Particular findings on lung CT in patients undergoing immunotherapy for bronchogenic carcinoma

Immune checkpoint inhibitors have revolutionized treatment for many cancer patients and enabled tremendous achievements in treatment. In 2015, the first immune checkpoint inhibitor, nivolumab, a targeted programmed death 1 (PD-1)-mediated inhibitor, was approved for patients with advanced non-small cell lung cancer (NSCLC) [1, 2]. Since then, a wealth of immune checkpoint inhibitors have joined nivolumab, including pembrolizumab, atezolizumab, and durvalumab, and have proven their efficacy in NSCLC patients. In the near future, immune checkpoint inhibitors will be used not only in an adjuvant setting, but also in a neoadjuvant setting [3].

As the number of patients receiving immune checkpoint inhibitors will considerably increase, all members of the clinical team should be familiar with the important clinical and radiological characteristics of this class of drugs. Special attention must be paid to the assessment of treatment response as well as to the identification and management of treatment-related adverse events.

Treatment response in patients with immune checkpoint inhibitors can be challenging as four different forms have been observed. Treatment response can manifest as a classical shrinkage in tumor size as well as an initial increase in tumor size and/or the development of a new lesion that shows a stable course during the continuation of treatment. Whereas the former scenario is not challenging for either clinicians or radiologists, the latter can be easily misinterpreted as treatment failure [4]. Based on the initial results of data from 487 patients with advanced melanoma treated with the PD‑1 immune checkpoint inhibitor ipililumab, so-called immune-related response criteria have been developed [5]. The phenomenon of an initial increase in the tumor burden and/or the appearance of a new lesion followed by a decrease in tumor burden has been described as pseudoprogression [6]. Infiltrating immune cells that target cancer cells are believed to be responsible for the increase in tumor volume [7]; however, pseudoprogression is a relatively uncommon phenomenon, with an incidence of only 0.6–9% of NSCLC patients [2, 8‐10] and, therefore, in the majority of patients progression of tumor burden following immune checkpoint inhibitor therapy is associated with treatment failure. Importantly, the frequency of findings in line with pseudoprogression is higher during the early treatment phase 4–6 weeks after treatment initiation, than at later time points when the incidence decreases [9].

Sarcoid-like reactions are a further type of atypical response pattern that are characterized by the infiltration of lymphocytes, mainly in lymph nodes but not exclusively, as granulomatous lymphocytes have also been described in other tissues and organs, such as the bone marrow [11‐13]. It has been proposed that a sarcoid-like reaction is a sign of treatment response [11]. Correct classification can be challenging, especially in the setting of NSCLC, as its appearance can mimic disease progression, and therefore, a precise clinical and radiological assessment is needed for treatment decision-making.

Pneumonitis is considered to be the most important immune-related adverse event in NSCLC patients [14]. According to a meta-analysis with 4413 patients from 8 randomized clinical trials, the incidence of all grades of pneumonitis was 3% of which 50% were high-grade clinically relevant cases. Pneumonitis was the most common cause of treatment-related deaths (4 of 2272 patients with high-grade cases) [14] and is the most therapy-limiting side effect. The symptoms are usually unspecific and up to one third of patients have no symptoms. The radiological changes associated with pneumonitis are unspecific and range from subtle ground-glass opacities to large consolidations that present as organizing pneumonia or non-specific interstitial pneumonia.

This article outlines the radiological findings of five patients with NSLC who were treated with immune checkpoint inhibitors, and who experienced either an atypical treatment response or a pulmonary immune-related adverse event.

This study was approved by the local ethics committee (EK: 1521/2015) and was performed in accordance with the guidelines of the Declaration of Helsinki. All patients gave written, informed consent prior to 2‑[¹⁸F]fluoro-2-deoxy-D-glucose ([¹⁸F]FDG) PET/CT examinations. Of the five patients reported in this manuscript three were also included in a previous manuscript [15]. Patients with an atypical response pattern or radiologically detectable immune-mediated adverse events were retrospectively identified based on a prospectively collected group of 70 NSCLC patients under PD1 or PD-1L therapy between 2016 and 2019. Demographic and clinical data, including patient age, sex, and previous therapies, were obtained from the institutional database (Table 1).

