Stereotactic body radiotherapy for early stage lung cancer—historical developments and future strategies

Introduction

Since the mid-1980s, efforts have been made to improve outcomes in non-small cell lung cancer (NSCLC) through escalating radiotherapy doses (1). However, attempts to dose escalate through either conventional fractionation or even altered fractionation has led to either disappointing tumour control or unacceptable toxicities (2-4). In the mid-1990s, the application of “intracranial radiosurgery” extra-cranially to treat small lung tumour targets was made possible with incremental technological advancements, starting first with the use of the rigid stereotactic body frame and then becoming mainstream when improvements in image guidance enabled frameless treatments and respiratory motion management. This was subsequently followed by a series of well-planned clinical studies in the early-2000s, which demonstrated efficacy and low rates of treatment-related toxicities (5-8). Since then, lung stereotactic body radiotherapy (SBRT) has firmly established itself as a standard treatment in early stage node negative medically inoperable NSCLC, effectively doubling biological effective dose (BED) and tumour control rates that were previously achieved with conventional radiotherapy (2). No other development in the management of NSCLC has had quite the same dramatic success. In this review, we will discuss the radiobiological principles underlying lung SBRT, technical considerations that are vital to its safe delivery, existing evidence supporting its use in various clinical settings and finally explore various strategies to optimise the therapeutic ratio in lung SBRT.

Search strategy

We searched the PubMed and MEDLINE databases for articles published in English from 1 January 2000 to 31 Dec 2016 with the keywords “conventional fractionation”, “stereotactic body radiotherapy”, “stereotactic ablative radiotherapy”, “dose escalation”, “biological effective dose”, “radiobiology”, “early stage”, “lung cancer”, “peripheral”, “central”, “toxicities”, “complications” “pneumonitis”, “Intensity Modulated Radiotherapy”, “Volumetric Modulated Arc Therapy”, “Proton therapy”, “molecular”, “genomics”, “biomarkers”. Articles were selected based on relevance, with priority given to highly cited articles, randomised clinical trials and articles written in English. Abstracts of main medical conferences were also included if survival and toxicity end-points were reported. Articles that were published before or after the search time frame were also included if they were widely referenced and highly regarded seminal work.

Radiobiology of Lung SBRT

SBRT is characterized by precision delivery of single large doses (generally ≥6 Gy) either in a single fraction or in a small number of fractions to a target volume (9). Delivery of radiation dose in this manner enables sharp escalation of BED as modelled by the classic linear quadratic (LQ) model resulting in better local tumour control probability (TCP) (2,10). The application of the LQ model to very large fraction sizes has been disputed due to in vitro and in vivo data suggesting an overestimation of cell killing at large single doses compared to more fractionated regimens (11). Furthermore, large radiation doses, similar to those used in SBRT, have been demonstrated to produce additional radiobiological effects including the induction of sphingomyelinase dependent ceramide-induced tumour endothelial cell apoptosis (12,13), vascular damage leading secondarily to tumour cell killing (14) as well as enhanced anti-tumour immune responses (15). However, correlation with actual outcome data for stage I NSCLC treated with typical lung SBRT dose-fractionations demonstrates accurate radiobiological modelling with both classic LQ model as well as a modified (16), “more realistic” version of the LQ model accounting for intra- and inter-tumour heterogeneity, therefore suggesting that additional radiobiological processes do not contribute significantly to cell killing in lung SBRT (17,18). This does not however mean that these additional radiobiological processes do not exist and they could yet be exploited in combination treatment strategies involving SBRT (19,20).

Technical considerations of lung SBRT

Precision delivery of high radiation doses to a moving tumour target in the lung requires respiratory motion control, dose construction with strict adherence to normal tissue dose constraints and treatment dose delivery with setup and target verifications (21-23).

