Radiation Pneumonitis

Radiation Pneumonitis:
Old Problem & New Tricks
Dr. Heba Gomaa
Radiation Oncologist
King Abdullah Medical City

Radiation-induced lung injury
• RILI was first described in 1898, soon after the development of
roentgenograms.
• The distinction between two separate types of RILI, radiation
pneumonitis and radiation fibrosis, was made in 1925.
• Both types of lung injury are observed today in patients who have
undergone thoracic irradiation for the treatment of lung, breast,
Oesophageal or hematologic malignancies.
• Radiation-induced damage to normal lung parenchyma remains a
dose-limiting factor in chest radiotherapy, and can involve other
structures within the thorax in addition to the lungs.

Radiation Pneumonitis
• 6 weeks to 6 months after completion
of RT
• Most severe 3-4 months after
treatment
• Non-specific including,
– Dyspnea (up to 93%)
– Non-productive cough (up to 58%)
--Small pleural effusions and rib
fractures may be seen, but
lymphadenopathy does not occur.
– Low grade transient fever (7%)
– Hemoptysis (rare)
• PE: crackles on auscultation
• LAB: Increased WBC, ESR
Radiation fibrosis
6 months to 2 years after
completion of RT
• Usually develops between 6
and 12 months
• The extent and severity of
fibrosis remains stable 2 years
after completion of RT
• Shortness of breath and
possibly leading to
pulmonary hypertension and
congestive heart
failure

Radiographic changes
CT is more sensitive and useful in evaluating
the precise distribution and pattern of RILD
The CT scan may take the form of a CT
pulmonary angiogram (CTPA) to exclude
pulmonary thromboembolism.
Early (radiation pneumonitis)
Most common findings
• Patchy or dense consolidation
• Ground-glass opacity
• Abnormalities largely limited to radiation
port.
• May gradually disappear but may lead to
fibrotic changes in cases of severe RILD.

Could it be Bilateral?
Findings may be seen outside the
radiation field and even in the
contralateral lung in up to 20% of
cases:
– Lymphocytic alveolitis,
– Hypersensitivity reaction
– Organising pnemonia
--Radiation Scatter,
-- Lymphatic Obstruction
Effusions which develop after 6
months of completion of RT should
be evaluated with thoracocentesis
to exclude malignancy.

Late (radiation fibrosis)
common findingsMost
• Streaky opacities
• Dense consolidation
with volume loss
• Traction bronchiectasis
in abnormal regions

Differential Diagnosis
 Infection.
 Lymphangitis
Carcinomatosis.
 Thromboembolic Disease .
 Drug-induced.
 Exacerbation of chronic
obstructive pulmonary
disease (COPD), interstitial
lung disease, or heart failure.
 Locally recurrent tumor.
 Radiation-induced neoplasm.
The risk increases with time
after treatment with the
median time interval
beingapproximately 9.6 years
Knowledge of the relationships
between CT manifestations and times
of initiation and completion of
radiation therapy
Knowledge of the relationships
between CT manifestations and times
of initiation and completion of
radiation therapy
> 40 Gy of at least 4 weeks for 3D CRT
or 1–2 weeks for SBRT
> 40 Gy of at least 4 weeks for 3D CRT
or 1–2 weeks for SBRT
Rapid onset does’nt exclude RIDI
Especially in old age, CMT drugs
Rapid onset does’nt exclude RIDI
Especially in old age, CMT drugs

DD
 Pulmonary opacities occurring
prior to completion of therapy or
outside of the radiation portal.
 Abrupt onset (unless there has
been recent discontinuation of
steroid therapy)
 “Tree-in-bud” appearance:
centrilobular nodules or
branching linear structures, more
likely TB
 Cavitation within an area of
radiation fibrosis generally
represents superimposed
infection

Recurrent tumor
• Usually manifest within 2 years after
treatment.
• Alteration in the contour of fibrosis.
• Soft tissue filling in of the dilated
bronchi within the fibrosis
• Nodules developing outside of
radiation fibrosis
• Pleural effusion long after
completion of treatment
• Bone destruction
• Tumor extending into
adjacent structures
– Irregularity of central airways
– Contralateral deviation of the
trachea
– Diaphragmatic elevation due
to phrenic nerve invasion by an
aorticopulmonary window
mass

Lymphangitis Carcinomatosis
Rapid progression of clinical
symptoms
Radiologic manifestations
– Interlobular septal
thickening (nodular and
irregular)
– Thickening of the
bronchovascular interstitium
– Peripherally located
wedge shaped densities

What is the Best Time for FDG PET
Imaging?
• Can confirm the presence of
recurrent tumor.
• But imaging is best delayed for at
least 3 months following therapy to
decrease false-positive findings
associated with tracer uptake in
areas of inflammation.

