Image-guided Adaptive Radiotherapy in Cervical Cancer

https://doi.org/10.1016/j.semradonc.2019.02.010Get rights and content

This paper reviews the conceptual, methodological, and technical innovations underpinning strategies for adaptive target volume selection and risk-adapted dose prescription in cervical cancer. An adaptive target volume concept has been developed which reflects tumor shrinkage at the end of initial chemo-radiation, which serves for an image-guided boost delivered through brachytherapy, with a risk-adapted dose prescription to different gross tumor- and clinical target volumes defined at diagnosis and after 40-50Gy external beam radiotherapy, and adaptation of the treatment technique according to the topography of the tumor after response and adjacent organs at risk. Clinical results of these innovations are presented based on prospective and retrospective multi-center trials (IntErnational study on MRI-based BRachytherapy in locally Advanced CErvical cancer [EMBRACE], retroEMBRACE) with large patient cohorts (n = 1416, n = 731). The potential benefit of applying these strategies and using a specific multi-parametric dose prescription protocol are explored (EMBRACE-II) and overall current and future research strategies are outlined. The challenges of dissemination and implementation of these complex new techniques into clinical practice are discussed.

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.

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    • Magnetic Resonance Imaging-Guided Adaptive Brachytherapy for the Treatment of Cervical Cancer and its Impact on Clinical Outcome

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      Citation 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].

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    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.

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