Respiratory motion management

Management of respiratory motion is absolutely necessary both at simulation and subsequently during treatment delivery. During simulation, patients are often immobilised with a whole-body vacuum cushion with or without abdominal compression and respiration motion is mostly accounted for through the use of multiple CT scans taken at various points of the normal respiratory cycle, 4-dimensional CT (4DCT) scans, slow CT scans, a CT scan acquired at deep inspiration breath-hold or other respiratory gating strategies. 4DCT scans are widely used but may be limited by irregular breathing. While slow CT is able to produce target volumes similar to 4DCT scans, they may not accurately capture lung tumours with small respiratory movements (24,25). Deep inspiration breath hold or respiratory gating techniques minimise respiratory motion and increase normal tissue sparing from increased lung volume (26). They can be performed either involuntarily through the use of a spirometer connected to a balloon valve (Active Breathing Control, Elekta, Stockholm, Sweden) or voluntarily with visual or audio-visual biofeedback systems such as SDX (Dyn’R, Toulouse, France) or Abches (APEX Medical, Tokyo, Japan) with high reproducibility (27,28). Internal fiducials, which facilitate target verification and tumour tracking, are occasionally used but are not necessary and insertion of fiducials carries significant risks of pneumothorax in a fragile patient population (23). Accounting for inter-patient variation in respiratory motion of gross tumour volume (GTV) using individually tailored respiratory management strategies ultimately creates a patient and treatment-specific internal target volume (ITV). This represents an individualised solution, which is in sharp contrast to the early days of SBRT when patients were simulated on a single CT scan and crude population based margins were applied to account for respiratory motion. Another margin will be added to the ITV for set-up uncertainties and slight patient movements during treatment, resulting in a planning target volume (PTV). Additional margins for microscopic disease are not added during SBRT based on the understanding that any microscopic disease extending from the tumour would be dealt with by the dose fall off or penumbra (22).

Dose distribution in SBRT

In an attempt to standardize dosimetry across institutions and clinical trials, radiation therapy oncology group (RTOG) provides a set of planning guidelines to produce compact dose distributions with heterogeneous doses within the target, and steep dose gradients outside. Planning constraints limiting “hot spots” (doses greater than 105% of prescription dose) to within the PTV and enforcing a conformity index of 1.2 make the use of multiple non-opposing, non-coplanar beams with large angles between or multiple arcs with at least 180 cumulative degrees rotation imperative. At the same time, moderate dose spillage is kept to a minimum, as determined by the PTV size. Normal tissue dose-volume constraints specific to different dose-fractionations are applied. Pencil beam algorithms, which do not correct for increased electron scattering in lower-density material tend to underestimate doses in lung tumours and are not recommended in SBRT planning (21,22).

Dose-volume constraints

The determinants of dose-limiting toxicity in SBRT are organs within the thorax such as lung, central airway, bronchi, oesophagus, heart, great vessels, spinal cord and organs outside including the brachial plexus nerves, skin, stomach, small intestines, liver, chest wall and ribs. Dose-volume constraints of these normal structures are well established in conventional radiotherapy (dose per fraction of 1.8 to 2.0 Gy) and moderately hypo-fractionated schedules (dose per fraction of 3 to 5 Gy) with lower total BED_{normal tissue} (29,30). While dose equivalence can be established using the LQ model, there is uncertainty when extreme hypo-fractionated (≥6 Gy) doses such as those used in SBRT are applied to small volumes, especially in serially organized tissue. Therefore, dose-volume constraints specific to different dose-fractionation schedules have been systematically defined during prospective clinical studies and correlated with observed rates of toxicities. Initially, delivering SBRT to central lung lesions was thought to be unsafe and reliable data on dose-volume constraints for mediastinal structures was not available. This has changed with a series of phase 1 dose-finding studies in central lung SBRT. The normal tissue dose-volume constraints across single-, 3-, 4-, 5- and 8-fraction lung SBRT schedules are summarised in Table 1 (21,31-37).

Table 1 Normal tissue dose-volume constraints across single-, 3-, 4-, 5- and 8-fraction lung SBRT schedules
Full table

Beam delivery

While 3-dimensional conformal radiotherapy (3D-CRT) and dynamic conformal arc therapy (DCAT) offer good PTV dose distributions and adherence to normal tissue dose constraints, volumetric modulated arc therapy (VMAT) has been found to be consistently better in both regards (38,39).

The clinical significance of this dosimetric advantage is however controversial. Intriguing data from a recently published large scale retrospective analysis of 803 patients treated with SBRT across five European and North American institutions found an association between low doses to the upper regions of the heart (atria and vessels) and non-cancer deaths post SBRT. The study demonstrated that a maximum point dose to the left atrium (D_max) of median 6.5 Gy [EQD2₃, α/β_{normal tissue} =3; hazard ratio (HR)=1.005, P=0.035] and dose to 90% of the vena cava (D_90%) of median 0.59 Gy (EQD2₃, α/β_{normal tissue} =3; HR=1.025, P=0.008) were significantly associated with non-cancer deaths (40). While the link between association and causation is unclear, it is perhaps an important reminder that most patients receiving SBRT are medically inoperable with underlying cardiac and pulmonary co-morbidities. Apparently insignificant dose spillage into surrounding normal tissue may be clinically relevant and attempts should therefore be made to keep them to a minimum.

