Stereotatic Ablative Body Radiotherapy

Introduction

Stereotactic ablative body radiotherapy (SABR) is a radiation treatment modality which gives a large dose of radiation concentrated on a small target volume (typically between 0.5 −36 cc ±2.5% in total with per-beam accuracy up to ≤0.75 mm radius 34), while limiting the dose to the surrounding organs. SABR currently has many uses in clinical treatments of stage I and oligometastatic malignancies, however since it is a relatively recent technique, statistically- significant comparative data/reporting in terms of relative effectiveness is lacking. This report serves to review and explore the current data in terms of treatments of various primary and oligometastatic malignancies. We will be giving a general overview of SABR operation, comparing patient survival rates and localized control, along with comparing SABR with various treatment techniques. Finally we will discuss the future development of SABR and the potential it has to improve patient outcomes.

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Discussion

Preamble

The development of stereotactic ablative body radiation therapy (SABR) began in the early 1990s at the Karolinska Institute (Stockholm, Sweden) with researchers Ingmar Lax and Henric Blomgren and was derived from the tech- niques and procedures of stereotactic radiosurgery (SRS)., the group at Karolinska Hospital began development of a methodology for SABR localization which was non-invasive in nature, which has led to clinical acceptance. The motivation behind the development of SABR was for the treatment and palliation of small (≤5cmin greatest dimension) metastases and primary tumours which were otherwise difficult to treat using conventional radiation therapy without delivering large doses to surrounding tissues/organs.

SABR consists of an immobilization box with CT fiducial implants, and a chest compression device to limit respiratory motion. Accuracy of target localization was limited to 5-8 mm in 90% of setups due to difficulty in reproducing the patient’s position within the box between imaging and treatment sessions 28. Abdominal compression is a unique mechanical feature of the body frame, which is effective for limiting motion due to respiration.

?shortcomings in accuracy of these frame-based approaches prompted SABR-practitioners to develop image-based methods for target localization. Initial approaches incorporated electronic portal imaging although other approaches were subsequently developed. Yenice et al. 37 describes frame-based SABR combined with daily CT imaging performed prior to each treatment. To facilitate improved reproducibility, the patient was setup initially in a standing position, after which the frame and patient were tilted backwards into a horizontal treatment position. The authors were able to demonstrate a localization accuracy of within 1 mm (1σ) in any direction. Daily CT was eventually replaced with localization based on electronic portal imaging (EPID), with little loss of targeting accuracy although with lower contrast resolution 28.

SABR operation

SABR uses between 100-150 beams at differing angles of high-dose radiation, given in 1 – 5 fractions of conformal treatment. Several beams are aimed at the target volume from different angles and are image-guided. To target the radiation precisely, patients are placed in specially designed body frames called ’immobilization devices’ for each treatment. This reduces the movement of the tumor location which could otherwise occur with small patient movements. Since SABR relies on precision in localisation of radiation, patient movements can affect the treatment performance and quality significantly (for example, breathing variation can cause up to 50% loss in planning target volume to the target for a single beam. 25) Like other forms of external beam radiation, the treatment itself is non-invasive.

Figure 1: Stereotactic ablative body radiotherapy (SABR) for a single metastatic lung tumor demon- strating operation. The right figure shows the beam configuration of SABR in which radiation is distributed in many diverse directions and the left figure shows the distributions of high-dose radia- tion confined to the tumor on axial, sagittal, and coronal images. 15

Figure 1 demonstrates a highly targeted SABR treatment. We can see how the use of highly focused beams at differing angles can be used in order to deliver dose to a volume with accuracy and precision. The CT images show the expected 3D isodose contours, and gradient at the boundaries of our planning target volume (PTV).

The sharp gradient is ideal, and is the principle behind SABR, which is used on smaller-volume tumors (stage I) or oligometastases in order to maximize tumor control probabilities (TCP) and reduce the normal tissue complication probabilities (NTCP).

SABR treatment platforms

There are various platforms for delivering SABR therapy for patients with liver tumors. The most common is using a linear accelerator equipped with an image guidance system to facilitate SABR treatment. SABR-specific units like the VeroQR (BrainLab, Munich, Germany) and CyberKnifeQR (Accuray, Sunnyvale, USA) are also on the market. All these modalities report comparable outcomes with their techniques.

The CyberKnife is a robotic SABR platform with a miniaturised linear accelerator mounted on a robotic arm possessing 6 degrees of freedom which align with the tumor to deliver the radiation using hundreds of beamlets which allows optimisation of tumor dose, sparing nearby normal tissues 21. The CyberKnife Synchrony Respiratory Tracking System utilizes real time imaging of chest position and correlates that with tumor position via two orthogonally mounted X-ray units. Fiducial implants are tracked in real time and used as tumour position surrogates. During treatment the system adjusts the position of the delivered beam during respiration so that the dose is delivered consistently to the moving tumor.

