Implementing spatially-fractionated radiation therapy (SFRT) techniques for palliative treatment of bulky tumours

Advanced Knowledge Exchange for Health Professionals

I.    Background on spatially fractional radiation therapy (SFRT)

Palliative external beam radiotherapy plays an important role in the palliation of symptoms such as pain and bleeding caused by incurable cancers. Despite this, approximately 1/4 to 1/3 of patients do not receive symptom relief and for the ones that do respond, symptoms can return requiring further treatment [1, 2].

Conventional palliative radiation therapy aims to encompass a uniform non-ablative dose to the target tumour plus a margin to allow for day-to-day variations in the treatment setup or movement during treatment. For small tumours less than 5cm in length, that are not adjacent to sensitive organs (such bowel), stereotactic ablative body radiotherapy (SABR) may be an alternative option.

A recent random controlled trial compared conventional radiation therapy with SABR for vertebral metastasis showed that the SABR results showed significantly higher 35% response rate compared to 14% for conventional radiotherapy) [3]. However, SABR is not feasible for patient treatments that have more mobile, larger soft tissue tumour types.  These tend to be located near sensitive organs and cause unwanted treatment complications.

What is spatially-fractionated radiation therapy?

Spatially fractionated radiation therapy (SFRT) is a non- nonuniform radiation dose distributed across the region with alternating high and low dose to the tumour site.  Mohiuddin M et al. (1990) reported unexpectedly significant responses for patients treated by SFRT [4] as compared to conventional RT. SFRT for bulky tumours possesses inherent advantages of stereotactic ablative body radiotherapy (SABR)-like high dose “peaks” coupled with inter-laced low dose “valleys” throughout the large target volumes and is referred to as  GRID (or Lattice) SFRT [5-6].

Yan W et al (2020) lists several radiobiological rationales for the SFRT effects, including:

• bystander effect;
• abscopal effect;
• vascular damage; and
• anti-tumour immune response [5].

The X-ray radiobiological mechanisms for high-dose SFRT have the potential to allow sparing of surrounding normal tissue whilst potentially delivering a significantly higher dose to at least a portion of the target tumour, thus potentially resulting in greater tumour destruction without significant toxicity. ‘Bystander effect’ is one of the most popular explanations for the SFRT radiobiological mechanisms which describes the ability of irradiated cells convey varying manifestations of damage to other cells not directly irradiation. The SFRT bystander effect appears to mostly refer to significant cell killing effects in the low dose valley regions located next to high-dose irradiated regions.

In this case, the high-dose SFRT technique may be particularly useful for the treatment of patients who have bulky tumours (typically greater than 7cm) tumours where conventional treatment options may not be suitable.

Nina A et al (2022) also reported radiobiological variations in non-irradiated metastatic sites (referred to as the abscopal effect) in a recent study using the SFRT concept and delivering the treatment as stereotactic body radiation therapy technique. An acronym that described one of these methods was PArtial Tumor irradiation (SBRT-PATHY). The irradiation exclusively targeted the HYpoxic segment of unresectable bulky tumours [6]. Using just SBRT-PATHY alone, showed that the bystander and abscopal response rates were 96% and 52% respectively, and no patient experienced acute or late toxicity of any grade (grade 1–4).

Summarising, there are 2 different types of spatially fractionated radiation therapy. They are either partial volume ablative body radiation therapy (PABR) or GRID/Lattice-RT. If high-dose SFRT is used in either of these techniques, it is thought to induce bystander (local) and abscopal (distant) effects which, potentially, can cause a higher tumour cell killing response for palliatively treated patients [7].

Figure 1 (a) illustrates a standard-of-care protocol as compared to SFRT. Standard palliative radiotherapy delivers a uniform prescribed dose to the tumour plus a large safety margin typically ranging 1cm to 2cm. This limits the total dose that can be given to adjacent normal organs. In contrast, the SABR technique delivers a higher ablative dose to the tumour plus margin and may not necessarily be safely delivered in the presence of an adjacent organ. Partial-boost SABR delivers ablative doses to the core of the tumour but lower, non-ablative doses to the periphery to spare adjacent normal organs. In GRID radiotherapy, ablative doses are delivered to multiple regions of the tumour. Both partial-boost SABR and GRID are a form of spatially fractionated radiotherapy (SFRT). The purpose of SFRT is not ablation of tumour. Rather, it is to achieve a more effective palliation of symptoms in a safe manner when compared to conventional radiotherapy.

II Overview of techniques and technologies for spatially-fractionated therapy (SFRT)

SFRT is a complex concept but not a new concept. Most SFRT studies prior to 2010 used RT planning utilising blocks of shielding material or MLC apertures to create GRID/Lattice-patterned holes of about 1cm diameter at the patient’s skin surface with alternating dose distributions [1, 7-8]. Despite the acceptable toxicity researchers reported, use of GRID block with a single field technique still involves radiation exposure to a significant volume of normal tissue and delivers the highest dose to the superficial tissue which mostly does not include the tumour tissue. Typical GRID apertures with Cerrobend (left), its dose distribution shown in the middle and an alternative multi-leaf collimator (MLC) are shown right in Figure 1.