Nevertheless, beyond its dosimetric benefits, VMAT offers a shorter treatment duration and better patient comfort and compliance compared to 3D-CRT and DCAT, making it a more attractive option for SBRT (39). With VMAT or any other forms of intensity-modulated radiotherapy (IMRT) however, one has to consider the “interplay effect” and the uncertainty it brings to actual dose delivery (25). In this regard, it is perhaps reassuring that clinical outcomes from VMAT and IMRT SBRT have been excellent (39) and with measures in place such as placing constraints on multileaf collimator (MLC) motion, limiting delivery to two arcs and treatment to more than 2 fractions, the risk of clinically significant “interplay effect” in VMAT can be safely mitigated (25,41,42).

SBRT and clinical outcomes

Some of the earliest work in lung SBRT was accomplished by investigators in Japan and at the Indiana University. In a landmark study by Uematsu et al., outcomes from 50 patients treated with SBRT to dose fractionation schedules ranging from 50 to 60 Gy in 5 to 10 fractions were published in 2001. Of note, they included 18 patients who had already received prior high dose conventional radiotherapy (40–60 Gy in 20–33 fractions) and had recurred with presumably radio-resistant disease. Despite this, 47 of 50 patients achieved long-term local control (LC). Three-year overall survival (OS) was 66% and cause-specific survival was 88% (8).

Further dose escalation to improve outcomes

Meanwhile, 47 patients at Indiana University with T1-T2 N0M0 NSCLC were recruited to a dose escalation study in which they received doses starting at 8 Gy per fraction for a total of 3 fractions delivered over 2 weeks. Doses were increased in increments of 2 Gy per fraction and despite pre-existing co-morbidities, the investigators demonstrated that the maximum tolerated dose (MTD) was not reached for T1 tumours while the MTD for T2 tumours larger than 5 cm was realised at 24 Gy per fraction. Seventy-two Gy in 3 fractions was equivalent to a BED₁₀ of 244.8 Gy, which was significantly higher than anything previously achieved through conventional fractionation without significant toxicity. Furthermore, LC was excellent with only 1 failure seen when dose per fraction was higher than 16 Gy vs. 9 failures at doses less than 16 Gy, alluding to a dose-response relationship (43,44).

This dose-response relationship became clear when a Japanese multi-institutional study led by Onishi et al. demonstrated that a minimum threshold BED₁₀ of 100 Gy, prescribed to the isocentre, was required to achieve significantly better LC leading to improved OS (5). More recently, a large scale retrospective review of SBRT outcomes for 747 patients across 65 centres in the United States suggested this dose-response survival function continues to rise beyond the threshold BED₁₀ of 100 Gy, extending past 105 Gy and potentially 110 Gy (45) while Koshy et al. demonstrated that for larger T2 tumours, this dose response may even continue up to a BED₁₀ as high as 150 Gy (46). However, uncertainty remains on whether these doses were defined as PTV-encompassing doses or isocentric doses. Previous studies have suggested that isocentric doses correlate better with local TCP (17) and without knowledge of the prescription doses or dose profile, it would be difficult to draw conclusions.

To achieve further dose escalation safely, studies such as JCOG 0702 have helped guide clinical practice. In this study, the subset of peripheral T2N0M0 NSCLC (>3 cm) was specifically studied based on earlier reports demonstrating improved LC in these T2 tumours when dose was escalated from 40 to 48 Gy in 4 fractions (P=0.0015) (47). The authors concluded that for peripheral PTVs smaller than 100 cc, the MTD at the D₉₅ of the PTV could be safely increased from 40 Gy in 4 fractions over 4–8 days (BED₁₀ =80 Gy) to 55 Gy in 4 fractions (BED₁₀ =130.6 Gy) (34). Larger tumours with PTV greater than 100 cc can be safely escalated to 50 Gy in 4 fractions (BED₁₀ =112.5 Gy) (48).