The different SABR platforms perform image guidance using various imaging modalities such as megavoltage (MV) orthogonal imaging, fluoroscopy, ultrasound, or MV/kV cone beam CT for checking the tumor location prior to treatment. SABR systems rely on imaging of some form of surrogate for the tumor(s) such as the liver itself, fiducial implants, air-diaphragm interface or air-rib interfaces which help ensure that dose is delivered accurately 16. Modern linac-based radiation delivery techniques like SABR have made the radiation delivery much faster and hence lessen the amount of uncertainties during treatment.

Oligometastases

Oligometastases are a concept defined by the prognosis of a cure, in contrast to the Thomford criteria, which determines the indication for surgical resection by clinical appearance 19,32. These two comparisons are highlighted in Table 1, and we can see the distinction between the two. The Thomford criteria is used as a means of palliation, where as the precise diagnosis of Oligometastatic tumours can only be determined when a patient is either cured or not cured. Therefore our definition of Oligometastases is a state of ’limited systemic metastatic tumours’ 19 where the use of ablative therapies (like SABR) can be curative, rather than just palliative.

Currently, Oligometastatic disease comprises 4 considerations:

1. Metastatic lesions limited in location and number 12, while a definite number of metastasis has not been estab- lished the most accepted is ≤5.
2. Patients whose state is transformed to oligometastatic disease after systemic treatment with a response where all lesions can now be radically treated 12. This reflects the inability of systemic treatment to destroy 1 or a number of resistant clones.
3. Primary tumour and most areas of metastatic disease in the patient are controlled but a limited number of metastases advance during systemic therapy 18,22. This is similar to (2) and considers the presence of resistant clones.
4. Recurrence of oligometastases (Oligorecurrance) present in patients who have been treated with curative intent and present with 1-5 lesions suitable for ablative therapy 18,22.

Table 1: Thomford Criteria for local palliative treatment and oligometastatic definitions 19,32

SABR is especially suited for the treatment of oligometastases. The concept of ’oligometastases’ was proposed by Hellman and Weichselbaum based on the apparent multi-step nature of cancer progression 12. The ’oligometastatic’ state exists between completely localized lesions and those which are widely metastatic. This is a useful concept, as when clinicians decide to perform local treatment such as pulmonary resections for metastatic tumors they presume curability to some extent 19.

There is controversy surrounding the existence of oligometastases, as it is difficult to verify their existence by the scientific method 4,24. Despite this, it is acknowledged that there are certain metastases which are in mid-course development into malignancies. Hence the definition shouldn’t be focused explicitly on whether or not they exist, but rather what clinical appearance constitutes the oligometastatic state.

Treatment of Lung Cancers

Lung cancer is a leading cause of cancer deaths world-wide, with an estimated 1.8 million people diagnosed in 2012, resulting in 1.6 million deaths 33. Non-small cell lung cancers (NSCLCs) represent 85% of all lung cancers and is the leading cause of lung cancer deaths 17. For inoperable early-stage (mostly stage I) NSCLC and for oligometastatic pulmonary secondaries, SABR is an established treatment modality.

Non-Small Cell Lung Cancer Primaries

For the treatment of primary NSCLC, there have been many statistically significant (p<0.05) cohort studies conducted over a range of biologically effective doses (BEDs), these conclude that given appropriate BEDs, long-term local control (progression-free survival [PFS]) and survival rates of 80-100% and 40-80% can be achieved respectively 7 when using SABR treatment.

The studies demonstrate the requirement of BED10 ≥100 Gy(Dose delivered to tissue with an αratio of 10) at the isocenter or periphery of the target volume so that local control and survival rate is optimized. BEDperipheryand BED10,isocenterwere also shown to be important factors with one study showing that for BED10,periphery>100 Gyat the clinical target volume (CTV) margin or BED10,periphery>80 Gyat the planning target volume (PTV) that local control is significantly improved 11.

β

Figure 2: Conventional radiotherapy vs SABR demonstrating SABR’s regional dose-effectiveness. 1

Figure 2 illustrates differences between treatment of NSCLC with conventional radiotherapy (left) and SABR (right).

Table 2: 1,3 and 5 year survival rates for SABR, limited resection, and full resections. 39

The above results make SABR an effective treatment for NSCLC primary malignancies. Results in Table 1 are from further studies which have shown overall 1,3 and 5 year survival rates for SABR are comparable to limited and full resections. Whilst SABR does have lower survival rates than full and limited resection, in the case of inoperability or where operations would be impractical, SABR is currently the best treatment modality especially when compared to conventional radiotherapy 5.

