MR-guidance in clinical reality: current treatment challenges and future perspectives

Tumors of the central nervous system (CNS) are frequently treated with RT. Specific entities are metastases, primary brain tumors (low-grade gliomas, anaplastic astrocytomas, oligodendrogliomas, glioblastomas), extra-axial tumors such as meningioma, and other benign entities including pituitary adenomas and vestibular schwannomas. A MRI-based planning workflow could potentially be both, cost- and time-saving while reducing uncertainties associated with CT-MRI registration [4]. MRI already represents the gold-standard imaging method for brain tumor diagnosis and the assessment of treatment response [5]. In this context, MRgRT allows for the first time to obtain both, structural and functional information during RT and to manage the adaptation of the prescribed dose during the treatment, in order to optimize outcome. To date, in daily clinical practice, a recent MRI is usually co-registered to bony structures of a simulation CT, achieving a high degree of confidence. Thus, due to these consolidated procedures, RT is already commonly delivered with a high level of precision to brain targets. Therefore, as well as hypothesized after the introduction of PET-MRI, a lot of concerns could be related to the real usefulness of MRgRT in brain RT.

However, a crucial difference emerges: the MRL systems enable a rapid adaptation, immediate target volume delineation [6] and quick tumor response assessment. An example is the treatment of a resection cavity, which can change significantly in shape and size between the simulation MRI and the initiation of treatment [4]. Furthermore, if hypofractionated stereotactic radiosurgery (SRS) is applied, the resection cavity could also change during the treatment course of 3–5 fractions, which would be visible using MRgRT. Tseng and colleagues assessed the dosimetric impact of the magnetic field, including the electron return effect at tissue-air boundaries in SRS and could show that neither target conformity nor dose gradient were negatively impacted [7]. Moreover, Wen and colleagues demonstrated, that excellent plan quality and dose delivery accuracy was achievable on the MRL system for treating multiple brain metastases with a single isocenter [8]. Besides high-dose fractionation schemes, it is expected that conventionally fractionated to moderately hypofractionated schedules will represent the standard-of-care in primary brain tumors due to improved therapeutic ratios. Nevertheless, it remains unknown, which advantages can result from the daily targeting and planning optimization by MRgRT, since the available MRI sequences, which are currently still very limited, may be improved in the future. To date, changes in gross tumor volume (GTV) [9] would at least allow early adaptation of the treatment plan.

In summary, MRgRT creates a new perspective towards an individualized, patient-centric planning approach using online adaptation for intracranial treatments. Furthermore, a significant increase in knowledge is expected concerning the biological processes, which occur during RT and its effect on patient survival for brain diseases.

MRI is increasingly used in head and neck (H&N) RT due to its superior soft tissue contrast and its versatility. MRI is utilized in treatment planning to delineate the GTV [10], the clinical target volume (CTV) [11] and to estimate the necessary PTV margin [12] and to assess the loco-regional treatment response [13]. Undoubtedly, the advent of MRL [3] opens the door to fully exploit the advantages of MRI over CBCT by its online adaptation capability during the treatment procedures (Fig. 1). The following significant improvements are anticipated:

Non-small-cell lung cancer (NSCLC) histology accounts for approximately 85% of all lung cancer cases. Of these, almost 30% present with locally advanced disease, and RT in combination with chemotherapy represents the treatment of choice for this patient group [16‐19]. Because of the low survival rates, dose escalation strategies for stage III NSCLC have been advocated [20, 21]. However, dose escalation for stage III NSCLC requires caution and should be thoroughly studied. Volumetric and positional changes throughout the course of RT have been reported, making adaptive irradiation for advanced lung cancer necessary in about 1/3 of the patients to ensure target coverage and reduce lung dose [22, 23]. Lung tumor motion is complex and is dependent on the location of the tumor in the lung and whether it is attached to rigid structures, such as the chest wall or vertebrae. Motion amplitudes of several centimeters have been reported in the literature [24]. By direct visualization of the “real-time” tumor position in combination with respiratory gated dose delivery, an MR-guided treatment unit can offer a much more accurate and precise dose delivery, without the use of any surrogate or statistical model for respiration [1, 25].

