2. Introduction
• The incidence and severity of radiation-induced damage depends on
• radiation dose delivered to different tissues or organs,
• the volume irradiated,
• fractionation schedule,
• concomitant treatment, and
• patient-specific aspects such as
• general health,
• comorbidity and
• genetic factors (such as radiosensitivity)
3. Introduction
• In SBRT of peripherally located lung lesions,
• the most common side effects are mild and transient and
• consist of skin rash, fibrosis in the high-dose area and a related cough.
• The Nordic phase II trial of SBRT treated NSCLC reported
• grade 1-2 pneumonitis 18%
• grade 1-2 dyspnea 18% and
• grade 1-2 fibrosis 35% .
• Serious toxicity (grade 3-4) in prospective trials
• are in the range of 16-30%
• mainly consisted of pulmonary related symptoms,
• majority presenting within the first year post treatment.
• A higher rate of serious toxicity has been noted with
• centrally located lesions and
• apical part of the lung
4. Time frame of toxicity
• The time for the manifestation of radiation response varies between different kinds of
cells, due to diversity in lengths of cell cycles.
• Range from a few hours to several years.
• Toxicity is often classified into acute or early toxicity and late toxicity.
• Early toxicity is generally defined as that appearing within 3 months from radiotherapy,
• Late toxicity appears after 3 months up to several years after the treatment.
• The early-responding cells are those that proliferate fast, like epithelial cells, and respond
to radiation within weeks from treatment.
• A short overall treatment time will reduce the cell repopulation time, which is an extra burden on
healthy cells but an advantage in terms of tumour control.
• Late-responding cells, like in the lungs and spinal cord, have a slower proliferation and
express damage after weeks or years after the treatment.
• These cells are less affected by the overall treatment time.
• Late-responding cells are more sensitive to the dose per fraction than early-responding cells.
• Early side-effects are often temporary and heal, while late side effects might be chronic.
Dobbs & Landberg, 2003; Steel, 2007
5. Introduction
Summary Of Common Toxicity Post SBRT In Stage I Lung Cancer
Toxicity Incidence
Radiation pneumonitis ≥G3: 4–8% (12–15% in pulmonary fibrosis)
Chest wall pain 11–15% (2–3% rib fractures)
Skin toxicity 4–6% (<1% skin ulceration)
Brachial plexopathy Rare
Fatal bleeding Rare (but 2-3% in centrally located tumours)
Late radiological changes 50-80%
7. Radiation Pneumonitis
• RP is one of the most common toxicities after SBRT.
• Most of the RP is of RTOG grade 1 or 2 and roughly asymptomatic; in
few cases, it may be more severe and clinically symptomatic.
• In large retrospective studies, the incidence of
• grade ≥2 RP was below 8%,
• grade ≥3 RP rate in the range of 2–3%;
• severe RP is higher only in patients with pre-existent idiopathic pulmonary
fibrosis
10. Radiation Pneumonitis
• The architecture of the lung can be considered as subunits arranged in
both parallel and series.
• Centrally, the structure is ‘‘in series’’ as the large vessels and airways in the
mediastinum and hilum support all of the distal vessels and airways to which they
are connected.
• Fibrosis/stenosis of a central vessel or bronchus will render the downstream alveoli
nonfunctional.
• Conversely, in the periphery, the smaller alveolar/capillary units function relatively
independently (i.e., ‘‘in parallel’’).
• Resection or injury to a region of lung will not compromise function of adjacent regions.
• The alveolar/capillary units appear far more sensitive to the effects of RT
than the central conducting airwaysand vessels.
• Therefore, most RT-induced injury is referable to these ‘‘peripheral’’
structures and the lung is classically considered a ‘‘parallel’’ organ
regarding RT induced effects.
11. Radiation Pneumonitis
• Radiation injury of the lung is categorized as two distinct phases:
• acute inflammatory (pneumonitis) and
• late fibroproliferative.
• In humans, the pneumonitis phase peaks between 2–3 months after
radiation exposure.
• This phase is characterized by a dense inflammatory cell infiltrate,
exudation of proteinaceous material, and edema.
• The chronic fibroproliferative phase occurs months to years after
exposure and is characterized by diffuse interstitial fibrosis, focal
scarring, and impaired ventilation.
13. Predictive Markers in Radiation Pneumonitis
• Risk factors and predictors of symptomatic RP following SBRT
• Patients-related
• Disease related
• Dosimetric and
• Diagnostic
14. Patient related
• Age >65 years,
• Poor performance status,
• Presence of co-morbidities
• Underlying subclinical interstitial lung disease (ILD),
• uncharacteristically extensive and fatal RP extending beyond the irradiated
field.
