. Furthermore, HPV integration has been correlated to viral load and survival. In this study, ...pre‐treatment plasma from 139 CC cases (50 primary surgery patients, 22 primary surgery + adjuvant oncological therapy patients, and 67 primary oncological therapy patients) was collected (2018–2020). Furthermore, plasma from 25 cervical intraepithelial neoplasia grade 3 patients and 15 healthy women (negative controls) were collected. Two next‐generation sequencing (NGS) panels were used to establish ccfHPV presence and human papillomavirus type 16 (HPV16) integration status. ccfHPV was detected in four primary surgery (8.0%), eight primary surgery + adjuvant oncology (36.4%), and 54 primary oncology (80.6%) patients. For primary oncology patients with HPV16‐related cancer (n = 37), more ccfHPVneg than ccfHPVpos patients had HPV16 integration (P = 0.04), and in patients with HPV16 integration (n = 13), ccfHPVpos patients had higher disease stages than ccfHPVneg patients (P = 0.05). In summary, ccfHPV presence is related to disease severity and may add to the debated Sedlis criteria used for identifying patients for adjuvant oncological therapy. However, ccfHPV detection is influenced by HPV integration status and disease stage, and these factors need to be considered in ccfHPVneg patients.
For cervical cancer (CC), circulating cell‐free HPV DNA (ccfHPV) may establish disease severity. Using targeted next‐generation sequencing of cell‐free DNA, we established ccfHPV presence and HPV16 integration status in CC patients. Our findings suggest that ccfHPV detection is related to disease severity but also influenced by HPV integration status and disease stage.
•Establish EBRT treatment planning compliance through a dummy-run (EMBRACE II).•Plan quality development after introducing novel EBRT planning concepts.•Individual feedback improves EBRT plan quality ...and inter-center consistency.
The EMBRACE II study combines state-of-the-art Image-Guided Adaptive Brachytherapy in cervix cancer with an advanced protocol for external beam radiotherapy (EBRT) which specifies target volume selection, contouring and treatment planning. In EMBRACE II, well-defined EBRT is an integral part of the overall treatment strategy with the primary aim of improving nodal control and reducing morbidity. The EMBRACE II EBRT planning concept is based on improved conformality through relaxed coverage criteria for all target volumes. For boosting of lymph nodes, a simultaneous integrated boost and coverage probability planning is applied. Before entering EMBRACE II, institutes had to go through accreditation.
As part of accreditation, a treatment planning dummy-run included educational blocks and submission of an examination case provided by the study coordinators. Seventy-one centers submitted 123 EBRT dose distributions. Replanning was required if hard constraints were violated or planning concepts were not fully accomplished. Dosimetric parameters of original and revised plans were compared.
Only 11 plans violated hard constraints. Twenty-seven centers passed after first submission. 27 needed one and 13 centers needed more revisions. The most common reasons for revisions were low conformality, relatively high OAR doses or insufficient lymph node coverage reduction. Individual feedback on planning concepts improved plan quality considerably, resulting in a median body V43Gy reduction of 158 cm3 from first plan submission to approved plan.
A dummy-run as applied in EMBRACE II, consisting of training and examination cases enabled us to test institutes’ treatment planning capabilities, and improve plan quality.
Abstract Background and purpose Variations in organ position, shape, and volume cause uncertainties in dose assessment for brachytherapy (BT) in cervix cancer. The purpose of this study was to ...evaluate uncertainties associated with bladder dose accumulation based on DVH parameter addition (previously called “the worst case assumption”) in fractionated BT. Materials and methods Forty-seven patients treated for locally advanced cervical cancer were included. All patients received EBRT combined with two individually planned 3D image-guided adaptive BT fractions. D 2 cm 3 and D 0.1 cm 3 were estimated by DVH parameter addition and compared to dose accumulations based on an in-house developed biomechanical deformable image registration (DIR) algorithm. Results DIR-based DVH analysis was possible in 42/47 patients. DVH parameter addition resulted in mean dose deviations relative to DIR of 0.4 ± 0.3 Gyαβ3 (1.5 ± 1.8%) and 1.9 ± 1.6 Gyαβ3 (5.2 ± 4.2%) for D 2 cm 3 and D 0.1 cm 3 , respectively. Dose deviations greater than 5% occurred in 2% and 38% of the patients for D 2 cm 3 and D 0.1 cm 3 , respectively. Visual inspection of the dose distributions showed that hotspots were located in the same region of the bladder during both BT fractions for the majority of patients. Conclusion DVH parameter addition provides a good estimate for D 2 cm 3 , whereas D 0.1 cm 3 is less robust to this approximation.
Parametrial boost (PB) with external beam radiotherapy (EBRT) aims to increase the dose in the parametrial regions where the contribution from intracavitary brachytherapy (IC BT) is insufficient. An ...alternative technique for parametrial boosting is combined intracavitary and interstitial (IC-IS) BT. We compared doses delivered by IC BT plus EBRT PB with doses delivered by IC-IS BT.
We reviewed 51 consecutive patients with locally advanced cervical cancer with parametrial involvement at diagnosis. At BT, 23 patients had persistent parametrial involvement and were treated with IC-IS BT. For the 23 patients, we simulated a treatment of IC BT combined with EBRT PB and compared it with the delivered IC-IS BT. Equivalent total doses in 2-Gy fractions of the target and organs at risk were evaluated, and the normal tissue volume irradiated to at least 60 Gy (V60).
The mean high-risk clinical target volume D90 was comparable (p = 0.8) for both techniques. However, with the EBRT PB scenario, 3 patients received high-risk clinical target volume D90 of <79 Gy, whereas IC-IS BT resulted in D90 of >84 Gy for all patients. Organs at risk D(2cm(3)) were significantly higher by a mean of 4-6 Gy (p < 0.001) with EBRT PB. The PB scenario resulted in a significantly higher V60 of 594 ± 596 cm(3) as compared with 228 ± 82 cm(3) with IC-IS BT (p = 0.004).
Combined IC-IS BT is superior than IC BT + EBRT PB both in terms of organ sparing and target coverage. The IC-IS BT was more conformal with less normal tissue exposure to intermediate doses (V60).
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