SBRT is a well-established technique for the management of stage I NSCLC, which has significantly improved local control (LC) in comparison to conventional fractionation. LC rates of ≥85% are achieved when the prescribed biologically equivalent tumor dose is ≥100 Gy [26‐29]. It is common practice to generate treatment volumes for lung SBRT from 4D-CT acquisition [29, 30]. However, this can lead in some instances to large treatment volumes whereas MR-guided SBRT treatment delivery for lung tumors has shown promising results in terms of treatment volume reduction and intra-fraction motion management [1, 2]. SBRT has also been shown to be an effective modality for treating patients after failure of conventional irradiation and metastatic lung tumors, achieving good local control with acceptable toxicity [31‐35]. Recent reports regarding online plan adaptation for SBRT treatments under MR-guidance have shown promising results [36‐38]. A mid-treatment approach for plan adaptation for centrally located thoracic tumors allowed reduction of OAR violations and recovery of PTV coverage due to interfractional changes [39].

In summary, MgRT offers improved accuracy of the target position by means of superior intra-fraction tumor visualization. MRgRT is expected to achieve prolonged disease-free survival and lower toxicity for thoracic lung tumors, especially in the field of re-irradiation and in the management of centrally located lesions, by using better intra-fraction motion management in combination with online plan adaptation.

The standard of care for patients with early breast cancer after breast conserving surgery is whole breast irradiation [40, 41]. Recently, new treatment approaches using partial breast irradiation (PBI) or accelerated partial breast irradiation (APBI) in low-risk tumors were analyzed [42]. PBI aims to reduce irradiated breast volume in order to decrease long-term side-effects of treatments, optimizing cosmetic outcomes and improving quality of life while maintaining local tumor control [43]. Nevertheless, conflicting results concerning toxicity and cosmetic outcome have been reported [44, 45].

A possible concern of the inconclusive data are differences in target volume delineation, the dosimetric characteristics and the dose-fractionation schedules of the various APBI techniques. Localization and delineation of the CTV on a postoperative CT remains difficult, even if additional clips are placed in the tumor bed. Furthermore, additional margins must be added to the CTV to account for chest wall movement and patient set-up in External Beam RT (EBRT), which may result in larger irradiated volumes in EBRT compared to brachytherapy or intra-operative APBI techniques [46, 47]. The challenge of adequate target definition in postoperative RT could be mastered with MRgRT, as MRI has excellent soft-tissue contrast, especially in the visualization of irregularities and spiculations [48].

Another approach could be the preoperative MRgRT APBI. Preoperative target delineation showed to have less inter-observer variation as compared to the postoperative setting [49, 50]. MRI has a high sensitivity for detection of invasive breast cancer and a good correlation with histopathology findings [48]. To date, different groups evaluated the concept of single dose APBI delivered prior to surgical resection and treated the first patients [51, 52]. Horton et al. [52] designed a phase I dose escalation trial of a single-dose preoperative radiation treatment for early stage breast cancer patients (node-negative, invasive breast cancer or DCIS ≤2 cm). There were three different dose escalation levels of 15 Gy (n = 8), 18 Gy (n = 8) or 21 Gy (n = 16) and lumpectomy was performed within 10 days. The CTV was delineated using a planning MRI, and included the GTV with an isotropic margin of 15 mm. Overall, no acute dose-limiting grade 3 radiation-related toxicities were reported. These early results seem encouraging and represent a first step toward a novel APBI approach [52].

In summary, set-up margins can be further reduced, as no co-registration of planning MRI and CT is required and dose delivery can be performed using respiratory gated MRgRT. This approach can reduce irradiated breast volume and therefore normal tissue toxicity, as cardiac toxicity [53, 54]. Moreover, MR-guided preoperative RT could potentially facilitate dose escalation and enable an ablative, definitive treatment approach for early-stage breast cancer. Obviously, the MRgRT approach for breast cancer needs to be tested in further clinical trials, but it already appears to have the potential to become a future “game changer” in the portfolio of individualized breast RT strategies.

Standard therapy for locally advanced cervical cancer is a combination of concurrent chemo-RT followed by brachytherapy [109]. Despite the wide application of daily image-guidance and advanced RT techniques including IMRT and VMAT, long-term urogenital and gastrointestinal side-effects are still frequent [110].

