Pitfalls in lung stereotactic body radiotherapy—a review of organ toxicities and dose constraints

Introduction

Stereotactic body radiotherapy (SBRT), which is also known as stereotactic ablative radiotherapy (SABR), has been established as a treatment for early-stage inoperable non-small cell lung cancer (NSCLC) in several international guidelines. One of the earliest phase I study data in lung SBRT was first published in 2003 by Timmerman and colleagues (1), with the same group subsequently reporting excellent phase II results (2). These two trials and similar landmark studies, now form the basis for lung SBRT practice internationally.

Although SBRT is a proven treatment option for early stage inoperable NSCLC, it is still fairly new and not available in many developing parts of the world. There are still uncertainties with regards to optimal radiotherapy dose-fractionation regimen and because of the large ablative doses used in SBRT, there is a potential for significant side effects. In this paper, we elaborate on the common toxicities reported in literature in relation to SBRT of lung tumors as well as factors that may increase these risks.

Organs at risks (OAR)

The common toxicities reported in literature relating to SBRT of lung tumors can be divided into general radiation therapy related, like fatigue, and specific toxicities relating to structures within the thorax such as the heart, chest wall (CW), lung, major airways, greater vessels and esophagus. Collectively, these structures are known as organs at risks. This is especially important to tumors located close to these structures [e.g., centrally located tumors (Figure 1)] or in situations where a patient may be at greater risk of toxicities (e.g., patients with reduced lung function).

Figure 1 Central “no-fly” zone (light green dashed lines) was initially defined by Timmerman et al. (3) as tumor within or touching the zone 2 cm in all directions around the proximal bronchial tree. The IASLC expanded this definition to include tumors within 2 cm to any mediastinal critical structure, including the esophagus, heart, major vessels, spinal cord, brachial plexus, phrenic and recurrent laryngeal nerve (4).

The radiobiological effects of extreme hypofractionation on tissues are not fully understood (5-7) and existing models may not provide accurate normal organ tolerances (8). It is thus not advisable to freely apply the OAR dose limits used in conventional radiotherapy on SBRT. However, due to the lack of long-term data and limited patient numbers, the linear-quadratic model is still often used for radiotherapy planning.

In 2010, with the increasing use of SBRT, the American Association of Physicist in Medicine Task Group 101 (AAPM TG101) (9) published their recommendations of OAR dose constraints (Table 1) in the first attempt at guiding radiotherapy planning. Notably, most of the recommended constraints were derived anecdotally and not validated. Subsequent published studies have helped refine organ constraints further with reasonable toxicity rates reported so far.

Reported toxicities in prospective series

Many well conducted prospective trial protocols have published OAR dose limitations (Table 1). These serve as guidelines for many centers and allow the safe and effective delivery of SBRT techniques.

Radiotherapy related toxicities are graded by severity based on the Common Terminology Criteria for Acute Adverse Events (CTCAE) (15) or the RTOG/EORTC (16) late radiation morbidity scoring schema. However, a common problem when reporting toxicities is the interplay of other factors e.g., infection, systemic treatment toxicities or comorbidities like chronic obstructive pulmonary disease (COPD) and tumor progression that can make the direct attribution from radiotherapy alone hard to interpret. Nonetheless, grade 3 toxicities and above (≥ G3) are considered severe as there would be impairment of function requiring some form of intervention.

A literature review of SBRT primary lung prospective trials was performed. Nineteen trials, from 21 published articles and 5 abstracts were found, with a total of 1,381 patients reported. Data that was reported from the same center and trial were combined as the patients were assumed to be from the same cohort. The study, trial type, size, tumor criteria, radiotherapy dose-fractionation, median follow-up and reported ≥ G3 toxicities are tabulated (Table 2). Reported ≥ G3 toxicities rates ranged from 0–29.8%. There were 21 cases of grade 5 (G5) toxicities.