Pulmonary Oligometastases

Surgical pulmonary metastasectomy has been recognized as a potentially curative treatment for pulmonary oligometas- tases, particularly for patients without other metastases. Published data aggregated from a number of studies reveals that the 5-year survival rate for these patients was 26-40% 23. According to the International Registry of Lung Metas- tases 31, with >5,000 cases, surgical resection for metastatic lung tumor can result in long-term survival. With the exclusion of the apparently ’favorable’ tumors, the survival outcome at 2 years was approximately 70%. A study performed by Norihisa et al. 23 finds that the overall survival rate at 2 years was 84%. Therefore, SABR appears to have similar potential to cure pulmonary oligometastases compared with surgical metastasectomy.

Treatment of Spinal Cord Oligometastases

Spinal metastases are the most common form of osseous metastases, with approximately 40% of patients with metastatic cancer having spinal metastases 13. Historically palliative treatment with external beam radiotherapy (EBRT) has been used in the treatment of spinal metastases and oligometastases, with a complete pain response rate (percentage of patients whose pain decreases or disappears after treatment) between 13% – 18% 10,35. Patients with metastatic progression are generally regarded as incurable, however for patients with limited metastatic progression with oligometastatic tumours long-term (24+ months) cures have been possible. The inherent advantage of the oligometastatic concept means that patients with metastatic spinal cord lesions may be curable using radical (intended to cure not palliate) local therapies like SABR.

Figure 3: Spine stereotactic ablative body radiotherapy example dose distribution plan prescribed to 24 Gy in two fractions with a spinal cord planning organ-at-risk limit of 17 Gy maximum point dose. The plan is zoomed on the target T8 vertebra, shown in axial (a), sagittal (b) and coronal (c) planes. The planning target volume is shown in pink wash, the spinal cord planning organ at-risk volume is shown in green wash. 6

Figure 3 illustrates treatment planning dose distribution for the treatment of spinal oligometastases using SABR.

A cohort study published by J.H. Chang et al. 6 yields statistically-significant (p<0.05) results which characterise the widespread failure-free survival (WFFS). WFFS is a variation of progression free survival (PFS), with widespread failure being defined as “development of metastatic disease not amenable to further locally ablative (minimally invasive) or extirpative (invasive, surgical intervention) therapies” 6. 60 Patients were treated with BED10 ranging between 40 −144.4 Gy(Median of 53.5 Gy), and 1 −3 (Median of 2) fractions of total dose between 16 −52.5 Gy

(Median of 24 Gy). PFS was 59% and 37% for 1 and 2 year outcomes respectively, WFFS rates were 67% and 59% and overall survival rates were 90% and 76%. Despite the limitations of the cohort study, these results highlight the excellent local control SABR treatment allows for with low morbidity.

Discussion

Randomized control trials (RCTs) are a form of study where patients are allocated at random (by chance alone) to receive one of several clinical interventions. One of these interventions is the standard of comparison or control. The control may be a standard practice, a placebo, or no intervention at all. RCTs seek to measure and compare the outcomes after the participants receive the interventions. Because RCT trials allocate patients for different comparison/control groups at random (and are not selected by a doctor or participant like in cohort studies), this reduces the patient selection bias limitation of the study. This is why RCTs are generally regarded as the ’gold standard’ of studies.

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There have been no randomized control trials (RCTs) on the use of SABR for treating spinal cord oligometastases. There have however been many cohort studies carried out, with the similar limitation of retrospective patient selection and outcome influence. Two cohort studies have shown promising results with local control rates between 80% – 90% with low toxicity rates when applying SABR to general spinal metastases. Few studies have studied the application of SABR for spinal oligometastases specifically however, due to the acknowledged potential problems with myelopathy 26 and vertebral compression fractures (VCFs) 27,38 resulting from treatment.

The studies discussed here show the strong potential SABR has as a curative treatment technique for spinal oligometastases, but also highlights the need for further RCT trials to be conducted.

Treatment of Metastatic Liver Disease

Metastatic liver disease is the most common hepatic malignancy, which makes up 45% of all liver malignancies 20. Patients with metastatic liver disease have median overall survival between 6-12 months. Since 80%-90% of patients are ineligible for surgical intervention 20, there is a need for non-surgical therapies to improve outcomes for these patients. Liver metastases arising from colorectal cancers appear to be oligometastatic in that the progression of cancer is slow with spread which can be limited to the liver for a long time before metastasizing elsewhere 21.

Figure 4: Demonstrating the tight prescription isodose (long broken arrow) around the planning target volume (solid arrow). The steep dose fall gradient is demonstrated by the 50% isodose curve (short broken arrow) around the prescription isodose 21.