Due to its excellent soft-tissue contrast, MRI is already widely applied for staging and post-treatment evaluation of cervical cancer, as it is superior in assessing tumor size as well as soft tissue invasion compared to conventional CT imaging [111, 112]. However, regarding image-guidance, CBCT is still routinely used in RT, while MRI is recommended as the imaging method of choice for brachytherapy [113]. MR-guided brachytherapy is gradually becoming standard of care by allowing superior sparing of surrounding radiosensitive organs combined with dose escalation compared to conventional 2D-planning [114‐117]. Based on the excellent results of MR-guidance in brachytherapy, it has been questioned for EBRT of cervical cancer, whether MRI could not only be applied for advanced tumor delineation but also for image-guidance [110, 114, 118]. The CTV for EBRT comprises the cervix and the uterus which are known to show significant inter- and intra-fractional motion due to the close proximity to hollow OARs [110, 119]. Large safety margins are usually needed in CBCT-imaged-guided RT to account for random and patient-specific organ movement [110, 119]. Due to the potential regression of cervical cancer of up to 60–80% of the pre-therapeutic tumor volume during EBRT, further pelvic organ motion might be expected during RT [118, 120].

MRgRT with its superior soft-tissue contrast allowing for precise and immediate detection of inter-fractional organ motion as well as tumor shrinkage in response to therapy includes the potential of reducing toxicity and potentiating dose escalation in EBRT for cervical cancer [110, 121]. Furthermore, functional MRI comprising non-invasive assessment of tissue perfusion, hypoxia or cellular density might be applied to guide RT treatment in cervical cancer with e.g. higher doses delivered to hypoxic tumor parts [110, 122‐127]. While first shuttle-based approaches have shown that offline MRgRT is feasible for cervical cancer, the high potential of the new hybrid MRL devices is an immediate online adaptive treatment based on the anatomy of the day [3, 128‐132]. Additionally, due to intra-fractional imaging, advanced motion management strategies, like gating become possible providing a “real-time” anatomical feedback with the advantage of further reducing safety margins [121]. A first case report about both, MR-guided EBRT and brachytherapy underlined the high potential of this new promising technique for cervical cancer [132].

In summary, MRg RT for cervical cancer can represent a promising tool to overcome the limits of conventional IGRT systems, in order to improve daily adaptive RT strategies. Further studies can confirm its potential disruptive role in this setting.

Metastatic solid cancer was long considered incurable and treatment consisted mainly of palliative chemotherapy. Local treatments, such as surgery or radiotherapy, with palliative, non-ablative doses were restricted to symptom control. The concept of oligometastatic disease (OMD) is currently challenging this dogma by defining an intermediate state of metastasized disease, with a more favorable disease biology and dynamic. OMD is characterized by a limited number of metastatic lesions and a low overall metastatic burden that opens a therapeutic window for radical treatment to all metastatic sites. Originally coined by Hellman and Weichselbaum in 1995 [133], the idea has gained traction particularly during recent years through several developments: a) improved diagnostics for early detection of low disease burden b) clinical implementation of minimally invasive and high-precision locally-ablative treatments (LAT) such as video- or robotic assisted surgery (VATS, RATS) or SBRT c) more effective systemic treatments that have led to a prolonged overall survival (OS) of metastatic patients and d) a better biological and clinical understanding of tumor biology.

In the treatment of oligometastatic disease, early efforts have mainly focused on the radical treatment of readily resectable lesions, like brain and adrenal metastases. With the improvement in diagnostic imaging and novel developments in non-invasive LAT modalities such as SBRT, prospective reports have surfaced recently that investigate radical treatment of all disease sites, potentially leading to improved clinical outcome [134‐136]. Still, a major concern is the potential toxicity from high local ablative radiotherapy dose, especially in anatomical regions not readily visualized with current IGRT methods (proximal bronchial tree, esophagus, duodenum, small and large bowel). The advent of MRgRT and the possibility to instantly adapt the RT dose to the daily anatomical situations open a window of opportunity to deliver high radiation doses while sparing surrounding normal tissue on a daily basis. In principle, all anatomical locations can be targeted in this way and most thoracic and abdominal indications have already been mentioned in this review. Therefore, we will focus our discussion on the advantages of MRgRT to the following clinical scenarios: