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Saturday 19 October 2019
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MRI-guided radiotherapy: A real time, personalised treatment method

The main purpose of radiotherapy is to destroy tumour cells while minimising the damage to healthy cells around the tumours. While this is mainly achieved through precise dose distribution methods such as intensity modulated radiotherapy (IMRT) or volumetric intensity modulated arc treatments (VMAT), correct administration of these techniques necessitates the process of precise imaging of the patient immediately before and during the course of the radiation treatment. This process is called image guidance or image-guided radiotherapy (IGRT). IGRT enables precision in radiotherapy by identifying the exact tumour position during treatment, ensuring that the planned tumourocidal dose reaches the target and better sparing the normal tissues surrounding the tumour from radiation. While IGRT is a relatively easy process for cranial targets where there is almost no movement during treatment, it is highly complex and critical for the treatment of anatomical sites such as the thorax, abdomen and pelvis where respiratory movement affects the position of  targets and normal organs up to 3cm.
 
Modern linear accelerators (Linac, a common radiotherapy device) are usually equipped with X-ray based IGRT systems where 2- or 3-Dimensional kilovoltage or megavoltage imaging is frequently used. These systems are used to detect systematic errors, position the patient correctly, enable the real-time modification of the treatment plan and detect changes in patient or tumour size. However, X-ray-based systems lack soft-tissue contrast, especially at the abdomen and pelvis, and this can necessitate insertion of invasive and high-cost fiducial gold markers in or around the  tumours in order to track them before and during treatment. Recently, integration of magnetic resonance (MR) imaging systems with linear accelerators has enabled us to improve targeting accuracy without requiring the aforementioned fiducial markers.  These systems can now perform real-time assessment of soft tissue anatomy and motion, using continuous cine mode imaging before and during radiotherapy. This has allowed for the correction of intrafractional errors with geometric accuracy of 1–2mm. 
 
Several MR-guided Linac systems are being developed, using different magnetic field strengths and orientations of the static magnetic field to the treatment beam, yet only two have been successful and are currently being used. There are several obstacles while integrating Linac and MR into the same treatment system. Firstly, an extensive magnetic shielding of the Linac components is needed to circumvent interference between the radiofrequency and magnetic fields. These critical components are mainly magnetron and port circulator, which cannot function properly in the presence of a magnetic field. The high-power radiofrequency energy that is needed to obtain high energy photons from the Linac might also significantly deteriorate MRI image quality. Secondly, the MRI’s magnetic field can cause alterations in planned dose delivery due the Lorentz force, which can both broaden the penumbra of a photon beam and cause an electron-return effect. The magnetic field can also divert both electrons travelling within the beam transport system and secondary electrons generated inside patients. In short, MR and Linac may severely disrupt each other’s functions.1
 
The first clinical treatment using an MR-guided Linac system was performed in 2014, using a Viewray MRIDian system in the US. Since then, more than 3000 patients have been treated worldwide. Another commercially available MR-guided Linac system was developed by Elekta and was recently approved for use in clinical treatments.2
 
MR-guided radiotherapy is not only a new technology but also a new treatment algorithm. Below are a few major differences of MR-guided radiotherapy when compared to conventional radiotherapy:
  • The patient set-up is made using MR images, which enables the best soft tissue contrast among the IGRT methods. This has the greatest advantage in the thorax, abdomen and pelvis. When motion-induced blurring occurs with MR imaging, this can easily be eliminated through several solutions such as treating during breath hold. 
  • Rigid immobilisation can be completely eliminated as adaptive plans can be used during all fractions. 
  • Invasive tracking methods that are commonly used in conventional radiotherapy methods, such as gold-marker insertion into the  tumour or invasive hydrogel injections to move away normal structures form tumours, can be eliminated as superior soft-tissue contrast is available with MR guided techniques 
  • Daily real-time replanning of the patient according to the ‘anatomy of the day’ by re-countouring the tumour and surrounding normal organs while patient is on the treatment bed (namely, adaptive planning)
  • Real time continuous tracking of the tumour by cine MR during beam on. All these steps lead to a  longer treatment time – approximately 2–3-times longer than conventional radiotherapy as expected, and this new algorithm requires a tremendous effort from the treatment team, which must be available in the control room during all these steps.
This MR-guided treatment algorithm also has several clinical advantages over conven-tional radiotherapy. Using the above methods, fewer margins are needed around the  tumours compared with conventional radiotherapy, which leads to lower normal tissue toxicity and better local control. The other major advantage of MR-guided systems is the adaptive radiotherapy process. In conventional radiotherapy, treatment plans are executed using a first-day anatomy and an optimal plan is generated to use for treatment purposes during all fractions by assuming that the anatomy is always the same. However, tumours usually shrink during the treatment process and normal organs deform daily the surrounding structures depending on their movement and/or fullness, in daily real life. Thus, applying an optimal plan of the first-day plan to all con-sequent fractions may cause under or overdosing the tumours and normal critical structures. Adaptive radiotherapy eliminates the under- and over-dosing of  tumours and critical normal structures respectively, by daily replanning according to anatomy of the day.
 