• Severe COPD
• reduced risk for radiation pneumonitis as compared to patients with milder
COPD,
• “tissue amount” theory - patients with severe COPD have less lung tissue to
generate an inflammatory response.
Kang, Cancers, 2015
Lindberg K, 2015
15. Radiation Pneumonitis & severe COPD
• No association found between pre-treatment PFT values and the
incidence of RP in patients with severe COPD GOLD III-IV.
• In the RTOG0236 prospective phase II trial, over a 2 years interval, the
mean percentages in FEV1and DLCO decline were 5.8% and 6.3%,
respectively, with minimal changes in blood gases and no significant
decline in oxygen saturation.
• No clinically significant changes in pulmonary function were evident after
SBRT, at a dose of 54 Gy in 3 fractions.
Guckenberger, JTO, 2012
Stanic, IJROBP, 2014
Ueki, JTO, 2015
SBRT can be safely delivered in patients with severe pulmonary
comorbidities and in patients with very poor pre-treatment
pulmonary function.
16. Patient related
• Smoking
• inversely correlated with the development of RP, particularly with regards to
smoking status at the time of RT and pack-years smoked .
• Possible reduction in radiation-induced inflammation and increases in
smoking-associated pulmonary and/or plasma glutathione, and consequent
prevention of oxidant lung injury.
• Female gender was a significant factor for predicting grade 2 RP in
• Potential confounding of reduced total lung volume among females which
may result in relatively higher doses delivered to the remaining normal lung
Kang, Cancers, 2015
Ivan, 2012
17. Disease related
• Severe toxicity and death after SBRT have been observed in central lesions,
compared to peripheral tumours,.
• For these tumours, the distance to radiosensitive OAR generally decreases,
leading to increased probability of high doses to OAR which may cause
toxicity.
• Central lesions associated with excessive toxicity,
• Phase II study from Indiana University where patients with centrally located
(hilar/pericentral) tumors treated to 60 to 66 Gy in three fractions had an 11-fold
higher risk of developing grade 3–5 toxicities when compared to similarly treated
peripherally located tumors.
• Updated results from this study at a median follow up of 50.2 months confirmed a
high incidence of grade 3 to 5 toxicity (27.3%), almost three times the rate for
peripheral lesions (10.4%).
Timmerman, J. Clin. Oncol. 2006
Fakiris, A.J, IJROBP, 2009
19. Disease related
• Systematic review of 20 studies including 563 central lesions
• the risk of grade 3-4 toxicity is reported to be less than 9%, which might still
be higher compared to patients treated for peripheral tumours.
• RTOG 0813
• maximum tolerated dose of 12 Gy × 5
• 7% dose limiting toxicity at this dose level.
• Due to the proximity to OAR, a prolonged treatment schedule with
more number of fractions might be advantageous,
• might be at the expense of decreased tumour control
Bezjak, IJROBP, 2016
Senthi, Radiotherapy and Oncology 2013
20. Central Airway Toxicity
• Given the proximity of centrally located lesions
to major airways, patients with these tumors
are at higher risk for a dose-related major
airway toxicity
• consequent atelectasis,
• stenosis/stricture,
• airway necrosis,
• fistula formation.
21. Disease related
• VUmc risk adapted strategy
60 Gy/3
60 Gy/5
60 Gy/8
54 Gy/3
55 Gy/5
60 Gy/8
Tumor description Dose
Older algorithms AAA/RapidArc/Pinnacle
T1 tumor surrounded by
lung tissue
T2 tumor or broad contact
with chest wall
Central tumor or near
brachial plexus
22. Disease related
• Mid and lower lobe tumours of lung are associated with increased risk of
symptomatic pneumonitis.
• move more with respiration and thus may lead to more normal tissues getting
irradiated.
• Ventilation and perfusion increases from apex to base in lungs
• can lead to increased oxygen free radical production with radiation and thus more damage.
• Supine position the gas exchange in lungs is reduced, more so in diseased
lungs.
• May lead to focal areas of hypoxia and increased production of angiogenic and
fibrogenic factors.
• As most radiation treatments are in supine position, the difference in gas exchange
can lead to increased lung injury.
Giridhar, APJCP, 2015
Ivan, Acta Oncologica, 2012
23. Dosimetric predictors
• The best supported dosimetric
correlates of RP are
• mean lung dose (MLD),
• unadjusted total lung mean doses above 4
Gy
• V5 and V20
• V20 greater than 4%
• Contralateral lung
• V5 >26%
• MLD
• ITV measure
• High Conformity index values Yamashita, Radiat. Oncol. 2007
Ong, Radiother. Oncol. 2010
Barriger, IJROBP, 2012
Bongers, EMCT, 2013
24. Biomarkers
• Higher levels of the biomarkers
• Serum levels of KL-6
• serum Krebs von den Lungen-6 (KL-6), a circulating mucin-like glycoprotein is produced
and secreted from type II pneumocytes,
• dependent on the number of regenerating pneumocytes and integrity of the alveolar-
capillary membrane - may be compromised before treatment and/or in the setting of RP.
