Toxicity management in thoracic chemoradioimmunotherapy: pirfenidone for low grade pneumonitis and lung fibrosis

With up to 34% radiation pneumonitis is the clinically most relevant side effect of thoracic chemoimmunoradiation (1). Since the introduction of immune-checkpoint inhibitors (ICIs) in clinical routine, i.e., mainly durvalumab, atezolizumab, pembrolizumab and nivolumab, the pathophysiology of therapy induced lung injury has become quite complex. ICIs themselves may cause pneumonitis and their combination with thoracic radiation may have a supra-additive effect. With approximately 10% treatment discontinuations (2), pneumonitis not only reduces adherence to immunotherapy after thoracic chemoradiotherapy (CRT), which leads to worse outcome (3), but also ends up in lung fibrosis that may significantly reduce pulmonary function and quality of life. Therapeutic approaches are primarily based on expert opinion (4) rather than on prospective trials so that the dosage and the duration of glucocorticoid treatment may vary substantially between clinics.

The clinical picture of radiation induced lung disease (RILD), starts out with a pneumonia-like condition (radiation pneumonitis) occurring within half a year followed by a period of fibrotic alterations until approximately 1 year after the end of thoracic radiation, resembles idiopathic fibrosis (IPF). From a pathophysiological point of view, RILD develops in five steps: early, latent, exudative, intermediate and fibrotic phase (5-7). In the early phase, which begins hours or days within radiation, platelet-derived growth factor-beta (PDGF-β) plays a crucial role. In a second wave—usually 6 to 8 weeks after radiation therapy (RT)—transforming growth factor-beta 1 (TGF-β1) levels are enhanced. Pirfenidone works antagonistically to both factors targeting the TGF-β1-Smad3 signaling pathway, whereby it inhibits the proliferation of fibroblast (8). Pirfenidone is a registered IPF medication, which—in a previous study in rodents—was shown to inhibit inflammatory cell infiltration and collagen deposition by downregulating the above mentioned pathway (9). This results in less lung fibrosis.

Based on these pre-clinical findings the authors of the current study wanted to test pirfenidone for its efficacy in RILD (8). The diagnosis and grading of RILD was performed centrally with accrual from 10 Chinese tertiary referral centers. However, 43% of the patient population was recruited at the Sun Yatsen University Cancer Centre (Guangzhou, P. R. China), which led the trial. Patients with grade 2 and 3 pneumonitis were randomized either to receive pirfenidone or not. The study medication was administered orally at a dose of 400 mg three times daily up to week 24 after randomization. All patients received glucocorticoids for 8–10 weeks at a weight adjusted dose. Follow-up visits occurred at week 4, 8, 16 and 24. The primary endpoint was the change in the diffusing capacity of the lung for carbon monoxide (DLCO) 24 weeks from baseline. Most of the patients had lung cancer [57% non-small cell lung cancer (NSCLC), 15% small-cell lung cancer (SCLC)], 20% esophageal cancer and 7% had other cancer types, which were not specified. Unfortunately, the Union for International Cancer Control (UICC) stages were not given. Similarly, the type of radiation, treatment technique and fractionation schedules were not specified. The only information in this regard is that the main proportion of patients (87%) received 44–66 gray (Gy) presumably in conventional fraction. The vast majority of patients had grade 2 pneumonitis (89%) and grade 1 pulmonary fibrosis (84%). The primary endpoint of this analysis was DLCO changes at 24 weeks after randomization compared to baseline. DLCO represents endothelial injury and is therefore a better measure for gas exchange than forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC), which primarily quantifies the flow of air in the bronchial system. Of the 123 patients who could be analyzed for primary outcome, 23/60 (38%) in the pirfenidone arm and 15/63 (24%) in the control arm were lost to follow-up. The general patient features at baseline seem to be balanced, although comparative statistics are missing. No significant differences between groups were observed in regards to radiation dosimetry parameters and the administration of glucocorticoids. The primary outcome measure was the delta change in DLCO between baseline and 24 weeks after randomization. Patients in the pirfenidone group experienced an average improvement of 8% compared to a 2.4% decrease in the control group. Of note, the overall rate of missing data at 24 weeks was 30%. The safety analysis revealed 45% pirfenidone related adverse events, none of which was severe (grade 1–2: 39%, grade 3: 6%). While the five deaths in the pirfenidone group were related either to tumor progression or coronavirus disease (COVID), three RILD associated deaths occurred in the control group. From these results the authors conclude that pirfenidone has the potential to preserve lung function and reduce radiation induced fibrotic alterations without relevant toxicity.