In this study atypical pulmonary findings in NSCLC patients in response to immune-checkpoint inhibitors were described. We showed two patients with pseudoprogression, both of whom were associated with medium-term treatment response. In addition, we presented a patient with a sarcoid-like reaction and two patients with pneumonitis, both of which can mimic a variety of different diseases.

The approval of immune checkpoint inhibitors has led to a paradigm change in the treatment of NSCLC patients; however, only ~20% of heavily pretreated NSCLC patients respond to immune checkpoint inhibitor therapy [1, 2]. Therefore, precise response evaluation as well as the detection and management of treatment-related adverse events, is of the utmost importance. Recent trials have demonstrated the diagnostic limitations of the commonly used RECIST in patients treated with immune checkpoint inhibitors. Considerable efforts have been undertaken to develop special response criteria, taking into account the particular treatment response patterns observed with immunotherapy. Several modified criteria have been published in the last few years, with the iRECIST criteria published in 2017 the most commonly used [17]. The iRECIST introduced two new response categories, namely, immune unconfirmed progressive disease (iUPD) and immune confirmed progressive disease (iCPD). In contrast to RECIST 1.1, an increase in tumor size or the development of new tumor manifestations must be confirmed by a second image examination performed 4–8 weeks after the first examination. In the interim, the category iUPD is used to classify the treatment response. If there is a further increase in tumor size or the appearance of new lesions at the second scan, the category iCPD is used to classify treatment response [17].

Pseudoprogression is the most commonly discussed atypical response pattern in patients who receive immune checkpoint inhibitor therapy. Although the laboratory [17] and radiological [7] manifestations of pseudoprogression have been described, there is no clinically used test to date that can differentiate between pseudoprogression and true progression with satisfactory certainty. The iRECIST aims to avoid the misclassification of pseudoprogression by introducing the concept of iUPD, which needs a confirmation after 4–8 weeks in order to classify iCPD. Initial progression in patients with pseudoprogression occurs most commonly within the first month after the initiation of treatment [18]. While it was initially believed that a follow-up between 4–8 weeks was suitable to confirm or rule out pseudoprogression [5], it has been recognized that lesions can remain enlarged over months even though they show a biological response [8]. From a clinical perspective, it is important to differentiate between true progression and pseudoprogression as early as possible, as the majority of patients do not benefit from treatment past defined disease progression [19]. In addition, increasing evidence shows that the response rate to chemotherapy is increased after immune checkpoint inhibitor therapy [20]. Correct identification of disease progression would enable a switch from immune checkpoint inhibitor therapy to subsequent chemotherapy.

The second form of atypical response pattern discussed in this manuscript is a sarcoid-like reaction. This might be biologically linked to the phenomenon of pseudoprogression, as both are believed to rely on the infiltration by immune cells of immune-active areas. A sarcoid-like response pattern has been associated with beneficial courses of disease in melanoma patients [11], and therefore, should not be misinterpreted as disease progression or pseudoprogression. In particular, when there are signs of treatment response (e.g., a reduction in size and glucose metabolism), the development of newly enlarged metabolically active lymph nodes (even intra-abdominal), and lung nodules in a perilymphatic distribution, are suggestive of a sarcoid-like reaction.

Pneumonitis is the most dangerous adverse event in NSCLC patients [14], with several reports of a fatal outcome [21]. As pneumonitis does not have a uniform radiological appearance, even slight signs, such as ground-glass opacities, atypical consolidations, and/or reticulations, should be reported as suspicious, especially in cases of clinical deterioration. All imaging findings in pneumonitis are non-specific and cannot be differentiated from infectious pneumonia. Any radiological signs suggestive of pneumonitis should prompt a discussion with the oncologist and an early initiation of cortisone treatment.

In conclusion, immune checkpoint inhibitors can lead to a variety of different atypical pulmonary response patterns and adverse reactions. A knowledge of a patient’s clinical information helps to correctly interpret these changes and to support treatment decision-making.