From Table 2 we see that SBRT doses vary between centers. Choice of dose regimen and are often determined by physician comfort, tumor and patient characteristics. These trials along with other retrospective series have increased our appreciation for the toxicities in lung SBRT and provided the evidence for organ dose tolerances. Recognizing these potential toxicities allows us provide an informed decision and allow for safe delivery of treatment.

Toxicities by site

Lung

One of the most common toxicities related to SBRT of the lung is radiation pneumonitis (RP) (Figure 2), which can range from asymptomatic to symptomatic breathlessness, fevers, cough and even death from respiratory failure. The non-specific presentation of RP and contributory comorbidities can make it difficult to distinguish an acute episode of radiation induced pneumonitis from other differentials like pneumonia or COPD exacerbations. This makes the comparison of incidence between studies difficult.

Figure 2 Case of grade 3 radiation pneumonitis (A) a 66-year-old male smoker with 3.5 cm peripheral primary lung tumor. CT scan shows bilateral emphysematous changes at the apices; (B) 6.5 months after SBRT of 48 Gy/4#. Patient had fever, cough and shortness of breath that did not improve with a course of antibiotics. Chest X-ray shows left upper and right middle zone air-space opacities; (C) CT scan shows left upper zone focal consolidation with patchy ground-glass changes in other areas in the lung. Patient was diagnosed with G3 radiation pneumonitis; (D) CT performed 2 months after treatment with steroids showed near resolution of previously noted parenchymal opacities. Scarring, volume loss and traction bronchiectasis in location of previous tumor. The V20 Gy was 4.3% (lungs-GTV) and 9.1% (ipsilateral lung). CT, computed tomography; GTV, gross tumour volume.

In a large pooled cohort study of 505 cases (39), the rate of ≥ G2 and ≥ G3 pneumonitis was 7% and 2% respectively. There was 1 case (0.2%) of G5 pneumonitis. Time from RT to onset of pneumonitis was a median of 0.4 years. The risk can vary with some series reporting up to 12% cases of life-threating RP (3,40). The risk of toxicities is noted to be more in patients with central and large lesions (3,41). Mid-lower lung lesions (42-44) are also at an increased risk of RP. This may partly be attributed to greater radiosensitivity of the area, functional importance of the lower lung (45) and increased respiratory motion (44), which results in a larger planning target volume (PTV).

An association between different dosimetric parameters and rates of RP has been noted in several studies. Barriger et al. reported mean lung dose (MLD) >4 Gy (4.3% vs. 17.6%; P=0.02) and a volume of lung receiving 20 Gy (V20 Gy) >4% (4.3% vs. 16.4%; P=0.03) being associated with an increased risk of G2-4 RP (46). Yamashita et al. and Inoue et al. similarly reported the predictive significance of MLD and V20 Gy (40,47). The ipsilateral MLD >9.14 Gy, total lung V5, V15, V20, V25 and V40 Gy ≥6.3% have also been associated with higher rates of RP (48-50). Doses to the contralateral lung V5 Gy >26% and MLD >3.6 Gy have been associated with increased rates of RP as well (51,52). Another parameter looked at is the conformity index (CI) which measures the ratio of volume treated to prescribed dose over the PTV. This is ideally kept as close to 1 as possible, to ensure the high dose region conforms to the target volume. Notably, RP occurs at a significantly increased frequency in patients with poor CI (P=0.0394) (40).

Patient related factors such as older age, pre-existing pulmonary comorbidities and female gender are associated with increased risk of RP (53-56). Interestingly, smoking was found to be protective against RP in some studies (54,57-60). Genetic factors such as single nucleotide polymorphisms (SNPs) of heat shock protein beta-1 (HSPB1) (61), methylene tetrahydrofolate reductase gene (MTHFR; rs1801133) (62), vascular endothelial growth factor (VEGF) gene (63), ataxia-telangiectasia mutated (ATM) (64-66) and Nijmegen breakage syndrome 1 (NBS1) genes (66) are also at increased risk of RP.

