Image-guided Adaptive Radiotherapy in Cervical Cancer
Introduction
Cervical cancer is one of the most common malignancies in women worldwide and the second most common cause of female cancer death. The survival rate for cervical cancer is 60%-70% in Western Europe and North America, compared to only 40%-50% in Central/Eastern Europe, and even lower in low and middle income countries. The lower survival rate in less affluent countries is largely due to more advanced disease at presentation because of the lack of systematic screening programmes.
The standard treatment for locally advanced cervical cancer is external beam radiotherapy (EBRT) with concomitant cisplatin-based chemotherapy followed by brachytherapy. For many decades, technological developments in cervix cancer brachytherapy have been limited and treatment planning has been based on X-rays and approaches originally developed by the classical brachytherapy schools in the early 20th century. The most commonly used system is the Manchester point A system which involves standard doses prescribed to a fixed point regardless of tumor size, topography, and response to EBRT, and doses to organs at risk (OAR). This has resulted in a double penalty of suboptimal local control and survival, particularly for patients with large tumors, and significant treatment-related morbidity, particularly affecting the bowel, bladder, and vagina, with a major impact on health-related quality of life in survivors.
Advanced imaging has become an important research field in radiation oncology. The ever-increasing information obtained from advanced imaging has evoked an increasing interest in the potential benefit of adapting the dose to different target volumes according to the risk of recurrence, for example, with simultaneous integrated boost strategies. Examples include head and neck cancer where the high-risk gross tumor volume (GTV) may receive 65Gy in 30 fractions, the intermediate-risk uninvolved nodal regions 60Gy in 30 fractions, and the low-risk uninvolved nodal regions 54Gy in 30 fractions. Similarly, in prostate cancer, different doses may be delivered to the seminal vesicles, the whole prostate and the GTV within the prostate as identified on PET/CT imaging.1, 2 There is also interest in adaptive radiotherapy where the radiation treatment plan delivered to a patient is modified during a course of radiotherapy to account for temporal changes in anatomy due to weight loss (eg, head and neck3), internal motion (eg, lung4), and tumor shrinkage.5 Diagrammatic representations of the ICRU89/GEC-ESTRO tumor response-adapted target concepts are shown in Figure 1. For cervix cancer, the power of morphologic imaging based on magnetic resonance imaging (MRI) has given rise to the development of response assessment and image-guided brachytherapy while multimodality imaging has been additionally explored for tissue characterization.6, 7, 8, 9, 10
For most tumor sites, strategies for prescribing variable dose levels to different target volumes are applied to the clinical situation at diagnosis when the GTV is relatively large, which limits the maximum dose that can be delivered. In contrast, adaptive strategies usually involve modification of the treatment plan to account for organ motion or shrinkage of target volumes only. Uniquely, these 2 strategies have been combined in cervical cancer treatment–an adaptive target volume concept has been developed which reflects tumor shrinkage and the topography of OAR at the end of initial chemo-radiation (after 45-50Gy), which serves for a brachytherapy boost with a risk-adapted dose prescription to different GTV and clinical target volume (CTV) volumes defined at diagnosis and at the end of chemo-radiation and constraints for OAR.
This paper reviews the conceptual, methodological, and technical innovations underpinning strategies for adaptive target volume selection and risk-adapted dose prescription for image-guided brachytherapy after chemo-radiation for cervical cancer. Clinical results of these innovations are presented. The potential benefits of extending these strategies to initial chemo-radiation for cervical cancer are explored. The challenges of dissemination and implementation of these complex new techniques are discussed.