In the last ten years, hypofractionated (higher dose per fraction with lower number of total fractions) treatments have replaced the majority of conventional fractionated treatments in radiotherapy.3 Primary and secondary tumours of the breast, lung, liver, pancreas, prostate, brain, hepatobiliary, and gynaecological system are increasingly being treated with hypofractionated treatments in recent years. MR-Linac has enabled us to treat the majority of these tumours effectively by applying the optimal total dose, with minimal side effects and without using any invasive markers. Treatment of oligometastatic diseases (limited number of metastasis) with stereotactic radiotherapy (SBRT) (total fraction number of 8 and less) have been associated with an improvement in overall survival in a recent study.4 The findings of this randomised study represent the strongest clinical evidence available in support of the management of oligometastatic state across multiple  tumour types. Thus, MR-guided SBRT is the safest and most effective radiotherapy method for treatment of several oligometastatic sites namely, lung, liver, adrenal, intrabdominal, and pelvic region. 
 
 Besides hypofractionated and SBRT treatments, more clinical data are needed to define the diseases that migh most benefit from MR-guided radiotherapy. Hepatopancreatobiliary system  tumours are the most obvious targets as the current impact of radiotherapy in these  tumours are highly controversial. Several clinical studies have shown that conventional doses of radiotherapy do not confer a survival advantage over chemotherapy alone in locally advanced inoperable pancreatic cancer.5 Until now, it has been common that suboptimal doses are given to pancreatic tumours, as the pancreas is surrounded by several critical normal structures and respiration causes severe movement of both tumours and normal organs during treatment. Stereotactic body radiotherapy (SBRT) was investigated as an alternative radiotherapy technique in order to apply effective doses to the pancreatic cancer. Local control rates exceeding 80% were reported by using SBRT in the management of pancreatic cancer in a retrospective series.6 MR-guided SBRT seems to
be a potential new treatment method to improve outcomes for such patients, thanks to adaptive radiotherapy and precise dose management of locally advanced pancreatic cancer.
 
In the future, by using MR-guided Linac, radiation oncologists will be better able to identify and treat a range of thoracic, abdominal, and pelvic tumours effectively. Using data from online MR guidance, we will be able to image biomarkers during treatment and thus be able to adapt the plan or even change the treatment intent based upon real-time data. Consideringall the aforementioned advantages of MR-guided radiotherapy, it seems that the future of IGRT will be MR-guided.
 
References 
1 van Herk M et al. Magnetic resonance imaging guided radiation therapy: A short Strengths, Weaknesses, Opportu-nities, and Threats Analysis. Int J Radiation Oncol Biol Phys 2018;101:1057–60.
2 Pollard JM et al. The future of image-guided radiotherapy will be MR guided. Br J Radiol 2017;90:20160667.
3 Nahum AE. The radiobiology of hypofractionation. Clin Oncol (R Coll Radiol) 2015;27(5):260–9.
4 Palma DA et al. Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): a randomised, phase 2, open-label trial. Lancet 2019;18;393:2051–8.
5 Badiyan SN et al. The role of radiation therapy for pancreatic cancer in the adjuvant and neoadjuvant settings. Surg Oncol Clin N Am 2017;26(3):431–53. 
6 Rudra S et al. Using adaptive magnetic resonance image guided radiation therapy for treatment of inoperable pancreatic cancer. Cancer Med 2019;00:1–10.