A pulmonary function test (PFT) done before SBRT does not always predict for RP (21,67). Changes in post-treatment PFT are usually minimal (18,23,24,68), although it will be decreased in the presence of RP or lung disease. The presence of baseline interstitial lung disease (48,49,69-71) and collagen vascular disease (CVD) (72) is a significant predictor of RP. In patients with idiopathic pulmonary fibrosis, the pre-treatment 18F-fluorodeoxyglucose (FDG) on positron emission tomography (PET) non-target lung uptake may serve as a biomarker for degree of baseline inflammation and predict the risk for RP (73).

Inflammatory cytokines to predict for RP has been extensively studied. Plasma transforming growth factor beta (TGFβ) is a cytokine which stimulates proliferation of fibroblasts, collagen synthesis and associated pulmonary fibrosis. It is chronically elevated in patients with CVD (72). TGFβ-1 polymorphisms (74) and elevated levels of TGFβ-1 after radiotherapy have been associated with an increased RP risk (75,76). Other serum biomarkers such as elevated pre- & post-treatment interleukin (IL)-6 (77,78) and IL-8 (79) have been associated with higher rates of RP. Pre-treatment levels of Krebs von den Lungen (KL-6), a circulating mucin-like glycoprotein expressed and secreted from bronchial epithelial cells and type II pneumocytes, and lung surfactant protein (SP-D) are also associated with an increased risk of severe RP (80). Elevated post-treatment KL-6 levels are correlated to higher RP incidence as well (81).

To date, these markers are not routinely screened and have not been prospectively validated for clinical use. In the future, a combination of biomarkers, patient and dosimetric parameters may improve the ability to predict RP and allow for better individualization of target doses to reduce lung toxicities.

Heart

A wide spectrum of heart toxicities are noted following conventional radiotherapy. Early toxicities include pericarditis and pericardial effusion. Late toxicities manifest 10–15 years after radiotherapy as disease of the coronary arteries, heart valves, conductive system and myocardium. Microvascular changes and accelerated coronary sclerosis are thought to contribute to the process (82). Studies on radiation effects of the heart are mostly obtained from conventionally treated breast and mediastinal lymphoma patients. Darby et al. showed a 7.4% increased risk of ischemic heart disease per Gy (mean heart dose) (83). An RTOG 0617 trial randomized patients between high vs. standard conventional dose RT for lung cancer and reported heart V5 and V30 Gy as significant predictors for worst survival (84,85).

The effects SBRT doses have on the heart are less understood. A large retrospective analysis of 803 patients treated with SBRT reported that maximum point dose (Dmax) to the left atrium of median 6.5 Gy (P=0.035) and dose to 90% of the vena cava (D90%) of median 0.59 Gy (P=0.008) were both associated with non-cancer deaths (86). Increased cardiac uptake on FDG PET after SBRT may be a marker of radiation induced myocardial injury and was noted to be associated with a cardiac V20 Gy >5 cm³ (87).

An institution in Florence treated 16 patients with paracardiac/cardiac lesions up to 36 Gy in 3 fractions at the 70% isodose line. At a median follow-up of 6.7 months, no cardiac event or echocardiography changes were noted (88). However, it is important to note that SBRT patients tend to have a better prognosis and therefore a longer time to develop late heart toxicities. It is thus advisable to keep heart doses to a minimum during radiotherapy planning.

Major vessels

Major vessels include the aorta, pulmonary vessels and superior vena cava. Radiation damage to these structures can result in hemoptysis, exsanguination secondary to rupture, aortic aneurysms or dissection and pulmonary hemorrhage.

Xue et al. recently published a logistic dose-response model for aorta and major vessels based on a total of 625 cases. They estimated that at Dmax =52.5 Gy in 5 fractions, the risk of grade 3–5 toxicity was 1.2%. At Dmax =45 Gy in 3 fractions, the risk was 2.3% (89). They concluded that following internationally recommended constraints, sufficiently high doses can be achieved with low risks to the vessels.