In spite of these encouraging results, which are a valuable contribution to research in toxicity management, some aspects regarding the definition of lung injury, composition of the patient population and the primary endpoint of DLCO at 24 weeks after randomization should be critically discussed.

First of all, it is unclear how the authors differentiate between lung injury caused by radiation or medicinal agents such as immunotherapy. Additionally, from the description of the study cohort it remains unclear whether patients with inflammatory and rheumatoid co-morbidities that may also cause fibrotic alterations of the lung tissue were excluded. The study does not mention in detail which antitumor therapies apart from radiation were administered (see patient Tab. 1). Judging from the recruitment period (2021/11 and 2023/12) it is highly likely that immunotherapy was part of the treatment concept both for lung and esophageal cancer patients. The authors only state that chemotherapy, targeted drugs and ICI were allowed during the study period at the discretion of the treating physician. Therapeutic concepts combining ICI with thoracic irradiation can cause pneumonitis and fibrosis in a two-fold way, i.e., either by immunotherapy or by radiation. Computed tomography (CT) image based diagnosis of pneumonitis/fibrosis is less clearcut after radiotherapy with modern technologies such as dynamic or step-and-shoot intensity modulated radiotherapy (IMRT) with its multiple beam angles and a large variety of dose levels compared to three-dimensional (3D)-radiation that consists of a limited number of beams. Moreover, in clinical practice, separating radiation pneumonitis from ICI-related pneumonitis is very difficult. Radiation field-limited changes and timing after radiotherapy argue for radiation, whereas multifocal pneumonia-like patterns can suggest ICI. In fact, an overlap of the two phenomena is frequently found. Hence, it seems that the endpoint of this investigation does not describe RILD alone but a kind of lung injury that emerges from a combined effect of radiotherapy and ICIs. Moreover, about 90% of the patients in both arms had pneumonitis grade 2, while at the same time 87% vs. 81% had pulmonary fibrosis grade 1 (Tab. 1). These numbers elucidate the difference between symptom orientated side effect grading by means of the Common Terminology Criteria of Adverse Events (CTCAE) compared to radiographic changes in follow-up CT scans. Hence, the effect of pirfenidone in this context is limited to a potentially prophylactic antifibrotic medication rather than a treatment for severe advanced stage fibrosis.

Secondly, the current analysis consists of relatively young patients (median age 62 years in the pirfenidone group vs. 61 years in controls) with NSCLC and SCLC as well as esophageal cancer. Lung cancer patients, which make up the majority of the study cohort (70% in the pirfenidone group vs. 74% of the controls), have per se a higher risk of pneumonitis/fibrosis than patients with esophageal cancer. In the former, the organ afflicted by the tumor is the lung itself, which means that its physiological function is compromised. Also the maximum radiation dose is delivered to the afflicted organ. Both aspects mark a difference to patients with esophageal cancer. Hence, it appears questionable to analyze patients with these disease entities together. Additionally, the different stages are also not mentioned. Indirectly one can infer from the parameter, radiotherapy dose, Gy/fractions, that early stage lung cancers were included as well as locally advanced (or even advanced?) stages: 50–70/4–10 fractions. Although radiation dosimetry parameters and glucocorticoid doses are balanced between groups, more information in this respect would have rounded off the picture since the treatment concepts for early stage lung cancer differ substantially from more advanced stages, which are—because of their larger tumor volume and the necessity to administer ICIs—more prone to pneumonitis and subsequent fibrosis than early stages.