Central lung SBRT

However, MTDs for peripherally located lesions cannot be applied to central lung tumours. Different definitions exists but in general, central lesions are distinguished as any tumour within or touching the zone of the proximal bronchial tree, defined as a volume of 2 cm in all directions around the proximal bronchial tree (carina, right and left main bronchi, right and left upper lobe bronchi, intermedius bronchus, right middle lobe bronchus, lingular bronchus, right and left lower lobe bronchi) as well as lesions which are immediately adjacent to the mediastinal or pericardial pleura, with a PTV expected to touch or include the pleura (6,31,49). When Timmerman et al. at the University of Indiana carried out a single-arm phase 2 study from 2002 and 2004, it quickly became obvious that SBRT to these central lung lesions resulted in higher rates of severe toxicities with 2-year freedom from severe toxicity rates of 54% (central) vs. 83% (peripheral) (P=0.004) (6) and they were subsequently excluded from the RTOG 0236 study. Other reports of severe and fatal toxicities after central lung SBRT followed (50,51). The clinical need to determine the MTDs for central lesions and establish reliable dose-volume constraints for each of the mediastinal structures resulted in investigators embarking on a series of dose-finding studies.

Dose finding studies in central lung SBRT

The EORTC sponsored LungTech trial (EORTC 22113-08113) led by Nestle et al. opened in late 2014. In this study, central tumours were treated with 60 Gy in 8 fractions and results are awaited (31). JROSG10-1 treated only T1 NSCLC patients and found the MTD to be 60 Gy in 8 fractions. At this dose, no grade 3 or worse adverse effect within 12 months of treatment was seen and all dose constraints could be met (32). RTOG 0813 led by Bezjak et al. reported their MTD to be 60 Gy in 5 fractions (1 fraction every 2 days). Thirty-three patients were treated with 60 Gy in 5 fractions with a median follow-up of 29.8 months and 38 patients were treated with 57.5 Gy in 5 fractions with a median follow-up of 33 months. Two-year LC and OS rate was upwards of 87% and 70.2% respectively. While overall rate of grade 3 or greater toxicities for all 71 patients was acceptable, the authors did report 2 (5.3%) grade 5 toxicities in the 11.5-Gy cohort and 1 (3%) grade 4 oesophageal perforation and 1 (3%) grade 5 pulmonary haemorrhage in the 12-Gy cohort (33). While these risks are low, they are severe and have to be discussed with patients. Longer fractionations appear to have a better safety profile and if efficacious, could represent a risk-adapted alternative for high-risk patients for whom severe toxicities may be catastrophic.

Single-fraction lung SBRT

The ideal dose fractionation has also been a subject of study in peripheral lung SBRT. A series of studies have looked at dose escalation in a single fraction and while many of them involve heterogeneous populations including both early stage NSCLC as well as pulmonary metastases from a variety of histologies, much can be learnt about tolerability as well as dose-response.

One of the earliest studies involving single-fraction SBRT led by Wulf et al. used 26 Gy in a single fraction to treat 1 early stage NSCLC and 25 small lung metastases including NSCLC metastases. Despite the heterogeneous disease treated, no local failures were seen with single-fraction 26 Gy at 11 months. More importantly, no severe acute or late normal tissue toxicity was observed (52).

Hof et al. treated patients with doses ranging from single-fraction 19 to 30 Gy at isocentre and found improved LC with doses equivalent to or higher than 26 Gy (P=0.032) (53). Again, no clinically significant treatment related toxicity was observed.

Meanwhile, Hara et al. treated 59 patients (11 early stage NSCLC and 48 metastases) using doses ranging from 26 Gy to more than 30 Gy (range, 30–34 Gy) and observed minimal toxicity with only 1 patient (1.7%) suffering grade 3 respiratory symptoms. Doses of 30 Gy and higher seemed to improve 2-year local progression free survival from 52% (<30 Gy) to 83% (P=0.07). However, the majority (88.1%) of tumours treated were smaller than 3 cm and maximum tumour size for all tumours was smaller than 4 cm (54). Studies have shown that larger treatment volumes greater than 50 cc (equivalent to a diameter greater than 4.5 cm) and patients who have received prior thoracic radiation are at significant risks of pulmonary toxicity even at single-fraction 25 Gy and higher doses should be used with caution (55).