Central airways

The proximity of centrally located lesions increases the risk of central airways toxicities. This can result in atelectasis, stenosis/stricture, airway necrosis, fistula formation or even fatal hemoptysis (90). A phase II study from Indiana University reported 11-fold higher risk of G3–5 toxicities, with 4 deaths associated with central location (3). The most common severe toxicity in the trial were hemoptysis, stenosis, airway occlusion and fistula formation. At median follow-up of 50.2 months, the risk of toxicity remained higher compared to peripheral lesions (27.3% vs. 10.4%) (17).

At conventional high dose (≥73.6 Gy) RT, Kelsey reported a 6% to 57% narrowing of mainstem bronchus in 17 of 18 patients (91). The degree of stenosis was dose dependent and progressed with increasing time after radiotherapy. It was worse if the patient received chemotherapy.

With SBRT, Song et al. reported that at doses of 40–60 Gy in 3–4 fractions to central tumors, 8 of 9 patients (89%) showed complete or partial bronchial stricture at a median follow-up time of 26.5 months (92). Karlsson et al. prescribed doses of 20–50 Gy in 2–5 fractions for central tumors and reported incidence of 24.3% radiation-induced atelectasis at a median time of 8 months (1.1–30.1 months). On analysis, there was a dose dependent correlation. The median 2 Gy equivalent doses to 0.1 cm³ of bronchial tree in patients who developed atelectasis was 210 vs. 105 Gy in who did not (P=0.031) (93).

Duijm et al. reported results in 134 patients treated with SBRT to central tumors. They correlated toxicities in different parts of the airway with dosimetric parameters. Higher grade toxicities such as occlusion and atelectasis were reported in the lobar and segmental bronchi. When 0.5 cc of segmental bronchi was irradiated to 50 Gy in 5 fractions, the likelihood of occlusion was 50%. For the mid- and mainstem bronchi, the 50% risk to develop grade 1 radiographically evident side effects was a Dmax of 55 and 65 Gy respectively (94).

Fatal hemoptysis attributed to high-dose RT are uncommon but have been reported in literature (95-98).

Esophagus

The esophagus is another dose limiting organ in central lung SBRT. Reported side effects range from mild esophagitis to life-threatening strictures, perforations and trachea-esophageal fistulas (1,99). Cox et al. reported 6.8% ≥G3 esophageal toxicities in 182 patients treated with 24 Gy single fraction paraspinal radiosurgery (100). The incidence increased with higher doses-volumes. At the median split D2.5 cm³ >14.02 Gy, the risk was increased 6-times (P=0.01). They recommended a Dmax of 22 Gy.

However, despite keeping SBRT doses-volume to constraints that are considered safe (D5 cc 14.5 Gy, D2 cc 15–20 Gy, and Dmax of 19 Gy), Abelson et al. reported 2 incidence of high grade toxicities (esophageal fistula and esophageal perforation) in 31 patients (101). Notably, these 2 patients had received chemotherapy which is felt to be a co-factor.

In a systematic review, which included data from 563 central lung tumors from 20 studies, the incidence of G3–4 toxicities was 8.6% (102). The risk of treatment related mortality was reduced when tumor biological equivalent dose (BED) was <210 Gy (3.6% vs. 1%). The authors concluded that acceptable control and limited toxicities could be achieved with appropriate fractionation regimens e.g., 50 Gy in 5, 54 Gy in 6, 56 Gy in 7 and 60 Gy in 8.

Further research is needed to establish more reliable dose limits for mediastinal structures. The RTOG 0813 (12,32), Nordic-HILUS (34) and EORTC LungTech (103) trials are phase II SBRT trials that will provide a better understanding of treatment of central lung tumors.

CW, skin and ribs

CW pain, rib fractures (Figure 3) and skin toxicities are associated with peripheral lung tumors. The mechanisms for CW pain are unclear and suspected to be due to damage of soft tissue, neurovascular bundle and bone (104). The correlation between rib fractures and CW pain is less certain, with majority of CW pain presenting without rib fractures or vice versa (105,106).