Figure 4 represents a treatment planning dose distribution in the transverse plane (with isodose contours) for the treatment of metastatic liver disease using SABR.

Prospective and retrospective cohort trials using the SABR modality for the treatment of liver oligometastases. These show a local control rate ranging from 70%-100% at 1 year and 60%-90% at 2 years follow-up. Median overall survival after SABR ranges from 10-34 months, with 2-year overall survival rates ranging from 30% to 83% respectively 21. They also show that BED10 >100 Gyis correlated with low local recurrence rates 9.

All studies previously mentioned did not show tumor size to be a predictor of outcome. Severe (grade 3 or higher) toxicity due to SABR to the liver is uncommonly reported. Currently there is no consensus regarding the organ at risk (OAR) dose volume constraints due to the different fractionation schemes and techniques used by each clinic 21. Analysis of normal tissue effects in the clinic recommends a mean liver dose of <15 Gyin three fractions and

<20 Gyin 6 fractions and ≥700 ccof normal liver receives ≤15 Gyin three to five fractions for a <5% risk of radiation-induced liver disease (RILD) 36.

No local ablative technique has been demonstrated as superior compared with other local ablative techniques in a RCT. Stintzing et al. 30 performed a matched comparative analysis of 60 patients with unresectable colorectal liver metastases. These patients were divided between SABR (24-26 Gy in 1 fraction) and Radiofrequency Ablation (RFA). 1-year localized control favored SABR (85%) compared to RFA (65%).

This means that SABR could further enhance survival benefits for unresectable liver oligometastases when compared with RFA.

Other treatment sites

Treatment of Primary Renal Cell Carcinoma

SABR has been shown to be an effective treatment technique for primary renal cell carcinoma (RCC). A prospective cohort study by Staehler et al. 29 treated 30 RCC patients with a single dose of 25 Gywith SABR. After a median follow up of 28.1 months, the complete response, partial response and stable disease rates were 20%, 57% and 23% respectively (PFS of 100%). Many other studies have found similar results with 2-year PFS ranging between 60% and 100% 3. For patients where surgical intervention is difficult or not possible, these outcomes make SABR an effective alternative treatment of RCC.

Treatment of Adrenal Oligometastases

Technical difficulties in local therapy for adrenal sites and the haematological spread of lesions have historically made OS for patients with adrenal oligometastases from NSCLC primaries without surgical resection short (8.5 month median OS with chemotherapy alone). SABR treatment has shown encouraging 1-year local control of 87-100% in more recent studies 8, when treated with 36-45 Gyin 3 −5 fractions. In the Holy et al. 14 study of SABR-treated adrenal oligometastases, a median overall survival of 23 months was achieved, comparable with surgical intervention (with a median OS of 21 months). These results prove SABR to be an effective treatment for NSCLC adrenal oligometastases especially when compared with surgical or chemotherapy treatments alone.

Future Development

Significance of RCTs and the future of SABR studies

A common theme throughout this review is the lack of RCTs comparing SABR treatments to surgical intervention and other treatments used in practice. We have previously defined and discussed RCTs and how they overcome patient selection biases in conventional cohort studies which limit the significance of the outcome. The fact that SABR has been found to be an effective treatment in most cases means it is primed for global adoption, the only piece missing is verification of the study results using RCTs. There have been a number of RCTs which have been proposed, we will be giving a brief overview of a few of these, potential ethical problems and their significance.

There are a number of SABR RCTs underway (Clinical Trials Identifiers: NCT02629458, NCT01753414, NCT02468024, NCT02984761,NCT03253978,NCT03071406) which aim to solve the patient selection bias limitations of their cohort predecessors.  The trials identified represent just a selection of a number of proposed RCTs studying differences between conventional radiotherapy, surgical resection, and SABR treatment. Whilst these trials will determine the efficacy of SABR with minimal bias, we cannot ignore the ethical concerns over equipoise (balance) requirements which have been raised for RCTs in radiotherapy 2.  with the acknowledgement of potential ethical problems, the future of SABR treatment and adoption hinges on the reliability of OS and PFS data, which RCTs maximise.

Conclusion

The aim of this report was to explore and review the SABR treatment modality in terms of its applications in the clinic based on past and current research. We have discussed the historical development of SABR, how SABR operates in order to treat small volume primary tumors and oligometastases. Furthermore we have evaluated current treatments of tumors and oligometastases, comparing with other treatments used to explain why SABR is an effective treatment option. Whilst most studies evaluated have shown SABR to be an effective treatment modality, there are flaws in patient selection and outcomes for retrospective and prospective cohort trails which most of them are based. SABR treatment effectiveness in terms of localized control, overall survival and progression-free survival needs to be further researched using RCTs.

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