RTOG 0915—fractionated vs. single-fraction SBRT

Comparing a single-fraction 34 Gy with the more commonly used 48 Gy in 4 consecutive daily fractions, RTOG 0915 aimed to ascertain the ideal lung SBRT dose fractionation. The primary end point of this study was rate of grade 3 or greater adverse events at 1 year and in this regard, single-fraction SBRT was found to be better tolerated {4 of 39 (34 Gy/1 fr) [10.3%, 95% confidence interval (CI), 2.9–24.2%] vs. 6 of 45 (48 Gy/4 fr) (13.3%, 95% CI, 5.1–26.8%)} while offering similar primary tumour control [2-year cumulative primary tumour failure rate 2.6% (34 Gy/1 fr) vs. 2.2% (48 Gy/4 fr)]. However, toxicities occurring at a later time point such as brachial plexopathies and longer-term decline in pulmonary function were not reported and could be clinically relevant. It is also important to note that while tumours less than 5 cm were eligible for the study, the median tumour diameter in the recruited single-fraction cohort was 2 cm (range, 1.00–4.98 cm) and it is possible that a higher toxicity rate may be seen if larger tumours had been treated (35).

Another concern with RTOG 0915 was that OS data beyond 1 year suggested a trend favouring 48 Gy/4 fr. This is despite the BED_tumour for single-fraction 34 Gy (BED₁₀ =149.6 Gy) being 44 Gy higher than the BED_tumour for 48 Gy/4 fr (BED₁₀ =105.6 Gy) (35). Even though this study was not powered to address differences in OS between the 2 treatment arms, advocates for fractionated SBRT have pointed to this to highlight concerns regarding tumour hypoxia-conferred radio-resistance, an effect thought to be more pronounced when treatment is delivered in a single fraction, therefore losing the protection that re-oxygenation offers fractionated treatments (20). Furthermore, single-fraction 34 Gy results in a much higher BED_{normal tissue} (α/β_{normal tissue} =3) of 419.3 Gy compared to a BED_{normal tissue} of 240 Gy for 48 Gy/4 fr and previous meta-analysis had found a detrimental effect on OS when BED₁₀ exceeds 146 Gy (56), possibly due to higher dose to normal tissue resulting in increased risk of occult toxicities and non-cancer related deaths (40,57).

For these reasons, at present, fractionated lung SBRT is more widely practised. Table 2 (35,36,52-55,58-64) summarizes a series of widely referenced lung SBRT studies involving both fractionated and single-fraction regimens.

Table 2 Data from the use of lung SBRT in medically inoperable patients
Full table

Surgery vs. SBRT

The earliest reports from Japan included a significant proportion of patients who were medically operable but refused surgery. For example, of the 257 patients reported by Onishi et al., 99 (38.5%) were medically operable. Five-year OS for these medically operable patients who received a minimum threshold BED₁₀ of 100 Gy was 72.3% (95% CI, 59.1–85.6%) for stage IA and 65.9% (95% CI, 43.0–88.9%) for stage IB (5). This was consistent with other studies, summarised in Table 3 (5,7,8,37,65-71), which reported excellent LC and 3-year OS rates upwards of 66%. This raised the question of whether SBRT should be offered as a reasonable alternative to medically operable patients. In particular, elderly patients with small peripheral lesions and borderline lung function or medical comorbidities, for which surgery and general anaesthesia are not without risks, are thought to benefit most from non-invasive SBRT. A Dutch population-based matched-pair comparison study between SBRT and surgery for the elderly cohort found 30-day mortality to be 8.3% after surgery vs. 1.7% after SBRT while 3-year survival rates between the two modalities were similar at 60% for surgery vs. 42% for SBRT (P=0.22) (72). Across all studies, SBRT for medically operable patients was expectedly well tolerated with incidence rates of Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or greater toxicity of up to 15% and a cumulative incidence of treatment related mortality of only 0.7% (68-71). On the other hand, overall complication rates from video-assisted and open thoracotomy lobectomy can be as high as 16.4% and 31.2% respectively (73) with 30-day post lobectomy mortality rates of about 2.4% (74).

