Article Type : Case Report
Authors : Sun J and Kumar P
Keywords : Durvalumab; Concurrent chemoradiotherapy
Background: Historically patients with
locally advanced stage III non-small cell lung cancer (NSCLC) were treated with
double platinum-based chemotherapy with concurrent radiotherapy. Durvalumab is
a selective, high-affinity, human IgG1 monoclonal antibody that blocks PD-L1
binding to PD-1 and CD80 receptors, allowing T cells to recognise and kill
tumour cells. The recent PACIFIC trial demonstrated that consolidation
durvalumab therapy significantly prolonged the progression-free and
overall-survival in patients with unresectable, stage III NSCLC whose disease
had responded after concurrent chemoradiotherapy. These results have led to the
growing recognition of consolidation durvalumab therapy after chemoradiotherapy
as the standard of care in this setting. However, this brings a new set of
challenges including the recognition and management of immunotherapy-related
toxicities including immunotherapy-related pneumonitis.
Case presentation: We present the case of
a 55-year-old female who presented with worsening shortness of breath and dry
cough after treatment with concurrent chemoradiotherapy (cCRT) and
consolidation durvalumab therapy for stage IIIB non-resectable NSCLC. Serial
imaging demonstrated the presence of new areas of multifocal consolidation in
the right middle and upper lobes, with subsequent development of new ground
glass opacities in the left upper lobe. Post-radiation pneumonitis was a less
likely differential given that the radiological changes occurred outside the
radiation field. Bronchoalveolar lavage excluded pulmonary infection and
progression of malignancy. A subsequent diagnosis of immunotherapy-related pneumonitis
was made. Her clinical symptoms and imaging improved with a tapering course of
steroid therapy.
Conclusion: Immunotherapy-related
pneumonitis is often considered a diagnosis of exclusion, with symptomatology
that may overlap with other conditions such as post-radiation pneumonitis,
pulmonary infection, and progression of malignancy. Timely recognition of the
clinical and radiological features of this condition are important to
facilitate early diagnosis and initiation of treatment.
Advanced NSCLC has
historically been a diagnosis associated with poor outcomes, high symptom
burden, and limited treatment options. The advent of immunotherapy durvalumab
consolidation therapy in stage III unresectable NSCLC has been shown to
significantly improve survival. However, this brings unique issues related to
‘survivorship’ after immunotherapy, such as immunotherapy-related adverse
effects (irAEs). Immunotherapy-related pneumonitis is a clinically serious and
potentially lethal adverse effect. The most common symptoms include dyspnoea,
decreased exercise tolerance, and cough. Fever and chest pain may also occur.
The differential of immunotherapy-related pneumonitis becomes particularly
challenging in the setting of lung cancer as it may be clinically
indistinguishable from other conditions such as post-radiation pneumonitis,
pulmonary infection, tumour progression or pseudo-progression, or acute
exacerbation of chronic obstructive pulmonary disease which may also occur
after treatment. Computed tomography (CT) scans of the chest are critical in
the diagnosis and management of pneumonitis. In this case report, we will
discuss a case of a patient who developed pneumonitis secondary to durvalumab
therapy.
A 55-year-old female presented with a 3-month history of persistent dry cough and was subsequently diagnosed with unresectable stage IIIB (T4N2M0) NSCLC located in the right perihilar region with extension into the right upper and middle lobes. She underwent cCRT including a regimen of cisplatin and etoposide with 60 Gray (Gy) radiotherapy in 30 fractions. Two months after completion of chemoradiotherapy, an interval positron emission tomography (PET) CT scan demonstrated partial structural and metabolic regression of the tumour, with imaging findings also suggestive of post-radiation pneumonitis affecting the right lower lobe (Figure 1). The patient complained of an ongoing mild dry cough at this time. She was commenced on a course of oral prednisolone 25 mg daily tapered over 2 weeks. After some improvement in her cough, she was commenced on consolidation durvalumab therapy. After two 14-day cycles of durvalumab, she developed acute worsening shortness of breath and dry cough.
Investigations included a CT pulmonary angiogram (CTPA) which was negative for pulmonary embolism, however there was a marked increase in consolidative changes in the right upper lobe (Figure 2). Durvalumab therapy was ceased, and the patient was commenced on oral prednisolone 25 mg daily. Oral prednisolone was tapered over the next 12 weeks with improvement in symptoms. However, serial CT scans during this time demonstrated new areas of multifocal consolidation in the right middle and upper lobes (Figure 3), with subsequent development of new ground glass opacities in the left upper lobe (Figure 3).
Two weeks after
completing the course of prednisolone, the patient began to develop rapidly
progressive breathlessness and dry cough resulting in hospitalisation. Repeat
CTPA revealed the development of bilateral hilar consolidation.
Differential diagnoses
The development of these
pulmonary changes were concerning for pulmonary infection (e.g., viral,
bacterial, Pneumocystis jirovecii pneumonia (PJP) infection),
immunotherapy-related pneumonitis, post-radiation pneumonitis or progression of
malignancy. The presence of bilateral progressive radiological changes outside
the radiation field made post-radiation pneumonitis less likely. PJP remained a
possibility given the prolonged course of steroid immunosuppression. Diagnostic
bronchoscopy with bronchoalveolar lavage did not reveal the evidence of malignancy
or infection, specifically, lavage was negative for PJP. Therefore, the
diagnosis of immunotherapy-related pneumonitis was made after careful exclusion
of other differentials.
The patient was
recommenced on a moderate dose of prednisolone to be tapered slowly. Her
shortness of breath and cough slowly improved over the next 3 months, and a
repeat CT chest showed marked improvement in the bilateral pulmonary changes.
Outcome and follow up
The patient’s case and
radiology were discussed at the Statewide Interstitial Lung disease
multi-disciplinary meeting (ILD-MDM). The consensus diagnosis was that of
durvalumab-induced pneumonitis, however, a further PET-CT was recommended to
exclude progressive malignancy.
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].
Immune checkpoint
inhibitors have revolutionised the treatment of locally advanced stage III
NSCLC. However, this brings a unique set of toxicities to treatment including
immunotherapy-related pneumonitis. There are ongoing gaps in the ability to
distinguish immunotherapy related pneumonitis from other causes, such as
post-radiation pneumonitis, pulmonary infection and cancer progression.
Therefore, the clinical presentation often presents as a diagnostic dilemma for
clinicians. Ideally, immune-related adverse effects are managed most
effectively when detected early via a multidisciplinary approach involving
medical oncologists, radiation oncologists, and respiratory physicians. Leading
into the future where immunotherapy becomes more integrated into standard of
care in cancer treatment, further research is required to explore a reliable
and early diagnosis of immunotherapy-related pneumonitis.