Section snippets
Response-adaptive Target Concept: ICRU and GEC-ESTRO Recommendations
In 2000, the GEC-ESTRO GYN Working Group was established to support and shape the emerging field of gynecological image-guided adaptive brachytherapy (IGABT). Clinicians from a few pioneering European IGABT centers (Leuven, Paris, Vienna) with different historical traditions met to discuss and agree on a common language for prescribing, recording, and reporting IGABT for cervix cancer. This culminated in the publication of 2 recommendations on contouring and dose reporting in 2005 and 2006.11,
Adaptive Treatment Planning
Adaptive treatment planning takes into account the changes during treatment and prescribes specific (boost) doses to the various volumes of interest. For definitive cervical cancer radiotherapy, these volumes are boosted through brachytherapy in order to achieve very high doses in defined small volumes, for example, the CTV-T_HRadapt, the GTV-Tres, and the CTV-T_IRadapt. In principle, such adaptive treatment planning may be used for any clinical scenario which may benefit from differential
Clinical Results–Retro-EMBRACE and EMBRACE
The first EMBRACE study (EMBRACE-I) was a prospective observational study of chemo-radiation and MRI-based IGABT. Quality assurance was carried out to ensure uniform target definition and dose reporting of IGABT according to GEC-ESTRO recommendations,38 but institutions could follow different practices regarding EBRT and brachytherapy techniques and dose prescription. Launched in 2008, the study closed at the end of 2015 with the accrual of 1416 patients. In 2010, the GEC-ESTRO GYN network
Current Research Questions–EMBRACE-II
In 2016, the GEC-ESTRO GYN network launched EMBRACE-II (www.embracestudy.dk, NCT03617133), a prospective interventional study with specific treatment interventions derived from the evidence collected from the first 2 EMBRACE studies.68 EMBRACE-II combines the most advanced techniques currently available for EBRT and brachytherapy in cervix cancer, that is, intensity-modulated radiotherapy (IMRT/VMAT) and MRI-based IGABT, with the delivery of concomitant chemotherapy to the highest standard. The
Training and Dissemination
There are numerous educational activities which have been developed to support the implementation of IGABT and IMRT/VMAT for cervical cancer. These include traditional face-to-face teaching courses and workshops conducted by radiotherapy professional organizations (eg, the ESTRO and ABS schools), national organizations (eg, the Dutch Cancer Society), individual institutions (eg, Vienna, Aarhus), and equipment manufacturers (eg, ELEKTA, Varian), as well as relatively new online courses such as
Future Research Questions
Overall, IGABT has resulted in significant improvements in local control for cervical cancer patients of all stages. However, there is potential for further improvement for patients with advanced local disease (eg, IIIB) and for patients with large or asymmetric CTV-T_HRadapt at the time of brachytherapy through the use of more sophisticated applicators for combined intracavitary/interstitial brachytherapy. For node-positive patients, there is the potential to adapt treatment strategy according
Conclusion
In cervical cancer, the implementation of adaptive target volume selection, adapted treatment technique, and risk-adapted dose prescription through image-guided brachytherapy boost has resulted in a significant improvement in pelvic control across all stages, while reducing serious morbidity. Current and future research will focus on additional adaptive strategies for both EBRT and brachytherapy to maximize the therapeutic ratio in individual patients.
References (79)
- et al.
Intensity modulated radiation therapy dose painting for localized prostate cancer using (1)(1)C-choline positron emission tomography scans
Int J Radiat Oncol Biol Phys
(2012) - et al.
Optimal adaptive IMRT strategy to spare the parotid glands in oropharyngeal cancer
Radiother Oncol
(2016) - et al.
Adaptive biological image-guided IMRT with anatomic and functional imaging in pharyngo-laryngeal tumors: Impact on target volume delineation and dose distribution using helical tomotherapy
Radiother Oncol
(2007) - et al.
Pharmacokinetic parameters derived from dynamic contrast enhanced MRI of cervical cancers predict chemoradiotherapy outcome
Radiother Oncol
(2013) - et al.
Assessment of early response to concurrent chemoradiotherapy in cervical cancer: Value of diffusion-weighted and dynamic contrast-enhanced MR imaging
Magn Reson Imaging
(2014) - et al.
Impact of hybrid PET/MR technology on multiparametric imaging and treatment response assessment of cervix cancer
Radiother Oncol
(2017) - et al.
Recommendations from Gynaecological (GYN) GEC-ESTRO Working Group (I): Concepts and terms in 3D image based 3D treatment planning in cervix cancer brachytherapy with emphasis on MRI assessment of GTV and CTV
Radiother Oncol
(2005) - et al.
Recommendations from Gynaecological (GYN) GEC ESTRO Working Group (II): Concepts and terms in 3D image-based treatment planning in cervix cancer brachytherapy-3D dose volume parameters and aspects of 3D image-based anatomy, radiation physics, radiobiology
Radiother Oncol
(2006) - et al.
Recommendations from Gynaecological (GYN) GEC-ESTRO Working Group: Considerations and pitfalls in commissioning and applicator reconstruction in 3D image-based treatment planning of cervix cancer brachytherapy
Radiother Oncol
(2010) - et al.