PFTs
 Pulmonary function tests (PFTs)
can be helpful in differentiating
whether symptoms are due to a
flare of COPD or an interstitial
process and to determine the
severity of respiratory
impairment.
 Obtained as a baseline prior to
radiation therapy and repeated in
response to symptoms
.

Borst et al. reported a decrease in first expiratory volume in 1 s (FEV1) as
early as three months post RT with continued deficits observed at 18 and 36 months.
The decrease in PFTs was dependent on mean lung dose (MLD) and underlying pulmonary
conditions such as COPD.
Diffusion capacity of lungs (DLCO) is another important PFT parameter affected by RP. Variations
in this parameter are also dose dependent with effects seen for MLD as low as 13 Gy .
In a prospective study of 128 patients with good long term follow up, DLCO decreased
progressively at an annual rate of 3.5%/year. Such impairments in DLCO have been reported by
several other groups. However, these changes in PFTs are dependent on tumor location and size.
For example, in one observational study of 82 patients with locally advanced lung cancer,
improvement in both FEV1 and DLCO were noted 3–4 months after radiation. Multivariate
analysis revealed that reduction in tumor size was correlated with these improvements

Bronchoscopy
 The main role for flexible fiberoptic bronchoscopy is to
evaluate for infection, bleeding, drug hypersensitivity, or
spread of the underlying malignancy.
 Bronchoscopy with bronchoalveolar lavage is performed in
the majority of patients.
 Transbronchial biopsy specimens may be useful for
assessment of infection or lymphangitic spread of tumor in
cases that are clinically atypical for RILI, but the size of the
specimens is usually too small to establish a diagnosis of
radiation pneumonitis.
 Bronchoalveolar lavage fluid (BALF) findings in radiation
pneumonitis are not specific, usually showing an increased
number of leukocytes (predominantly lymphocytes). The
majority of BAL lymphocytes post-irradiation are CD4+.

Patient Related Risk Factors
 Prior thoracic irradiation.
 Volume loss due to lung collapse.
 Older age.
 Poor pretreatment performance status.
 Poor pretreatment lung function, (FEV(1).
 Mid- to lower lung tumor location
 Chronic obstructive pulmonary disease (COPD).
 Interstitial lung disease (ILD) Clinically, extensive ILD is sometimes considered a
contraindication for thoracic RT.
Recent reports have implicated even subclinical ILD to be associated with severe RP.
 Female sex.
 Endocrine therapy for breast cancer.
Several studies suggest that concurrent, but not sequential use of tamoxifen increases the
rate of pulmonary fibrosis in women treated for breast cancer .
 Glucocorticoid withdrawal during radiotherapy.
 Smoking.

Smoking
(Is it considered as a risk factor?)
A meta-analysis published by Vogelius et al. found that
ongoing smoking protects against RP (p = 0.008)
and a history of smoking shows borderline to
signiﬁcant protection (p = 0.006).
Decreased inﬂammatory reaction among smokers
Smoking associated hypoxia
Resistance against oxidative stress and decreased
capacity to repair DNA damage in non -smoking
patients
Smokers are more likely to have pulmonary symptoms
at baseline, and hence less likely to recognize and
report symptoms.
A small retrospective study compared the incidence of
clinical radiation pneumonitis in active smokers and
nonsmokers, among 405 women who underwent
radiotherapy for treatment of breast or esophageal
cancer. The authors found that none of the subjects
who were active cigarette smokers developed clinical
pneumonitis following irradiation.

cancer
Treatment Related
Risk Factors

Volume of lung
irradiated
 The risk of radiation-induced injury
is directly related to the volume of
irradiated lung .
In patients with breast cancer, for
example, the risk of transient lung
inflammation following adjuvant chest
wall irradiation is approximately 5
percent.
The risk is higher with increasing lung
volume in the tangential fields,
treatment to the regional lymph nodes
(supraclavicular, axillary apex, and
internal mammary regions .
In one report, when tangential beam
irradiation was utilized following breast-
conserving surgery, pneumonitis was
observed only when >10 percent of the
lung was irradiated.

Dose of Radiation
 Most studies have validated V20 and mean lung dose (MLD) as
the most frequently correlated parameters, though several other
variables have also shown to be predictive, including volume of lung
receiving 5 Gy (V5), 13 Gy (V13), 25 Gy (V25) and 30 Gy (V30).
 In 2010, a group of physicians and physicists analyzed more than 70
articles as part of the QUANTEC series to determine the radiation
dose and lung volumes that predict a greater risk of pneumonitis .
 They concluded that MLD and V20 were the best supported for
routine clinical practice and recommended keeping the V20 to <30
to 35 percent and MLD <20 to 23 Gy to keep the risk of
pneumonitis <20 percent.

Time-dose factor
 In a systematic review, the use of twice daily fractionation
appeared to reduce the risk of RILI compared with
administration of the same total daily dose as a single
fraction.
 However, in a study of 37 patients receiving radiation for
NSCLC, 14 developed radiation pneumonitis, suggesting no
benefit to the twice daily fractionation regimen.
 Due to lack of clear benefit and the increase in logistical
difficulties, twice daily dose fractionation is rarely used for
NSCLC. On the other hand, twice daily fractionation is used
for limited stage small cell lung cancer.

Technique
In a secondary analysis of the NRG Oncology
clinical trial (RTOG 0617) that included 482
patients with locally advanced NSCLC, IMRT was
administered to 227 patients and 3D-CRT to 255.
 Two-year overall survival, progression-free
survival, local failure, and distant metastasis-free
survival were not different between the groups,
but the rate of grade 3 pneumonitis was less with
IMRT (7.9 versus 3.5 percent, p = 0.039).
 This data strongly supports the routine use of
IMRT for management of LA-NSCLC.

Stereotactic body radiation therapy
 Clinically significant radiation pneumonitis
develops in fewer patients (5 to 15 percent)
treated with SBRT compared with conventional
radiation therapy .
This is likely attributable to lower irradiated lung
volumes and a lower mean lung dose. The risk of
RILI increases once the V20 exceeds 10 percent or
the mean lung dose is higher than 6 Gy.

Treatment Modality: Protons vs.
Photons
The use of protons rather than photons may decrease the incidence of radiation pneumonitis as the
mass of protons limits tissue penetration and allows more precise dosing. In a systematic review of
proton beam therapy for breast cancer, 1 of 102 (<1 percent) patients across four studies developed
radiation pneumonitis
In a phase 2 study of high dose proton therapy in combination with weekly carboplatin for unresectable
NSCLC, 1 of 44 treated patients developed pneumonitis, suggesting that high-dose proton therapy
administered concurrently with chemotherapy is well-tolerated
We await the results of RTOG 1308, a Phase III randomized trial comparing overall survival after proton
versus photon CRT for inoperable LA-NSCLC; speciﬁcally studying RP as one of the secondary end points.

Induction & Concurrent
Chemotherapy
 The use of induction chemotherapy prior to
chemoradiotherapy may increase the risk of radiation
pneumonitis.
Patients receiving concurrent
doxorubicin,taxanes, dactinomycin, bleomycin, cyclop
hosphamide, vincristine, mitomycin, gemcitabine,
recombinant interferon-alpha, and bevacizumab are
at a higher risk of developing RILI.
Concurrent anthracycline-based chemotherapy and
radiation associated with increased risk of RP and are
generally avoided in the treatment of breast cancer.

Paclitaxel
 It is likely that sequential
administration of paclitaxel
and radiation therapy
diminishes the risk of radiation
pneumonitis as compared with
concurrent treatment.
 However, women who receive
taxanes as a component of
their adjuvant therapy for
breast cancer may also need
to have a smaller volume of
lung included in the radiation
field.

Gemcitabine
 Gemcitabine is included in many
lung cancer treatment protocols
and is a potent radiation
sensitizer. When given as
concurrent therapy at standard
doses, pulmonary toxicity is
prohibitive.
 toxicity appears less with
conformal (three-dimensional)
compared with two-dimensional
treatment planning .
 Toxicity is greater with regimens
that include induction
chemotherapy prior to
chemoradiotherapy.