Figure 3 Asymptomatic rib fracture (blue arrow) noted 33 months after 48 Gy/4# SBRT of a peripheral tumor. The chest wall V30 Gy was 83.6 cc.

Creach et al. reported that CW doses receiving V30–40 Gy was most predictive of CW pain. A V30 Gy threshold of 0.7% and V40 Gy threshold of 0.19% was correlated with a 15% risk of CW pain (106). Mutter et al. reported similar findings in that V30 Gy >70 cm³ correlated with the presence of CW pain (104). Stephans et al. reported similar dose volume constraints and by maintaining V30 Gy ≤30 cm³ and V60 Gy ≤3 cm³ should result in a <10–15% risk of late CW toxicity (107).

Grills et al. reported in 483 patients, the incidence of rib fracture was 8% at median time of 0.9 years. This was associated with a higher BED and the optimal BED cut off was 132 Gy (11% vs. 5%; P=0.007) (39). Other reported parameters for dose constraints to rib or CW are Dmax =50 Gy, V40 Gy <5 cc (105) and the dose to 2 cm³ of rib (D2 cm³). At rib D2 cm³ <21 Gy/3#, the risk of the ribs fracture is close to 0%. At 27.3/3# and 49.8/3#, the risks are 5% and 50% respectively (108).

Obesity, diabetes and posterior tumors close to skin surface at an increased risk of skin and CW toxicities (109,110). Treatment factors to reduce skin toxicities should be undertaken by reducing the bolus effects from immobilization devices, calculating the skin doses and using multiple non-coplanar beams. The recommended constraints to skin reduce toxicities were reported as Dmax <50% prescribed dose (110), and reducing the volume of the CW receiving 30 Gy (V30 Gy <50 mL, 22% vs. ≥51 mL, 44%; P=0.02) (109).

Bonger’s et al. compared different fractionation regimens in which 60 Gy was delivered in 3, 5 or 8 fractions depending on tumor location and did not note a significant difference between CW toxicities (111). However, in challenging cases not meeting dose constraints, longer fractionation regimens e.g., 70 Gy in 10 fractions may be a suitable alternative to reduce the risk of CW toxicities and produce similar local control rates (112).

Brachial plexus

Brachial plexus injury can happen during SBRT of apical lung tumors. Injury to the plexus can present as neuropathic pain in the shoulder or arm, motor weakness or paresthesia (113). Chang et al. reported that in patients with central tumors, the brachial plexopathy incidence was higher when Dmax >35 Gy and V30>0.2 cm³ (P=0.001) (114). By limiting total dose delivered to the plexus to <26 Gy in 3–4 fractions, there would be a decreased risk of brachial plexopathy at 2 years (46% vs. 8%, P=0.04) (115).

Thoracic re-irradiation

Recurrent lung tumours after prior radical treatment poses technical challenges due to concerns of cumulative doses. SBRT of recurrent lesion could possibly provide better control benefit and reduce the toxicities because of smaller margins and tighter dose constraints. Most of the data comes from retrospective reports and a few prospective studies of both conventional and hypofractionated regimens.

Irradiation outcomes after SBRT reirradiation have yielded variable toxicity results. Reported severe ≥ grade 3 toxicity rates varied between 0% in some studies (116-122), to as high as a 10% incidence of G5 bleeding (123). Some studies noted no association between toxicities and lung dosimetric parameter, BED or overlap with prior radiotherapy fields (123-126). The risk is however increased with central tumour reirradiation.

