Approximately one-third
of patients with NSCLC have stage III locally advanced disease at diagnosis [1,2].
Historically, the standard of care for patients with good performance status
and unresectable stage III NSCLC was concurrent platinum-based doublet
chemotherapy and radiotherapy followed by observation alone [3]. However,
survival among patients who received chemoradiotherapy remained poor, with a
phase III clinical trial demonstrating that a combination of concurrent
cisplatin, etoposide, and chest radiotherapy resulted in a benefit in median
overall survival (OS) of 15 months, with 3- and 5-year survival of 17% and 15%
respectively [3,4]. More recently, the use of immune checkpoint inhibitors has
altered the landscape of anti-cancer treatment in patients with stage III lung
cancer diagnoses.
The phase III PACIFIC
trial represents a landmark advancement in the treatment of unresectable, stage
III NSCLC patients whose disease had responded or stabilised after cCRT [3].
One year maintenance durvalumab therapy significantly improved progression-free
survival (PFS) (HR 0.52; 95% CI 0.42-0.65, p< 0.0001; median 16.8 versus 5.6
months) and overall survival (OS) (HR 0.68, 95% CI 0.53-0.87, p= 0.00251)
versus placebo. These results have led to the growing recognition of the
‘PACIFIC regimen’ (durvalumab after cCRT) as the standard of care in this
setting [5]. An updated exploratory analyses 5 years post randomisation
demonstrated ongoing PFS and OS benefits of durvalumab compared to placebo. The
estimated 5-year PFS and OS rates were 33.1% and 42.9% for durvalumab and 19.0%
and 33.4% for placebo respectively. Survival benefit favoured durvalumab versus
placebo across all PDL-1 subgroups; the only exception was OS in the post-hoc
subgroup with PD-L1 tumour cell (TC) expression <1% (HR 1.15, 95% CI 0.75-1.74)
although PFS still favoured durvalumab in this subgroup (HR 0.80, 95% CI
0.53-1.20) [6]. Further research is
still required to determine the optimal duration of durvalumab treatment
following cCRT.
Consolidation durvalumab
has demonstrated improved PFS and OS compared to placebo however it has not
come without its associated immune-related toxicities. The most common adverse
effect of any grade in those receiving anti-PDL1 treatment are fatigue,
gastrointestinal (bloody diarrhoea, abdominal pain, hepatitis, and jaundice),
endocrine (altered thyroid function and hypocalcaemia), peripheral neuropathy,
and dermatological irAEs [3]. Respiratory adverse events, such as pneumonitis,
are the most common cause of immune-related deaths and have been reported to
occur 7 to 24 months after commencing treatment [3,7]. Patients with suspected
pneumonitis may present with non-specific respiratory symptoms of shortness of
breath, cough, fever, or chest pain [7].
Pneumonitis is of
particular interest in stage III NSCLC, as these patients are also at high risk
of developing radiation pneumonitis due to the temporal proximity of
chemotherapy, radiation treatment, and consolidation with durvalumab. Real
world studies have suggested differences in the frequencies of pneumonitis
among patients who received durvalumab consolidation therapy after
chemoradiotherapy. These heterogeneities were thought to be related to the
differences in volume of lung parenchyma that received 20 Gy (V20) and mean
lung dose (MLD). Many previous reports have shown a correlation between V20/MLD
and the incidence/severity of pneumonitis [8]. The National Comprehensive
Cancer Network (NCCN) guidelines recommend that V20 should not exceed 35-40%
and that the MLD should not exceed 20 Gy [9]. There was a trend towards more
rapid onset of pneumonitis in patients receiving radiotherapy (RT) and immune
checkpoint inhibitor (ICI) (median time of onset 1.2 months, range 0.1-34.3)
compared with patients who received RT (median onset 3.1 months, range 0.4-12.0)
or ICI alone (median onset 2.7 months, range 0.1-17.4, p=0.12) [10].
Differentiating between
radiation pneumonitis and immune-related pneumonitis can be challenging
clinically due to timing of onset and overlapping symptoms, and thus the
comparison of morphology on CT imaging is increasingly important. Both RT- and
ICI-pneumonitis can often manifest as ground-glass opacities (GGOs) and
consolidations on CT, and both frequently assume a pattern of cryptogenic
organising pneumonia (COP) or acute interstitial pneumonia/acute respiratory
distress syndrome (AIP/ARDS) but differ in their spatial distribution [3,10-12].