Thirdly, studies like this are inherently characterized by a certain degree of subjectivity since the diagnosis and grading of side effects always depends on the treating physician. When classifying the degree of pneumonitis/fibrosis methodological uncertainties remain since there are no clear cutoffs—neither in imaging nor in pulmonary function tests (PFTs)—that would inform clinical decision making. A central review of the CT images was undertaken and discrepancies were consensually discussed. The final decision was taken by a radiation-oncologist based on follow-up imaging, which revealed that most of the patients had grade 1 pulmonary fibrosis (87% in the pirfenidone group vs. 81% of the controls). This is not an uncommon finding in patients who underwent thoracic irradiation. The decisive question in this context is whether these changes are of pathological value so that they would impact the patients’ activity in daily life. In this regard, PFTs may help out. DLCO change within 1 year is a validated measure for disease progression in IPF patients (10) so that it is plausible to use it as a measure for RILD. However, as noted by the authors under limitations, the number of patients who could not be assessed for the primary endpoint, i.e., DLCO at 24 weeks after randomization, is quite high with 23/60 (38%) in the experimental arm and 15/63 (24%) among controls. In the pirfenidone group 19/60 (32%) of the patients could not even be assessed at 16 weeks. Most of these losses were attributable to tumor progression (11/60 and 8/63) and death (3/60 and 4/63). Although, compared to a previous study with 89% missing data (11), the numbers in the current analysis are lower but still not negligible so that the lack of data might question the validity of the analysis. As commented by Balestro (12), the novelty of the study consists of the prospectively randomized testing of a combined therapy approach for RILD which results in an improvement of PFTs. In this regard, however, it seems doubtful whether the quantity of the DLCO, FEV1 and FVC changes have a clinical meaning in the sense that patients note the difference in daily life. The standards for clinical significance of these three PFT parameters published by the European Respiratory Society (ERS) and the American Thoracic Society (ATS) are 10%, 12% and 12%, respectively (13), which means that changes below these cutoffs do not make themselves felt. In the current study, none of the PFT changes—although statistically significant—exceeds these ERS/ATS thresholds (see Tab. 2). From Fig. 2, it becomes evident that—with respect to the primary outcome measure, i.e., DLCO at 24 weeks—5 patients had a decrease in DLCO of more than 10% (all of which were members of the control group) and 11 (eight in the experimental group and 3 in the control group) patients had an improvement of more than 10%. Hence, based on the above mentioned ERS/ATS standards, the measurable clinical benefit of pirfenidone at 24 weeks after randomization that would be discernable by the patient seems to be limited to these 8/123 (6.5%) individuals (Fig. 2). Alternatively, one could imagine an earlier time point for the PFT measurements since pirfenidone—as shown above—exerts its effect in the early phase of RILD, starting with a down-regulation of PDGF within a few hours and a continued negative effect on fibroblast proliferation by blockage of TGF-β1 within 6 to 8 weeks after RT. Taking into account that a radiation course needs 4 to 6 weeks, it seems that short term DLCO measurements up to three months after the end of radiation treatment, which is usually the first follow-up visit, could reveal a more pronounced effect (14). With regard to the study design this would have the advantage that—being earlier in the timeline—more patients might reach the endpoint. In evaluating the clinical significance, time dependent changes assessed by the 6 minutes walking test might have been eludicating. This test has the potential to better represent clinically relevant changes in basic activity of daily life (BADL) than PFT changes below the threshold for minimal clinically important differences (MCIDs).

In summary, considering the high number of missing data in the pirfenidone arm (38%) at 24 weeks, the questionable clinical effect of pirfenidone with PFT improvements below the clinically relevant threshold together with the fact that only two thirds of the patients tolerated the intended dose level of 400 mg should cause the reader to take the results of this phase 2 study with a grain of salt. They can be considered—as the authors correctly state—preliminary with the necessity of validation in larger prospective studies. Last but not least, it has to be emphasized that in patients treated both with radiation and systemic treatment (chemotherapy, targeted drugs, ICI) overlapping pathogenic mechanisms cause lung injury.

Acknowledgments

None.

Footnote

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