• elevated pre-treatment KL-6 levels (>500.0 U/mL)
• Elevated levels of surfactant protein-D (SP-D) were associated with increased
risk of severe RP
• SP-D (>110.0 ng/mL)
• presence of an interstitial pneumonitis shadow on pre-treatment CT.
• IL 1a and IL 6
• Serum TGF B1
Yamashita, Radiat. Oncol. 2007
Kong, Cancer Control. 2008
Iwata Radiother. Oncol. 2011
27. Management of RP
• Radiation pneumonitis is usually a diagnosis of exclusion. Differentials
include
• disease progression,
• concomitant infection,
• exacerbation of chronic obstructive pulmonary disease,
• reactivation of latent tuberculosis
• Presence of copious, purulent sputum, high grade fever and myalgia
may be pointers toward an infective pathology.
• A complete blood count, throat swab, sputum culture/ sensitivity and chest
imaging may be warranted based on the clinical assessment
28. Management of RP
• The management includes:
1. General supportive management
2. Mobilization of airway secretions
3. Anti-inflammatory therapy
4. Management of acute exacerbations
• General supportive management includes good nutrition, regular
exercise and vaccinations.
• Pneumococcal and influenza vaccines should be considered in
patients with lung fibrosis.
29. Management of RP
• Steroids:
• Form the mainstay of treatment of radiation pneumonitis.
• Once infection and disease progression are ruled out, the patient should receive oral
prednisolone 1 mg/kg (max- 60 mg) for a period of two weeks followed by slow
tapering over weeks.
• ACE inhibitors:
• Enalapril is believed to decrease vascular remodelling and decrease levels of TGF B
and thus decrease lung fibrosis
• Studies in rats have shown ACE inhibitors to be useful.
• Limited data regarding its efficacy in humans. Enalapril at low doses can be tried on
an experimental basis.
• Patient’s blood pressure should be monitored and bilateral renal artery stenosis
should be ruled out before starting the drug.
30. Management of RP
• Supplemental Oxygen therapy: oxygen therapy can be used to reduce
the increased work of breathing.
• Pentoxyphylline:
• Dose of 400 mg thrice daily and continued for a period of two weeks.
• No robust data
• Anti-oxidants:
• Vitamin A, C and E supplements can be added as supportive therapy.
• Other immunosuppressant like azathioprine can be tried in refractory
cases.
33. Esophageal Toxicity
• Esophageal toxicity is a known complication of centrally located
tumors, ranging from mild esophagitis to stricture, perforation,
and/or tracheoesophageal fistula.
• Although the mechanism of fistula formation is poorly understood, it
is likely related to the impaired angiogenesis leading to delayed and
dysfunctional wound healing as well as predisposition to fistula
formation by radiation and chronic inflammation.
• Post-SBRT administration of chemotherapy can be an important
modifier of radiation sensitivity.
34. Vascular Injury
• SBRT to central tumors also increases the dose to the central vascular
structures, particularly the aorta.
• Although typically thought of as relatively radio-resistant, elevated
doses may lead to severe toxicity.
• Aortic toxicities, defined as
• hemoptysis secondary to aortic damage,
• exsanguination secondary to aortic rupture,
• aortic aneurysm in the irradiated region, or
• Aortic dissection
• Literature sparse – reported in re-irradiated patients.
35. Spontaneous Pneumothorax
• Rare complication of SBRT
• may occur as a result of radiation-induced pulmonary changes, apical pleural
injury, and/or parenchymal injury
• Postulated contributing factors include
• tumor related air trapping and consequent alveolar space rupture,
• RT-induced dense pulmonary/pleural fibrosis leading to rupture of subpleural
blebs
36. Chest Wall and Skin Toxicities
• Chest wall toxicities are usually associated with SBRT for peripherally located lung
tumors and include
• skin toxicity, rib fracture, and chronic chest wall pain.
• Patients with tumors more than 1–2 cm from the chest wall and 5 cm from the
posterior skin are at very low risk of toxicity.
• Chest wall pain and rib fracture
• Target responsible for this toxicity include the underlying large peripheral intercostal nerves
and bone.
• Patient-related factors may also increase the risk of CWP, including younger patient age and
continued smoking.
