Overlap time is an independent risk factor of radiation pneumonitis for patients treated with simultaneous EGFR-TKI and thoracic radiotherapy

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the standard treatment modality for stage IV NSCLC patients harboring EGFR-sensitive mutations [1, 2]. Among these patients, those who progress despite achieving stable disease during treatment are indicated for thoracic radiotherapy (TRT) to improve local control and prognosis. In 2018, Xu et al. found that the addition of consolidative local ablation treatment (LAT) for stage IV EGFR-mutant oligometastatic NSCLC treated with TKI can significantly improve overall survival (40.5 versus 31.5 months, P < 0.001) [3]. This was confirmed in subsequent studies [4‐7].

However, despite the survival benefit of the combination of radiotherapy and TKI, the occurrence of radiation pneumonitis (RP) cannot be ignored. In 2014, Zhuang et al. reported that 37.5% (9/24) of patients treated with the combination of erlotinib and TRT experience grade ≥ 2 RP [8]. In our previous study, 63.6% (7/11) of patients simultaneously treated with TRT and osimertinib, developed grade ≥ 2 RP [9]. However, despite this high frequency of RP, its exact rate and risk factors among NSCLC patients treated with the combination of EGFR-TKI and TRT have not been completely evaluated. Thus, this study aimed to explore the rate and risk factors of RP for EGFR-mutant NSCLC patients simultaneously treated with first-generation EGFR-TKI and TRT.

RP is an important complication of simultaneous treatment with first-generation EGFR-TKI and TRT for EGFR-mutant NSCLC. However, its exact rate and risk factors in this population are unclear. In this study, 44.78% (30/67) of the patients simultaneously treated with first-generation EGFR-TKI and TRT developed grade ≥ 2 RP. In univariant analysis, a dose per fraction of ≥ 3 Gy was found to be a protective factor of grade ≥ 2 PR which is conflict with our knowledge, after correlation analysis, we found the dose per fraction was negative correlation with overlap time and PTV, so we think the result is only a statistical correlation and can be explained by a shorter overlap time and smaller PTV. Through multivariate analysis we found the EGFR-TKIs gefitinib and erlotinib, ipsilateral lung V30 > 34%, and overlap time of > 20 days for EGFR-TKI and thoracic radiotherapy increased the risk of grade ≥ 2 RP.

Combination treatment with first-generation EGFR-TKI and TRT is being increasingly used owing to its profound prognostic benefit [3, 5, 7]. However, RP has also been frequently reported in this modality [3, 8, 9]. Further, previous phase I clinical trials to explore the safety of simultaneous EGFR-TKI and TRT for unresectable untreated stage III NSCLC harboring EGFR mutations were terminated earlier owe to lung toxicity [11, 12]. Consistent with the findings reported by Zhuang et al. [13], the rate of grade ≥ 2 RP for patients treated with the combination of EGFR-TKI and TRT was higher than that for patients receiving concurrent chemoradiotherapy. Similar findings were reported by Zheng et al. and Chang et al. who reported that 20% (2/10) and 12% (3/25) of their patients developed grade ≥ 3 RP when treated with this modality [6, 14].

The high rate of grade ≥ 2 RP may be explained by some therapeutic mechanisms. First, as the target of EGFR-TKI, EGFR is primarily expressed in alveolar epithelial cells and is important for their proliferation and regeneration. EGFR inhibition suppresses the proliferation of alveolar epithelial cells and prevents their self-repair in response to radiation damage [15]. Second, erlotinib combined with radiation induces the accumulation of tumor cells in the G₁ and G₂-M phase, resulting in a reduction of them in the S phase. Erlotinib was also found play important roles in apoptosis induction, accelerated cellular repopulation, DNA damage repair, and enhanced radiosensitivity of tumor cells. All these can also increase radiation injury in normal lung tissue [16]. In addition, Harada et al. reported that gefitinib can upregulate important genes, including S100A8, S100A6, and stefinA3. These genes are known to be involved in neutrophil sequestration, acute inflammation, and airway remodeling [17]. Miyake et al. also reported that gefitinib can increase inflammatory cell infiltration and pro-inflammatory cytokine expression and augment pneumonitis [18]. However, further studies are still needed to elucidate the exact mechanism for the high rate of RP in combination treatment with first-generation EGFR-TKI and TRT.

Zhuang et al. reported that the lung dosimetric parameters and PTV are the predictive factors of RP for patients simultaneously treated with EGFR-TKI and TRT [19]. Consistent findings were observed in our study. In this study, we found that type of EGFR-TKI, ipsilateral lung V30, and overlap time of first-generation EGFR-TKI and TRT are independent predictive factors for grade 2 or worse RP. Patients treated with icotinib have a lower rate of grade ≥ 2 RP than gefitinib and erlotinib, which is consistent with previous reports that icotinib has a lower rate of adverse events than gefitinib and has the narrowest and safest toxicity spectrum [20, 21]. The broad therapeutic window and high selectivity towards the target EGFR of icotinib may be a reason for the safer toxicity spectrum [22]. Additionally, icotinib is metabolized by several enzymes and has a shorter half-life than other EGFR-TKIs, thus decreasing the accumulation of icotinib [23‐25]. This result highlights that icotinib may be a safer choice for simultaneous treatment with TRT. The total lung V20 and MLD have been verified to be reliable biomarkers for predicting the risk of RP [26, 27]. In this study, we found that the ipsilateral lung V30 is the most powerful predictor of grade ≥ 2 RP in simultaneous treatment with first-generation EGFR-TKI and TRT. An ipsilateral lung V30 of > 34% was an independent risk factor. An overlap time of > 20 days for the first-generation EGFR-TKI and TRT was also an independent risk factor. This indicates that a shorter overlap time may be safer. Given that the type of EGFR-TKI and overlap time of EGFR-TKI and TRT were associated with the risk of grade ≥ 2 RP, the EGFR-TKI may be responsible for the high rate of grade ≥ 2 RP in this combination treatment.

Despite the related adverse effects, TRT should not be completely ruled out as it remains beneficial for patients who develop disease progression. Possible solutions to mitigate the adverse effects include performing low-dose radiotherapy, using icotinib, or suspending EGFR-TKI treatment during TRT for patients at high risk of RP.

In conclusion, the frequency of grade ≥ 2 RP is higher in simultaneous EGFR-TKI and TRT treatment than that in concurrent chemoradiotherapy. Icotinib, ipsilateral lung V30 ≤ 34%, and shorter overlap time of ≤ 20 days for EGFR-TKI and thoracic radiotherapy were protective factors against the risk of RP in these patients. Caution should be exercised in the use of simultaneous TRT and EGFR-TKI, and the treatment strategies can be optimized to reduce the rate of RP for patients treat with simultaneous EGFR-TKI and thoracic radiotherapy.