Our Peter MacCallum group have so far treated 5 inoperable or metastatic sarcoma patients with the partial ablative body radiotherapy (PABR) technique with anecdotal evidence of noticeable response (Figure 3). Each treatment was delivered for this small patient number as an ad hoc basis. A much larger trial study would be valuable to establish a more standardised, efficient radiation therapy protocol.

The prescribed dose used in the January 2022 trial was 5 fractions, 50Gy to the core and 20Gy to the periphery given twice per week. The series of CT images obtained after the radiation therapy demonstrated a significant reduction in tumour size from 18.9 x 16.3cm to 14.5 x 12.7cm within 2.5 months. The patients reported improved appetite and resolution of pain.

Advanced radiation therapy planning and delivery systems enabled highly conformal radiation dose distribution that possibly improve on the therapeutic ratio of SFRT. A number of planning studies as well as clinical trials are being conducted using various techniques, technologies and different treatment modalities including 3D-CRT, VMAT, Tomotherapy and proton beam therapy (PBT), in order to evaluate the feasibility of conducting SFRT [3-11]. Most are commonly available in RT facilities and SFRT could be readily set up for more widespread trials in Australia.

For any new treatment technique, it’s necessary to have a consistent record and report systems that ensures the clinical data is recorded in a transparent and reproducible manner. There are so far few consensus guidelines that adequately consider the technical [12] and clinical [7] considerations. For example,

Technical:         it’s essential to have a consistent, clinically deliverable treatment protocol;

Clinical:             it’s important to obtain preliminary data which can establish a correlation of radiation dose prescription to the changes in target and non-target regions for bulky tumours.

More importantly, its impact on cytokines and peripheral immune cells could lead to bystander and abscopal effects – such underlying mechanisms are of particular interest in the current era of immune-modulating agents that are increasingly combined with radiotherapy [13].

The Peter MacCallum Hospital is currently undergoing a feasibility study of GRID-RT and comparing it to the PABR technique (funded by ANZSA 2022 Sarcoma Research Grant (GID50)). The study aims to prepare prospective clinical trials with SFRT here in Australasia. Figure 4 (left) illustrates an example of two full-arc VMAT technique with 10 degree couch rotations to enable GRID dose distribution (20Gy peak dose).

Pencil beam particle therapy (PBT) scanning is advantageous for generating GRID or Lattice patterns using a constant spot spacing. Several planning studies, in the last five years, have demonstrated this potentially effective and efficient GRID-PBT method with a superior dosimetry result when compared to the photon GRID technique [12-16]. In addition, a few phase-I clinical trials are being implemented this year to investigate the clinical effectiveness of SFRT using different treatment modalities. This includes PBT, e.g. Pro-GRID trial (NCT05121545 available in clinicaltrials.gov).

Figure 4 (middle/right) shows an example of a chondrosarcoma planning study with GRID-PBT and using proton spot scanning with 2cm spacing.

III What to consider when implementing SFRT techniques?

There are several ill-defined factors when considering SFRT. The author lists the following bare minimum set of clinical and technical factors that should be documented when considering clinically implementing SFRT:

i) Clinical Factors

• Disease sites (e.g. primary sarcomas, treated with pre-operative RT or recurrent RT);
• Identifying the histology and disease stage (e.g. Grade 2-3 myxoid liposarcoma, chordoma, chondrosarcoma, retroperitoneal leiomyosarcoma;
• Absence/presence of previous and/or concurrent systemic therapy, (e.g. neoadjuvant chemotherapy);
• Availability of pre-therapy, during and post-therapy imaging assessments, (e.g. MRI, PET/CT, Diagnostic CT);
• Patient factors, (e.g. > 18 years old, not having scleroderma);
• Dose prescription, (e.g. a range of 15-20Gy in 1 fraction in addition to 50.4 Gy/25-28 fractions to the PTV or 50Gy central boost from 20Gy given in 5 fractions) ;
• SFRT timing, (e.g. start with SFRT followed by a conventional dose within 1-2 days);
• EUD of SFRT, (e.g. quantify equivalency to conventional techniques for sarcoma and normal tissues);
• Dose margins, (e.g. 1-2cm boost-GTV margin for PABR and 1cm PTV margin);
• OAR constraints, (e.g. 1-2cm gap from high-dose grid region to spare radiosensitive organs and skin dose less than 150% prescription); and
• Follow-up assessment, (e.g. imaging and/or consultation).

ii) Physics and technical factors

• Treatment modalities (e.g. 3D conformal RT with GRID collimator or MLC-aperture, Tomotherapy, VMAT or Protons;
• Beam energy and dose-rate, e.g. 10MV flattening filter free beam with 2400MU/min or 70-245MeV proton spot scanning beams;
• GRID/Lattice shape e.g. sphere, rectangular or cylindrical;
• GRID/Lattice size and spacing, e.g. 1-2cm spheres with 2-3 cm spacing
• GRID/Lattice placement e.g. to maintain within GTV, 1-2 cm away from OARs, diagonal patterns in beam-eye’s view
• Beam/Arc geometry, e.g. a number of beams or arcs, non-coplanar beams, field size, multi-isocentres, collimators.
• Dose heterogeneity: typically peak-to-valley ratio of 3-5, maximum dose less than 150%
• Modulation factors, e.g. MU/cGy to quantify extent modulation for a given prescription in relation to conventional treatment techniques
• Deliverability and delivery accuracy, e.g. verification measurement methods
• Image guidance, e.g. daily CBCT, mid-treatment CBCT
• Motion management with large motion, e.g. free-breathing gating, breath-hold, abdominal compression.
• Adaptive approach due to anatomical change across treatment course
• Additional resources, e.g. planning time, plan check and QA time, and treatment time.