• Obesity is a significant risk factor
• with one study showing a nearly double increased in risk of chronic CWP for patients with 29 BMI
compared to patients with <29 BMI (27% vs. 13%, respectively; p = 0.01)
• Among the group with elevated BMI, diabetes mellitus (DM) was also highly correlated with
pain
Welsh, IJROBP, 2011
37. Chest Wall and Skin Toxicities
Shaikh, Cancer Treatment reviews, 2014
• Conservative management
with
• anti-inflammatories,
• analgesics,
• neuropathic specific
medications
38. Skin Toxicity
• Rare
• Subsets at high risk for skin toxicity, including
• those with a large body habitus and
• posterior tumors location with limited distance
between the lesion and overlying skin.
• Additional dosimetric risk factors include
• treatment delivery through a limited number of
coplanar beams,
• among lesions within 2.5 cm of the chest wall, volume
of the chest wall receiving 30 Gy (V30)
• Immobilization devices – loss of skin sparing effect
Hoppe, IJROBP, 2008
39. Brachial Plexopathy
• SBRT for tumors located in the apex can cause RIBP.
• Mechanistically, RIBP is thought to be due to an initial microvascular injury
and later on radiation induced fibrosis and a direct neurological injury
• Symptoms of upper extremity paresthesias, motor weakness, and
neuropathic pain.
• Objective signs of RIBP on clinical examinations include decreased/absent
muscle stretch reflexes, hypestesia/hypalgesia and weakness
• Neurophysiological examinations typically reveal demyelinating conduction
block on motor nerve conduction studies and myokymic discharge and
fasciculation potentials on needle examination evaluations
40. Vagus Nerve Injury
• Rare
• Left vagus nerve is at risk when left
upper lobe lesions are treated given its
close association with the lung
parenchyma.
• In the right hemithorax, the VN
branches into the right recurrent
laryngeal nerve (RLN), where it is at risk
for injury as it drapes over the apical
pleura and courses back toward the
tracheoesophageal groove.
• Data suggest that generally both VN
and RecLN are relatively resistant to
SBRT; literature reports of vocal cord
paralysis from ipsilateral VN and RLN
injury.
44. Ways to Avoid Complications
• Patient Selection
• Should include an evaluation of the patient’s functional status and any comorbid
conditions that may impact the safety and efficacy of SBRT.
• Specifically, patients should be evaluated both functionally and radiographically for
baseline pulmonary abnormalities, including IP shadows on pretreatment CT scans
• Simulation/Motion Management
• Robust immobilization system and an accurate pre-treatment verification of PTV
positioning are crucial.
• Unnecessary immobilization may lead to added skin toxicity and thus should be
avoided.
• Respiration management can reduce ITV
• Minimization of target uncertainty with techniques such as active breath control
(ABC), cone-beam CT, and/or respiratory gating can decrease PTV margins.
45. Ways to Avoid Complications
• Dose/Fractionation
• Local control of lung tumors generally requires a biologically effective dose
(BED) of at least 100Gy.
• Less intensive fractionation schemes for SBRT or risk-adapted approaches
have been advocated
• Target Delineation
• All at-risk structures/organs should be contoured individually, with planning
organ at risk volume (PRV) margins allowed for intrafraction movement, to
avoid preventable complications.
• Avoid including immediately adjacent OARs in the target volume
46. Ways to Avoid Complications
• Plan Optimization/Beam Arrangement/Weighting
• Use of SBRT beam angle/weighting optimization with tight aperture margins is
crucial for creating a sharp dose gradient
• Planning techniques (RapidArc treatment delivery), increasing the number of non-
coplanar beam angles, and using alternative beam arrangements and beam
weighting can reduce chest wall toxicity
• Treatment Delivery
• Real-time tumor tracking can reduce ITV and PTV margins, and consequently
adjacent normal tissue dose.
• Helical tomotherapy (HT) may improve OAR sparing for those in very close proximity
to the PTV, as is the case with central lung tumors.
• Flattening filter-free (FFF) linear accelerators,
• capable of delivering dose rates up to four times that of conventional linear accelerators,
• allow for shorter treatment delivery times and reduce the opportunity for intrafraction
motion
• exposure of normal tissue to scattered dose outside the field.
47. Summary
• Lung SBRT is an accurate and precise technique to treat lung tumors
with high ‘ablative’ doses.
• SBRT has proven excellent local control and good toxicity profile.
• Toxicities are rare, but difficult to treat.
• Most of these toxicities are avoidable by paying attention to detail at
all steps from patient selection to treatment delivery.
• Dose-adapted fractionation schedules and ongoing prospective trials
should provide further evidence of SBRT safety trying to reduce
toxicities and complications.