Table 3 Data from the use of lung SBRT in both medically inoperable and operable patients
Full table

Three separate randomised studies [ACOSOG Z4099 (NCT01336894), STARS (NCT00840749) and ROSEL (NCT00687986)] attempted to compare surgery with mediastinal lymph node sampling vs. SBRT delivering a minimum BED₁₀ of 100 Gy but all suffered from poor accrual and closed prematurely. A total of 58 individual patient data from STARS and ROSEL trials were subsequently pooled and analyzed by Chang et al. Estimated OS at 3 years was 95% in the SABR group compared with 79% in the surgery group (log-rank P=0.037). The 3-year pooled estimated LC, regional control (RC) and distant control (DC) for the SBRT cohort vs. surgery cohort were similar at 96% vs. 100%, 90% vs. 96%, and 97% vs. 91%, respectively (75). SBRT appeared to be better tolerated than surgery with fewer grade 3 and greater toxicities (10% vs. 44%) and no treatment related deaths (0% vs. 4%). The authors concluded that for medically operable patients, SBRT showed at least clinical equipoise when compared to surgery. Furthermore, patient reported quality of life outcomes with SBRT have been found to be at least equal if not better than surgery (76,77).

On the other hand, with surgery and mediastinal lymph node sampling, up to 35% of patients can be upstaged, with half of these upstagings bringing about the addition of adjuvant chemotherapy (78). However, multiple studies have shown similar rates of regional and distant recurrences (62,72,75,79) for SBRT compared to surgery, perhaps due to sterilization of micrometastases through incidental mediastinal, hilar dose or the triggering of a systemic immune response against micrometastases (80). Furthermore, endobronchial lymph node sampling might be able to reduce some of the false negatives with PET-CT, which can be as high as 33.3% in higher risk central T2 lesions with a solid appearance on imaging (81,82). Isolated recurrences if they do occur can also be salvaged with definitive radiotherapy or in a few occasions salvage surgery (83-87). All in all, an argument could be made that for patients at a higher risk from surgery, SBRT should at least be discussed as an alternative.

Optimizing SBRT therapeutic ratio

Complications are rare in SBRT but relatively large hypo-fractionated doses mean that they can be potentially life threatening (33,58,88). These include central airway toxicities such as bronchial stenosis resulting in atelectasis (89), bronchial necrosis or hemoptysis (51), esophageal toxicities such as strictures, perforation or trachea-oesophageal fistulas (90), aortic toxicities such as hemoptysis secondary to aortic damage or aortic rupture, aortic aneurysm or aortic dissection (91), severe skin toxicities (92), chest wall pain including rib fractures (93-95), symptomatic radiation pneumonitis (RP) (96,97), and brachial plexopathies (98). Rarer complications include vagal nerve injury (99) and spontaneous pneumothorax (100). A post-treatment decline in pulmonary function can also be observed but it is usually not clinically significant (101).

Dosimetric parameters associated with these toxicities have been demonstrated (88-92,94,95,98,102) and have led to the establishment of dose volume constraints as previously shown in Table 1 (21,31-37). These constraints can be achieved through more precise delivery of radiotherapy with motion management strategies, intensity modulation and non-coplanar beam deliveries (38,39) backed by meticulous quality assurance. More fractionated regimens can also be used if there is a need for gentler doses to the normal tissue. This way, one can effectively kill two birds with one stone, achieving the minimum BED_tumour of 100 Gy for optimal local control and cure while reducing the toxicities of treatment by utilizing the benefits of fractionation.

However, dosimetric parameters alone do not adequately account for inter-patient variation in baseline normal tissue characteristics and intrinsic radiosensitivity. To account for these individual differences, considerations based on pre-treatment clinical, normal tissue and radiological characteristics need to be made. Pulmonary function tests are often performed prior to SBRT but appear to correlate poorly with grade ≥ 2 RP and patients with poor pulmonary function achieve cause specific survival and toxicity outcomes similar to patients with better function (103). Some institutions have sought to use baseline radiological characteristics as a means to identify patients at greater risk of RP. Subclinical interstitial lung disease manifesting as honeycombing on pre-treatment CT had been found to be associated with fatal interstitial pneumonitis post-surgery (104) and similar correlations with poor outcomes have been established in high-dose radiotherapy (66,105). Combining dosimetric parameters, age and extent of pulmonary fibrosis as determined according to the modified criteria of Kazerooni et al. (106) in a retrospective review of 122 patients, Tsujino et al. from Hyogo Cancer Centre proposed a predictive score which was able to predict the incidence of grade ≥ 3 RP with an area under the curve (AUC) of 0.888 (107). However, this cohort of patients received high dose conventional radiation concurrent with chemotherapy. The use of concurrent radiation sensitizers and likely larger treatment volumes mean that their findings may have limited applicability to SBRT treatments. Furthermore, while age is a predictive factor in this study, other studies have consistently shown that elderly patients tolerate SBRT treatments just as well as younger patients (62,72). For instance, Winship Cancer Institute of Emory University demonstrated an incidence of grade ≥3 RP of only 3.5% in their cohort of patients with a median age of 85. Interestingly, patients who were not on angiotensin converting enzyme inhibitors (ACE-I) were at a higher risk of RP [odds ratio (OR) 5.83, 95% CI, 1.29–26.32] suggesting that there are complex biological mechanisms underpinning RP (62).