IV. Final remarks

Literature studies of clinical efficacy, using spatially fractionated radiation therapy (SFRT), have increased over the last decade. High-dose SFRT has great potential as a palliative method for bulky tumours with deep-seated location, complex shape, or adjacent critical organs. SFRT is not a new therapy technique. But, with the recent technology advancements in modern radiation therapy, it can be technically complex in concept.

In summary, there are mainly two different SFRT techniques used for patient tumour volume boost irradiation and GRID/Lattice dose pattern delivery. It can clinically utilise either fixed apertures (e.g. GRID collimator or MLC) or dynamically modulated photon beams or proton spot scanning beams.

 Hence, SFRT can be implemented with modern readily available treatment facilities or the new Australian proton facilities. However, several of the physical and biological factors are ill-defined at this stage. Hence, for an optimum radiation therapeutic outcome, there will need to be clear documentation and reporting of the results while studying each of the variable SFRT factors.

References

[1] Wright CM, Halkett G, Carey Smith R, Moorin R. Sarcoma epidemiology and cancer-related hospitalisation in Western Australia from 1982 to 2016: a descriptive study using linked administrative data. BMC Cancer. 2020;20(1):625.

[2] Tween H, Peake D, Spooner D, Sherriff J. Radiotherapy for the Palliation of Advanced Sarcomas-The Effectiveness of Radiotherapy in Providing Symptomatic Improvement for Advanced Sarcomas in a Single Centre Cohort. Healthcare (Basel). 2019;7(4).

[3] Cilla S, Deodato F, Ianiro A, Macchia G, Picardi V, Buwenge M, et al. Partially ablative radiotherapy (PAR) for large mass tumors using simultaneous integrated boost: A dose-escalation feasibility study. J Appl Clin Med Phys. 2018;19(6):35-43.

[4] Mohiuddin M et al. Palliative treatment of advanced cancer using multiple nonconfluent pencil beam radiation. A pilot study. Cancer. 1990;66(1):114-118.

[5] Yan W, Khan MK, Wu X, Simone CB, 2nd, Fan J, Gressen E, et al. Spatially fractionated radiation therapy: History, present and the future. Clin Transl Radiat Oncol. 2020;20:30-8.

[6] Tubin S et al. Novel stereotactic body radiation therapy (SBRT)-based partial tumor irradiation targeting hypoxic segment of bulky tumors (SBRT-PATHY): improvement of the radiotherapy outcome by exploiting the bystander and abscopal effects. Radiat Oncol. 2019;14(1):21.

[7] Nina A et al. An international consensus on the design of prospective clinical–translational trials in spatially fractionated radiation therapy. Advanced in Radiation Oncology. 2022;7(2):100866

[8] Neuner G, et al. High-dose spatially fractionated GRID radiation therapy (SFGRT): a comparison of treatment outcomes with Cerrobend vs. MLC SFGRT. Int J Radiat Oncol Biol Phys 2012;82(5):1642-9.

[9] Wu X et al. On modern technical approaches of three-dimensional high-dose lattice radiotherapy (LRT). Cureus. Published online March 5, 2010. doi:10.7759/cureus.9

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[11] Sheikh K et al. Comparison of treatment planning approaches for spatially fractionated irradiation of deep tumors. J Appl Clin Med Phys 2019; 20:6:125-133

[12] Zhang H, Wu X, Zhang X, Chang SX, Megooni A, Donnelly ED, et al. Photon GRID Radiation Therapy: A Physics and Dosimetry White Paper from the Radiosurgery Society (RSS) GRID/LATTICE, Microbeam and FLASH Radiotherapy Working Group. Radiat Res. 2020;194(6):665-77.

[13] Jiang L, Li X, Zhang J, et al. Combined high-dose LATTICE radiation therapy and immune checkpoint blockade for advanced bulky tumors: The concept and a case report. Front Oncol. 2021;10:3270.

[14] Gao et al. Spatially fractionated (GRID) radiation therapy using proton pencil beam scanning (PBS): Feasibility study and clinical implementation. Med Phy. 2018;45(4):1645-1653

[15] Tsubouchi T., Henry T., Ureba A. A Quantitative evaluation of potential irradiation geometries for carbon-ion beam grid therapy. Med Phys. 2018 Mar;45(3):1210–1221

[16] Halthore et al. Pencil Beam Scanning Proton GRID Therapy of Bulky Tumors: A Feasibility Study. Int J Radiat Oncol Biol Phys 2021;111(3):e523

Adam Yeo PhD, 5 September 2022