There are no universally accepted criteria to define the components of
pneumonitis caused mainly by RT and that caused mainly by ICI. Furthermore,
both RT and ICI may act synergistically to promote inflammation of the lung
parenchyma [10]. The distinction between RT vs. ICI pneumonitis is clinically
relevant as treatment algorithms for RT versus ICI pneumonitis differ in that
ICI-pneumonitis requires higher doses of steroids and occasionally
immunosuppressive agents and may necessitate prolonged or indefinite
discontinuation of ICI [10]. Radiation pneumonitis classically displays
unilateral involvement, smaller areas confined to the radiation field, and
sharp borders, whereas immune-related pneumonitis tends to be bilateral with a
larger area involved and is less likely to display sharp borders [3]. Among
patients who receive both RT and ICIs, some changes were confined to the
ipsilateral lung with sharp borders resembling RT-pneumonitis, while others
resembled the bilateral distribution of typical ICI pneumonitis [3,10,12].
In addition to immune-induced
pneumonitis is considered a diagnosis of exclusion, and workup to rule out
other aetiologies, including pulmonary infection and cancer progression should
take place [11]. There is an increased incidence of severe pneumonitis, both
radiation- and immune-related in patients with poorer performance status, worse
lung function, prior respiratory disease, and smoking history [3,13]. Pulmonary
function testing is not routinely performed prior to commencement of ICI
treatment, however, is often used as part of the diagnosis of pneumonitis,
which commonly demonstrates a restrictive pattern and significantly decreased
gas transfer [3]. In selected cases, a diagnostic bronchoscopy with
bronchoalveolar lavage (BAL), with or without a transbronchial biopsy could be
considered; however, their role in diagnosis has not been clearly defined in
current clinical practice guidelines. In cases of clinical and radiologic
doubt, bronchoscopy with BAL could help to rule out infections and malignancy
as competing diagnoses, especially in suspected grade 2-4 pneumonitis [11-13].
Recently, the identification of biomarkers in BAL which could indicate the
occurrence of ICI-related pneumonitis is under research. Elevated levels of
interleukin (IL)-17A and IL-35 have been found to be associated with the
development and severity of ICI-related pneumonitis [12,14]. A multidisciplinary
approach involving medical oncologists, infectious disease and respiratory
physicians is recommended.
Guidelines on the
management of irAEs have been published from the European Society for Medical
Oncology (ESMO), the American Society for Clinical Oncology/National
Comprehensive Cancer Network (ASCO/NCCN), and the Society for Immunotherapy of
Cancer (SITC). In grade I pneumonitis, the clinician should consider
withholding ICI, monitor the patient clinically every 2-3 days and offer a
repeat CT chest in 3 weeks; upon radiographic resolution, the ICI could be
resumed, and no further imaging is needed. Upon clinical or radiographic
deterioration, the patient should be treated as grade II. In grade II
pneumonitis, ICI should be withheld and treatment with corticosteroids should
be initiated (prednisone 1 mg/kg orally), and empirical antibiotics should be
considered. If symptoms improve after 48-72 hours, corticosteroids should be
tapered for 6 weeks; upon clinical deterioration, the patient should be treated
as grade 3-4. In grade 3-4 pneumonitis, treatment with ICI should be
permanently discontinued and treatment should consist of corticosteroids
([methyl] prednisolone 2-4 mg/kg/day or equivalent) and empirical antibiotics
should be administered. Upon clinical improvement after 48-72 hours, the
corticosteroids could be reduced to 1 mg/kg and then tapered over 8 weeks. Upon
clinical deterioration after 48-72 hours, additional immunosuppressive
strategies should be implemented (e.g. addition of infliximab, mycophenolate
mofetil, or cyclophosphamide), weighing the benefit/risk ratio for the patient
[13].
Rechallenge with
checkpoint inhibitors following immune-related adverse events is highly
controversial. In the PACIFIC study, durvalumab rechallenge was an option for
patients who developed ? grade 2 pneumonitis after initiation of durvalumab,
which resolved to grade 1, and who achieved reduction in prednisone or an
equivalent to a dose of ? 10 mg/day [8,11]. In a retrospective study of 302
patients who received durvalumab post chemoradiotherapy for NSCLC, pneumonitis
of any grade was observed in 83% of patients and severe pneumonitis was
observed in 34% of patients. In more than 80% of the patients who were
rechallenged with durvalumab based on the rechallenge criteria of the PACIFIC
study, severe relapse did not occur. The PACIFIC trial rechallenge criteria
have also been endorsed in the European Society for Medical Oncology (ESMO)
guidelines [8,12].