Recommendations from Gynaecological (GYN) GEC-ESTRO Working Group (IV): Basic principles and parameters for MR imaging within the frame of image based adaptive cervix cancer brachytherapy
Radiother Oncol
(2012)
Image and laparoscopic guided interstitial brachytherapy for locally advanced primary or recurrent gynaecological cancer using the adaptive GEC ESTRO target concept
Radiother Oncol
Treatment of locally advanced vaginal cancer with radiochemotherapy and magnetic resonance image-guided adaptive brachytherapy: Dose-volume parameters and first clinical results
Int J Radiat Oncol Biol Phys
A novel applicator design for intracavitary brachytherapy of the nasopharynx: Simulated reconstruction, image-guided adaptive brachytherapy planning, and dosimetry
Brachytherapy
Translating response during therapy into ultimate treatment outcome: A personalized 4-dimensional MRI tumor volumetric regression approach in cervical cancer
Int J Radiat Oncol Biol Phys
Assessment of parametrial response by growth pattern in patients with International Federation of Gynecology and Obstetrics Stage IIB and IIIB cervical cancer: Analysis of patients from a prospective, multicenter trial (EMBRACE)
Int J Radiat Oncol Biol Phys
A volumetric analysis of GTVD and CTVHR as defined by the GEC ESTRO recommendations in FIGO stage IIB and IIIB cervical cancer patients treated with IGABT in a prospective multicentric trial (EMBRACE)
Radiother Oncol
The Vienna applicator for combined intracavitary and interstitial brachytherapy of cervical cancer: Clinical feasibility and preliminary results
Int J Radiat Oncol Biol Phys
The Vienna applicator for combined intracavitary and interstitial brachytherapy of cervical cancer: Design, application, treatment planning, and dosimetric results
Int J Radiat Oncol Biol Phys
Clinical use of the Utrecht applicator for combined intracavitary/interstitial brachytherapy treatment in locally advanced cervical cancer
Int J Radiat Oncol Biol Phys
Combined intracavitary and interstitial brachytherapy of cervical cancer using the novel hybrid applicator Venezia: Clinical feasibility and initial results
Brachytherapy
Individualised 3D printed vaginal template for MRI guided brachytherapy in locally advanced cervical cancer
Radiother Oncol
Clinical outcome of protocol based image (MRI) guided adaptive brachytherapy combined with 3D conformal radiotherapy with or without chemotherapy in patients with locally advanced cervical cancer
Radiother Oncol
From point A to the sculpted pear: MR image guidance significantly improves tumour dose and sparing of organs at risk in brachytherapy of cervical cancer
Radiother Oncol
Isodose surface volumes in cervix cancer brachytherapy: change of practice from standard (Point A) to individualized image guided adaptive (EMBRACE I) brachytherapy
Radiother Oncol
Quality assurance in MR image guided adaptive brachytherapy for cervical cancer: Final results of the EMBRACE study dummy run
Radiother Oncol
Image guided brachytherapy in locally advanced cervical cancer: Improved pelvic control and survival in RetroEMBRACE, a multicenter cohort study
Radiother Oncol
Carcinoma of the intact uterine cervix treated with radiotherapy alone: A French cooperative study: Update and multivariate analysis of prognostics factors
Int J Radiat Oncol Biol Phys
Tumor size, irradiation dose, and long-term outcome of carcinoma of uterine cervix
Int J Radiat Oncol Biol Phys
Substantial improvement in UK cervical cancer survival with chemoradiotherapy: Results of a Royal College of Radiologists' audit
Clin Oncol (R Coll Radiol)
Trends in the utilization of brachytherapy in cervical cancer in the United States
Int J Radiat Oncol Biol Phys
National Cancer Data Base analysis of radiation therapy consolidation modality for cervical cancer: The impact of new technological advancements
Int J Radiat Oncol Biol Phys
Impact of 3D image-based PDR brachytherapy on outcome of patients treated for cervix carcinoma in France: Results of the French STIC prospective study
Radiother Oncol
Effect of tumor dose, volume and overall treatment time on local control after radiochemotherapy including MRI guided brachytherapy of locally advanced cervical cancer
Radiother Oncol
Image guided adaptive brachytherapy with combined intracavitary and interstitial technique improves the therapeutic ratio in locally advanced cervical cancer: Analysis from the retroEMBRACE study
Radiother Oncol
OC-0392: Impact of image-guided brachytherapy on pattern of relapse in the RetroEMBRACE cervical cancer study
Radiother Oncol
OC-0055: Local failures after radiochemotherapy and MR-image-guided brachytherapy in cervical cancer patients
Radiother Oncol
Health-related quality of life in locally advanced cervical cancer patients after definitive chemoradiation therapy including image guided adaptive brachytherapy: An analysis from the EMBRACE study
Int J Radiat Oncol Biol Phys
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
Int J Radiat Oncol Biol Phys
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
Radiother Oncol
Cited by (56)
Tetrabromobisphenol a exacerbates the overall radioactive hazard to zebrafish (Danio rerio)
2023, Environmental PollutionMagnetic Resonance Imaging-Guided Adaptive Brachytherapy for the Treatment of Cervical Cancer and its Impact on Clinical Outcome
2022, Clinical OncologyCitation Excerpt :This has rekindled interest in brachytherapy during the past two decades. Groupe European de Curietherapie of the European Society for Radiotherapy and Oncology (GEC-ESTRO) has been in the forefront of developing image-guided adaptive brachytherapy (IGABT) techniques, standardising the concept, language and protocols [4–7]. Now, following recommendations of the American Brachytherapy Society and the Royal College of Radiologists, CT/MRI-based gynaecological brachytherapy has become the standard of care for curative management of cervical cancer in the UK [8,9].
ACR Appropriateness Criteria® Staging and Follow-up of Primary Vaginal Cancer
2021, Journal of the American College of RadiologyBeginning of clinical treatment using the 1.5 Tesla MR-Linac system in Japan: a narrative review
2024, Translational Cancer Research
Financial Disclosure: The EMBRACE studies have been supported by Varian Medical Systems, Elekta, Danish Cancer Society, R108-A6854-14-S31 and R150-A10177 and the Christian Doppler Laboratory for Medical Radiation Research for Radiation Oncology (Medical University of Vienna, Austria).
Conflict of Interest: None.