Kilburn et al. (127) reported an incident (9.1%) of grade 5 aorta-esophageal fistula after reirradiation of a central tumour. The patient’s aorta and esophagus had received an estimated summed EQD2 of 200 and 106 Gy (128) respectively. Trovo et al. (125) reported high incidences of grade 5 (1 pneumonitis and 1 hemoptysis) and grade 4 (4 pneumonitis) toxicities after 30 Gy in 5–6 fractions in 17 patients with central tumour recurrences. The heart Dmax (mean 27 vs. 10 Gy), D5 (minimum dose to at least 5% of the heart volume) (mean 10 vs. 5 Gy) and D10 (mean 7 vs. 3 Gy) were associated with risk of severe pneumonitis. Peulen et al. (123) reported 3 deaths (10.3%) from massive bleeding and 1 grade 4 toxicity (superior vena cava stenosis and gastro-tracheal fistula) in patients with central lesion (n=11) vs. no G4–5 toxicity in peripheral lesions (n=21). Patients with a larger initial and reirradiation CTVs and a shorter interval between initial SBRT and reirradiation were at risk of more severe toxicities. Evans et al. reviewed patients who had undergone retreatment radiotherapy. Two of 35 (5.7%) patients had G5 toxicities at a median follow-up of 42 months. When 1 cm³ of aorta had a composite dose of ≥120 vs. <120 Gy, the rate of G5 aortic toxicity was 25% vs. 0% respectively (P=0.047) (129).

A team from MD Anderson have reported the largest cohort series of lung SBRT reirradiation so far. Early results after doses of 50 Gy in 4 factions, reported grade 3 toxicities of dermatitis, CW pain and brachial plexopathy (130) which were appeared related to high doses of >35 Gy to skin and ribs and >40 Gy to brachial plexus respectively. Subsequent reports (131,132) in larger cohorts reported incidences of grade 3 esophagitis, CW ulcers and cough. The reported severe pneumonitis rates was 20.8% (132). Analysis showed association between grade 3 pneumonitis and out-of-field relapse (131), ECOG 2-3 and FEV1 ≤65% before SBRT, V₂₀ ≥30% of the composite plan, and an previous PTV spanning bilateral mediastinum (132). It is proposed that possible reason lesser rates of pneumonitis were noted in-field relapses was that previously irradiated areas are fibrotic and less susceptible to additional damage from RP. CW pain requiring narcotics was more common in patients with in-field relapses. The dose constrains used were reported (Table 3).

Recently Chao et al. (133) reported a multi-institutional prospective trial using proton therapy for lung irradiation in 57 patients recurrent NSCLC. Median reirradiation dose prescribed was 66.6 Gy with 68% having concurrent chemotherapy. Cumulative point dose constrain to the spinal cord was 75 Gy (RBE). Forty-two percent ≥ grade 3 acute or late toxicities were reported at a median follow-up of 7.8 months. There were 6 possible or probable RT related grade 5 toxicities—bronchopulmonary hemorrhage, neutropenic sepsis, anorexia, pneumonitis, hypoxic respiratory failure/pleural effusion and tracheoesophageal fistula. Central region overlap (≥41 cm³), concurrent chemotherapy, composite mean heart dose ≥3.94 Gy and median esophagus dose of ≥12.45 Gy were associated with more toxicities.

The interpretation of results from various trials can be difficult because of heterogeneous cohorts and individually small numbers. De Bari et al. (128) and the MD Anderson (130-132) group have published their dose constraints recommendations. However, as there still many variables that cannot be accounted for e.g., disease free interval, previous radiation toxicities, individual characteristics, the OAR constraints in this setting remains poorly defined (134). Outcome results are promising but caution must still be exercised especially in reirradiation of centrally located tumors.

Conclusions

Published literature in lung SBRT have reported good local control rates with acceptable toxicity profiles. However, with the high doses per fraction used, there is an increased risk of normal tissue toxicity compared with conventionally fractionated radiation therapy. Care must be taken to minimize radiation exposure to normal structures. This is especially important for centrally located tumors. The available trial protocols and international consensus serve as good guidelines for SBRT dose constraints. Different dose-regimens have been used to increase the BED delivered and reduce toxicities. Future trials will aid in our understanding of the organ dose tolerances. Studies in biomarkers and individual patient risks are underway to better tailor our SBRT treatments.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Kam-Weng Fong, Kevin Lee Min Chua) for the series “Radiotherapy in Lung Cancer” published in Journal of Xiangya Medicine. The article has undergone external peer review.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/jxym.2018.09.04). The series “Radiotherapy in Lung Cancer” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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