Pemetrexed
 The exact interaction of
Pemetrexed with irradiation is
not known, although it appears to
have some radiosensitizing and
radiation recall effects.
In the PROCLAIM trial of 598 patients with
unresectable nonsquamous NSCLC, thoracic
radiation therapy was administered
concurrently with either pemetrexed
.plus cisplatinetoposideorcisplatinplus
The overall incidence of pneumonitis was
higher with pemetrexed-cisplatin group
than with etoposide-cisplatin, although the
incidence of pneumonitis ≥grade 3 was not
increased.

Radiation Recall Pneumonitis
can occur when certain antineoplastic agents
(eg, doxorubicin, erlotinib, etoposide, gemcitabine,
paclitaxel, pemetrexed) are administered to a
patient who has received prior radiation therapy to
the lung .
 Patients typically develop symptoms such as cough
and dyspnea, associated with radiographic opacities
that conform to the prior radiation field.

When to treat ?
• Patients who are asymptomatic or have minimal symptoms may experience a
spontaneous resolution, so we do not initiate treatment unless symptoms appear
or pulmonary function declines by more than 10 percent.
• We continue to monitor these patients at regular intervals with assessment of
symptoms, chest radiography, and pulmonary function, as indicated. Patients may
benefit from supportive care.
 Supportive care may include antitussive therapy, supplemental oxygen, and
treatment of comorbid diseases, such as chronic obstructive pulmonary disease
(COPD) or heart failure, which may contribute to symptoms.
 Antitussive therapy, such as dextromethorphan or codeine, may provide
symptomatic relief of cough.
 Therapy with supplemental oxygen is indicated for patients with a resting pulse
oxygen saturation ≤88 percent.
 Improvement in mild symptoms has been described with high dose inhaled
glucocorticoids (budesonide 800 micrograms twice a day) for 14 days.

Many experts, suggest the use of oral glucocorticoids for patients with a subacute
onset of radiation pneumonitis, moderate to severe symptoms (eg, dyspnea that
interferes with activities of daily living), and evidence of impaired respiratory function.
• Glucocorticoids — Prednisone (approximately 40 to 60 mg/day) is generally given
for two to four weeks, with a gradual taper over 3 to 12 weeks, although the
guidelines for tapering are poorly defined [65]. Generally speaking, the taper is
done with close monitoring of symptoms.
• If the patient experiences relapse of symptoms we return to full dose for two
weeks and try again with a slower taper, particularly when the dose is 20 mg per
day or less. The recommendation for prednisone use is based upon clinical
experience and multiple reports of a prompt response to therapy.
• prophylaxis for Pneumocystis pneumonia when the prednisone dose exceeds 20
mg a day for more than a month is suggested by many experts.
• Azathioprine and cyclosporine were both effective in treating the symptoms of
radiation pneumonitis in single case reports; these agents may be considered in
patients who do not tolerate glucocorticoids or who have disease refractory to
glucocorticoid therapy.

 There are no established guidelines for the management of
radiation-induced lung fibrosis.
 Inflammation is not prominent and anti-inflammatory
therapy, specifically glucocorticoids, should be avoided to
prevent unnecessary side effects.
 Supportive care such as oxygen supplementation,
pulmonary rehabilitation, mucociliary clearance, and
vaccinations against influenza and pneumococcus should be
instituted, as appropriate.
 Inhibitors of collagen synthesis as colchicine, penicillamine,
interferon-gamma, or pirfenidone, may have the potential
to modify the progression of fibrosis. However, there are no
controlled studies with these agents in humans with RILI.

Prognosis
 Significant improvements
in the perfusion and
ventilation of radiation-
injured lung tissue may be
noted from 3 to 18 months
after radiation therapy.
 After 18 months, further
significant improvement is
unusual.

Prevention
 The best known strategies for reducing RILI are
those that limit the radiation dose and volume
of normal lung tissue irradiated.
 Preliminary data have suggested possible
benefit to pentoxifylline, angiotensin converting
enzyme inhibitors, and amifostine, but adequate
randomized trials are lacking.
 Patients with a greater risk for RP even when
standard dosimetric lung parameters (such as
mean lung dose and V20) are met should be
counseled about the additional risk of RP and
every effort should be made to reduce the lung
dosimetric parameters to as low a value as
reasonably achievable.

Radiation Pneumonitis

More Related Content

What's hot (20)

Similar to Radiation Pneumonitis (20)

Recently uploaded (20)

Radiation Pneumonitis