Invariably, normal tissue toxicity is the result of an acute inflammatory response within the microenvironment to radiation injury, through expression and maintenance of inflammatory cytokines, fibrotic cytokines, chemokines and recruitment of inflammatory cells, leading subsequently to scar formation or fibrosis (108,109). Identification and monitoring of blood-borne inflammatory biomarkers such as transforming growth factor β (TGFβ), IL-6, Krebs von den Lungen (KL-6) and surfactant protein (SP-D) can potentially account for inter-individual differences in responses to radiation injury beyond clinical, radiological and dosimetric parameters (109,110). Indeed, in an attempt to further stratify patients’ risk of RP, Yamashita et al. prospectively combined individual pre-treatment blood biomarkers KL-6 and SP-D with presence of interstitial pneumonitis on CT imaging. Despite all patients meeting dose constraints as per JCOG 0403 protocol, they found an increased risk of severe RP in patients with elevated KL-6 [32% (high) vs. 3% (low), P=0.0002], elevated SP-D [29% (high) vs. 3% (low), P=0.0002] and interstitial pneumonitis on CT [57% (high) vs. 2% (low), P<0.0001]. To date, these biomarkers have not been validated in a larger independent cohort prospectively but they demonstrate the clinical benefits of identifying these susceptible, more radiosensitive patients a priori (110). Furthermore, up to 80% of inter-individual differences in normal tissue toxicity can be attributed to genetic differences underpinning inflammatory and DNA damage responses (108,111,112). Discussed in greater detail in the companion review by Tan et al. (113), high throughput sequencing techniques can identify common low penetrance allelic variations predictive of a more radiosensitive phenotype. Specific to definitive thoracic radiotherapy, several studies have demonstrated associations between radiation-induced pneumonitis and single nucleotide polymorphisms (SNPs) of heat-shock protein beta-1 (HSPB1) (114), TGFβ1 (115), ataxia-telangiectasia mutated (ATM) and Nijmegen breakage syndrome 1 (NBS1) (116) genes but they have not been validated in large-scale prospective genome-wide association studies (GWAS). Nevertheless, these genotyping findings, when integrated with epigenetic factors, post-translational modifications, cell signalling networks and metabolism in an all-encompassing “omics” approach, allow identification of critical pathways and complex interactions crucial to the development of normal tissue toxicity (112). Combined with imaging features, blood-borne biomarkers and functional cellular assays, this integrated predictive model can add a paradigm of biological precision to risk stratification and dose prescription in high risk SBRT involving central tumours or larger (≥ T2) peripheral tumours with borderline normal tissue doses; patients predicted to be at risk of toxicities can either be offered a more conservative dose regimen or alternative means of dose escalation can be explored by exploiting the dosimetric advantages of particle therapy, a technology which will be discussed in greater detail shortly. On the other hand, patients at low risk of toxicities can have their dose escalated further to maximise TCP. This risk-stratified approach is illustrated in Figure 1.

Figure 1 Proposed combinatorial risk-stratification models for predicting “radiosensitive” phenotypes for dose escalation strategies and patients at risk for nodal and distant failure for treatment intensification strategies post SBRT, thereby optimising the therapeutic ratio. SUV, standardised uptake value; KL-6, Krebs von den Lungen; SP-D, surfactant protein D; SNP, single nucleotide polymorphisms; HSPB1, heat-shock protein B1; TGFβ1, transforming growth factor β1; ATM, ataxia-telangiectasia mutated; Fr, fraction; SBRT, stereotactic body radiotherapy; PTV, planning target volume; OAR, organ at risk.

Future directions

Moving forward, exciting developments on the horizon offer new strategies and technologies, which can be complementary to and synergistic with lung SBRT. Particle beam therapy (PBT) enables irradiation of tumours at depth while allowing a very sharp dose gradient distal to the target. Initially limited to large teaching institutions, recent innovations have helped to drive down the size, cost and complexity of PBT facilities, making them far more accessible. Examples of these innovations include the vertically arranged proton therapy system in Aizawa Hospital, Matsumoto, Japan (Sumitomo Heavy Industries, Tokyo, Japan), the S250 (Mevion, Massachusetts, US) with its gantry mounted proton accelerator and superconducting synchrocyclotron and the Radiance 330 (ProTom International, Texas, US) with its modular design allowing customisation based on individual facility needs. On the back of these innovations, the number of PBT centres is expected to rise and it is projected that by 2017, there would be 27 PBT centres in the United States (US) alone (117). While concerns surrounding organ motion and interplay effects in lung PBT remain (118), with further improvements in motion management technology, the superior dosimetry offered by PBT can be harnessed to enhance tumour dose escalation and critical tissue sparing, especially when treating central lung tumours. In addition, particle irradiation may stimulate changes within the tumour microenvironment, which could potentially suppress metastatic processes such as cell migration and invasion (119). So far, early comparisons suggest that hypo-fractionation through PBT may offer additional clinical benefits over SBRT with conventional X-rays. In a systematic review by Chi et al. which pooled 72 SBRT studies and 9 single-arm hypo-fractionated PBT studies from 2000 to 2016, before adjusting for potential confounding variables, PBT was associated with improved OS (P=0.005) and PFS (P=0.01) while significantly reducing rates of ≥ grade 3 RP (P<0.001), ≥ grade 3 chest-wall toxicities (P=0.03) and rib fractures (P<0.001) (120). As PBT technology continues to evolve, direct comparison studies will be eagerly awaited.

In recent times, immune modulating strategies have dominated the headlines in oncology. The fervent embrace of immunotherapy in NSCLC started with early successes using checkpoint inhibitors in metastatic disease (121-123). In the companion review by Tharmalingam and Hoskin, the authors concluded that SBRT is most systematically immunogenic as demonstrated in both in vivo murine models (15,124) and reported clinical cases (125) and would therefore be the ideal candidate for combination with immune modulating strategies (126). This approach will be the subject of investigation in the Dutch PEMBRO-RT study (127) (NCT02492568) but only in the setting of metastatic disease. In early stage disease, nodal and distant failures can be as high as 30% (36,60). Histologic features such as micropapillary-predominant, solid with mucin-predominant subtypes (128,129) and vascular invasion (130), pre-treatment SUV max on ¹⁸F-FDG PET (131) and gene-expression profiles (130,132) can predict for higher risk early stage disease (133) and stratify these patients for treatment intensification with further systemic treatment or combination with immunotherapy. To this end, large-scale genotyping efforts such as the Lung TRACERx Study (134) have provided new insights into tumour evolution and biology. Multi-region whole-exome sequencing of 100 early stage NSCLC in the TRACERx cohort found that intra-tumour heterogeneity, mediated through chromosome instability, was associated with an increased risk of recurrence or death following surgery (HR=4.9, P=4.4×10⁻⁴) (135). Furthermore, owing to the sub-clonal nature of early stage lung cancer relapse and metastasis, tumour-specific phylogenetic profiling of circulating tumour DNA (ctDNA) in serially collected liquid biopsies, was able to quantify sustained presence of sub-clonal single nucleotide variants in ctDNA post-surgery, which preceded subsequent relapse and adjuvant chemotherapy resistance (136). Taken together, high throughput genomic profiling of tumours and ctDNA can be exploited to identify “high risk” early stage NSCLC for treatment intensification following SBRT. This strategy is illustrated in Figure 1.

Conclusions

In the past 2 decades, through a series of well-planned clinical trials and advancements in radiotherapy technology, lung SBRT has cemented its place in the management of early stage NSCLC. The era of precision medicine has not only divulged new insights into the biology of this disease but also into inter-individual differences in responses to radiation injury. Going forward, with new tools at our disposal, these insights will inspire new intelligent strategies to further improve our cure rates of early stage NSCLC.

Acknowledgements

Funding: ML Chua is supported by the National Medical Research Council Singapore Transition Award (#NMRC/TA/0030/2014), and the Duke-NUS Oncology Academic Program Proton Research Program.

Footnote

Conflicts of Interest: KL Chua has received speaker honorarium from Varian Medical Systems; ML Chua has received speaker honorarium from Varian Medical Systems, and research funding from GenomeDx Biosciences. The remaining authors have no conflicts of interest to declare.

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